Lu Tian

All Publications

• Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association Pang, M., Gabelle, A., Saha-Chaudhuri, P., Huijbers, W., Gafson, A., Matthews, P. M., Tian, L., Rubino, I., Hughes, R., de Moor, C., Belachew, S., Shen, C. 2023

  Abstract

  INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy.METHODS: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE).RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P= 0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P=0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline.DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development.HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Abeta) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Abeta removal therapy have a pattern of more severe neurodegenerative process.

  View details for DOI 10.1002/alz.13431

  View details for PubMedID 37882364

• Low-dose naltrexone use for the management of post-acute sequelae of COVID-19. International immunopharmacology Bonilla, H., Tian, L., Marconi, V. C., Shafer, R., McComsey, G. A., Miglis, M., Yang, P., Bonilla, A., Eggert, L., Geng, L. N. 2023; 124 (Pt B): 110966

  Abstract

  The global prevalence of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) stands at approximately 43 % among individuals who have previously had acute COVID-19. In contrast, in the United States, the National Center for Health Statistics (NCHS) estimates that around 11 % of individuals who have been infected with SARS-CoV-2 go on to experience long COVID. The underlying causes of PASC remains under investigation, and there are no currently established FDA-approved therapies. One of the leading hypotheses for the cause of PASC is the persistent activation of innate immune cells with increase systemic inflammation. Naltrexone is a medication with anti-inflammatory and immunomodulatory properties that has been used in other conditions that overlap with PASC. We performed a retrospective review of a clinical cohort of 59 patients at a single academic center who received low-dose naltrexone (LDN) off-label as a potential therapeutic intervention for PASC. The use of LDN was associated with a fewer number of symptoms, improved clinical symptoms (fatigue, post-exertional malaise, unrefreshing sleep, and abnormal sleep pattern), and a better functional status. This observation warrants testing in rigorous, randomized, placebo-controlled clinical trials.

  View details for DOI 10.1016/j.intimp.2023.110966

  View details for PubMedID 37804660

• Can earlier biomarker measurements explain a treatment effect on diabetes incidence? A robust comparison of five surrogate markers. BMJ open diabetes research & care Parast, L., Tian, L., Cai, T., Palaniappan, L. P. 2023; 11 (5)

  Abstract

  We measured and compared five individual surrogate markers-change from baseline to 1 year after randomization in hemoglobin A1c (HbA1c), fasting glucose, 2-hour postchallenge glucose, triglyceride-glucose index (TyG) index, and homeostatic model assessment of insulin resistance (HOMA-IR)-in terms of their ability to explain a treatment effect on reducing the risk of type 2 diabetes mellitus at 2, 3, and 4 years after treatment initiation.Study participants were from the Diabetes Prevention Program study, randomly assigned to either a lifestyle intervention (n=1023) or placebo (n=1030). The surrogate markers were measured at baseline and 1 year, and diabetes incidence was examined at 2, 3, and 4 years postrandomization. Surrogacy was evaluated using a robust model-free estimate of the proportion of treatment effect explained (PTE) by the surrogate marker.Across all time points, change in fasting glucose and HOMA-IR explained higher proportions of the treatment effect than 2-hour glucose, TyG index, or HbA1c. For example, at 2 years, glucose explained the highest (80.1%) proportion of the treatment effect, followed by HOMA-IR (77.7%), 2-hour glucose (76.2%), and HbA1c (74.6%); the TyG index explained the smallest (70.3%) proportion.These data suggest that, of the five examined surrogate markers, glucose and HOMA-IR were the superior surrogate markers in terms of PTE, compared with 2-hour glucose, HbA1c, and TyG index.

  View details for DOI 10.1136/bmjdrc-2023-003585

  View details for PubMedID 37907279

• Characteristics of people with PAD identified with ankle brachial index testing in three US cities Cetlin, M., Xu, S., Zhao, L., Tian, L., McDermott, M. M. SAGE PUBLICATIONS LTD. 2023: 504-505

  View details for Web of Science ID 001083593400033

• Ischemic leg symptom severity and response to supervised exercise in peripheral artery disease (PAD): results from three randomized clinical trials Whipple, M. O., Zhao, L., Tian, L., Zhang, D., McDermott, M. M. SAGE PUBLICATIONS LTD. 2023: 501-502

  View details for Web of Science ID 001083593400028

• Time course of improved walking performance and patient reported outcome measures in response to supervised treadmill exercise in peripheral artery disease: a randomized clinical trial Byskosh, N. C., Tian, L., Zhao, L., Zhang, D., McDermott, M. M. SAGE PUBLICATIONS LTD. 2023: 499

  View details for Web of Science ID 001083593400023

• Using Restricted Mean Survival Time to Improve Interpretability of Time-to-Event Data Analysis. Clinical journal of the American Society of Nephrology : CJASN Charu, V., Tian, L., Kurella-Tamura, M., Montez-Rath, M. E. 2023

  View details for DOI 10.2215/CJN.0000000000000323

  View details for PubMedID 37707829

• The colocatome as a spatial -omic reveals shared microenvironment features between tumour-stroma assembloids and human lung cancer. bioRxiv : the preprint server for biology Bouchard, G., Zhang, W., Li, I., Ilerten, I., Bhattacharya, A., Li, Y., Trope, W., Shrager, J. B., Kuo, C., Tian, L., Giaccia, A. J., Plevritis, S. K. 2023

  Abstract

  Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour-stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the "colocatome" as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour-stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids' colocatome recapitulates the tumour-stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries.

  View details for DOI 10.1101/2023.09.11.557278

  View details for PubMedID 37745466

  View details for PubMedCentralID PMC10515823

• Altered expression of the L-arginine/nitric oxide pathway in ovarian cancer: metabolic biomarkers and biological implications. BMC cancer Chen, L., Tang, Q., Zhang, K., Huang, Q., Ding, Y., Jin, B., Liu, S., Hwa, K., Chou, C. J., Zhang, Y., Thyparambil, S., Liao, W., Han, Z., Mortensen, R., Schilling, J., Li, Z., Heaton, R., Tian, L., Cohen, H. J., Sylvester, K. G., Arent, R. C., Zhao, X., McElhinney, D. B., Wu, Y., Bai, W., Ling, X. B. 2023; 23 (1): 844

  Abstract

  Ovarian cancer (OC) is a highly lethal gynecological malignancy. Extensive research has shown that OC cells undergo significant metabolic alterations during tumorigenesis. In this study, we aim to leverage these metabolic changes as potential biomarkers for assessing ovarian cancer.A functional module-based approach was utilized to identify key gene expression pathways that distinguish different stages of ovarian cancer (OC) within a tissue biopsy cohort. This cohort consisted of control samples (n = 79), stage I/II samples (n = 280), and stage III/IV samples (n = 1016). To further explore these altered molecular pathways, minimal spanning tree (MST) analysis was applied, leading to the formulation of metabolic biomarker hypotheses for OC liquid biopsy. To validate, a multiple reaction monitoring (MRM) based quantitative LCMS/MS method was developed. This method allowed for the precise quantification of targeted metabolite biomarkers using an OC blood cohort comprising control samples (n = 464), benign samples (n = 3), and OC samples (n = 13).Eleven functional modules were identified as significant differentiators (false discovery rate, FDR < 0.05) between normal and early-stage, or early-stage and late-stage ovarian cancer (OC) tumor tissues. MST analysis revealed that the metabolic L-arginine/nitric oxide (L-ARG/NO) pathway was reprogrammed, and the modules related to "DNA replication" and "DNA repair and recombination" served as anchor modules connecting the other nine modules. Based on this analysis, symmetric dimethylarginine (SDMA) and arginine were proposed as potential liquid biopsy biomarkers for OC assessment. Our quantitative LCMS/MS analysis on our OC blood cohort provided direct evidence supporting the use of the SDMA-to-arginine ratio as a liquid biopsy panel to distinguish between normal and OC samples, with an area under the ROC curve (AUC) of 98.3%.Our comprehensive analysis of tissue genomics and blood quantitative LC/MSMS metabolic data shed light on the metabolic reprogramming underlying OC pathophysiology. These findings offer new insights into the potential diagnostic utility of the SDMA-to-arginine ratio for OC assessment. Further validation studies using adequately powered OC cohorts are warranted to fully establish the clinical effectiveness of this diagnostic test.

  View details for DOI 10.1186/s12885-023-11192-8

  View details for PubMedID 37684587

  View details for PubMedCentralID 8192829

• Home-Based Walking Exercise and Supervised Treadmill Exercise in Patients With Peripheral Artery Disease: An Individual Participant Data Meta-Analysis. JAMA network open Thangada, N. D., Zhang, D., Tian, L., Zhao, L., Rejeski, W. J., Ho, K. J., Ferrucci, L., Spring, B., Kibbe, M. R., Polonsky, T. S., Criqui, M. H., McDermott, M. M. 2023; 6 (9): e2334590

  Abstract

  Few people with lower extremity peripheral artery disease (PAD) participate in supervised treadmill exercise covered by the Center for Medicare and Medicaid Services. In people with PAD, the benefits of home-based walking exercise, relative to supervised exercise, remain unclear.To study whether home-based walking exercise improves 6-minute walk (6MW) more than supervised treadmill exercise in people with PAD (defined as Ankle Brachial Index ≤0.90).Data were combined from 5 randomized clinical trials of exercise therapy for PAD using individual participant data meta-analyses, published from 2009 to 2022.Of the 5 clinical trials, 3 clinical trials compared supervised treadmill exercise to nonexercise control (N = 370) and 2 clinical trials compared an effective home-based walking exercise intervention to nonexercise control (N = 349).Individual participant-level data from 5 randomized clinical trials led by 1 investigative team were combined. The 5 randomized clinical trials included 3 clinical trials of supervised treadmill exercise and 2 effective home-based walking exercise interventions.Change in 6MW distance, maximum treadmill walking distance, and Walking Impairment Questionnaire at 6-month follow-up. The supervised treadmill exercise intervention consisted of treadmill exercise in the presence of an exercise physiologist, conducted 3 days weekly for up to 50 minutes per session. Home-based walking exercise consisted of a behavioral intervention in which a coach helped participants walk for exercise in or around home for up to 5 days per week for 50 minutes per session.A total of 719 participants with PAD (mean [SD] age, 68.8 [9.5] years; 46.5% female) were included (349 in a home-based exercise clinical trial and 370 in a supervised exercise trial). Compared with nonexercise control, supervised treadmill exercise was associated with significantly improved 6MW by 32.9 m (95% CI, 20.6-45.6; P < .001) and home-based walking exercise was associated with significantly improved 6MW by 50.7 m (95% CI, 34.8-66.7; P < .001). Compared with supervised treadmill exercise, home-based walking exercise was associated with significantly greater improvement in 6MW distance (between-group difference: 23.8 m [95% CI, 3.6, 44.0; P = .02]) but significantly less improvement in maximum treadmill walking distance (between-group difference:-132.5 m [95% CI, -192.9 to -72.1; P < .001]).In this individual participant data meta-analyses, compared with supervised exercise, home-based walking exercise was associated with greater improvement in 6MW in people with PAD. These findings support home-based walking exercise as a first-line therapy for walking limitations in PAD.

  View details for DOI 10.1001/jamanetworkopen.2023.34590

  View details for PubMedID 37733346

• Hospitalizations during home-based walking exercise interventions in peripheral artery disease: Results from two randomized clinical trials. Vascular medicine (London, England) Thangada, N. D., Xu, S., Tian, L., Zhao, L., Criqui, M. H., Ferrucci, L., Rejeski, W. J., Leeuwenburgh, C., Manini, T., Spring, B., Treat-Jacobson, D., Forman, D. E., Bazzano, L., Guralnik, J., Sufit, R., Polonsky, T., Kibbe, M. R., McDermott, M. M. 2023: 1358863X231191909

  View details for DOI 10.1177/1358863X231191909

  View details for PubMedID 37622748

• Use the Receiver Operating Characteristic to Assess Model Accuracy-Reply. JAMA cardiology Wang, X., Claggett, B. L., Tian, L. 2023

  View details for DOI 10.1001/jamacardio.2023.2247

  View details for PubMedID 37556135

• Benchmarking clinical risk prediction algorithms with ensemble machine learning: An illustration of the superlearner algorithm for the non-invasive diagnosis of liver fibrosis in non-alcoholic fatty liver disease. medRxiv : the preprint server for health sciences Charu, V., Liang, J. W., Mannalithara, A., Kwong, A., Tian, L., Kim, W. R. 2023

  Abstract

  Background and Aims: Ensemble machine learning (ML) methods can combine many individual models into a single 'super' model using an optimal weighted combination. Here we demonstrate how an underutilized ensemble model, the superlearner, can be used as a benchmark for model performance in clinical risk prediction. We illustrate this by implementing a superlearner to predict liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).Methods: We trained a superlearner based on 23 demographic and clinical variables, with the goal of predicting stage 2 or higher liver fibrosis. The superlearner was trained on data from the Non-alcoholic steatohepatitis - clinical research network observational study (NASH-CRN, n=648), and validated using data from participants in a randomized trial for NASH ('FLINT' trial, n=270) and data from examinees with NAFLD who participated in the National Health and Nutrition Examination Survey (NHANES, n=1244). We compared the performance of the superlearner with existing models, including FIB-4, NFS, Forns, APRI, BARD and SAFE.Results: In the FLINT and NHANES validation sets, the superlearner (derived from 12 base models) discriminates patients with significant fibrosis from those without well, with AUCs of 0.79 (95% CI: 0.73-0.84) and 0.74 (95% CI: 0.68-0.79). Among the existing scores considered, the SAFE score performed similarly to the superlearner, and the superlearner and SAFE scores outperformed FIB-4, APRI, Forns, and BARD scores in the validation datasets. A superlearner model derived from 12 base models performed as well as one derived from 90 base models.Conclusions: The superlearner, thought of as the "best-in-class" ML prediction, performed better than most existing models commonly used in practice in detecting fibrotic NASH. The superlearner can be used to benchmark the performance of conventional clinical risk prediction models.

  View details for DOI 10.1101/2023.08.02.23293569

  View details for PubMedID 37577485

• Evaluating the Duration of Response With Mirvetuximab Soravtansine for Treating Platinum-Resistant Ovarian Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology McCaw, Z. R., Tian, L., Wei, L. J. 2023: JCO2300288

  View details for DOI 10.1200/JCO.23.00288

  View details for PubMedID 37535885

• Hybrid controlled clinical trials using concurrent registries in Amyotrophic Lateral Sclerosis: A feasibility study. Clinical pharmacology and therapeutics van Eijk, R. P., van den Berg, L. H., Roes, K. C., Tian, L., Lai, T. L., Nelson, L. M., Li, C., Scowcroft, A., Garcia-Segovia, J., Lu, Y. 2023

  Abstract

  Hybrid designs with both randomised arms and an external control cohort preserve key features of randomisation and utilise external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis (ALS). The proposed methodology was evaluated in a randomised, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomised clinical trial, to identify concurrently non-participating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the non-participating patients. Augmenting the randomised controls with matched external controls could have avoided unnecessary randomisation of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilising a concurrent registry with rigorous matching can minimise bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.

  View details for DOI 10.1002/cpt.2994

  View details for PubMedID 37422655

• Overall and patient-specific comparative effectiveness of dimethyl fumarate versus teriflunomide: A novel approach to precision medicine applied to the German NeuroTrans Data Multiple Sclerosis Registry. Multiple sclerosis journal - experimental, translational and clinical Jiang, X., Simoneau, G., Zuercher, M., Heer, Y., van Hoevell, P., Harrington, A., Castro-Borrero, W., de Moor, C., Pellegrini, F., Tian, L., Bergmann, A., Braune, S. 2023; 9 (3): 20552173231194353

  Abstract

  Background: Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses.Objective: This retrospective study assessed overall and patient-specific effects of dimethyl fumarate (DMF) versus teriflunomide (TERI) in patients with relapsing-remitting MS.Methods: A novel precision medicine (PM) scoring approach leverages advanced machine learning methods and adjusts for imbalances in baseline characteristics between patients receiving different treatments. Using the German NeuroTransData registry, we implemented and internally validated different scoring systems to distinguish patient-specific effects of DMF relative to TERI based on annualized relapse rates, time to first relapse, and time to confirmed disease progression.Results: Among 2791 patients, there was superior ATE of DMF versus TERI for the two relapse-related endpoints (p=0.037 and 0.018). Low to moderate signals of treatment effect heterogeneity were detected according to individualized scores. A MS patient subgroup was identified for whom DMF was more effective than TERI (p=0.013): older (45 versus 38 years), longer MS duration (110 versus 50 months), not newly diagnosed (74% versus 40%), and no prior glatiramer acetate usage (35% versus 5%).Conclusion: The implemented approach can disentangle prognostic differences from treatment effect heterogeneity and provide unbiased patient-specific profiling of comparative effectiveness based on real-world data.

  View details for DOI 10.1177/20552173231194353

  View details for PubMedID 37641619

• Heterogeneous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD. medRxiv : the preprint server for health sciences Charu, V., Liang, J. W., Chertow, G. M., Li, Z. J., Montez-Rath, M. E., Geldsetzer, P., de Boer, I. H., Tian, L., Tamura, M. K. 2023

  Abstract

  Objective: Clear criteria to individualize glycemic targets are lacking. In this post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD), we evaluate whether the kidney failure risk equation (KFRE) can identify patients who disproportionately benefit from intensive glycemic control on kidney microvascular outcomes.Research design and methods: We divided the ACCORD trial population in quartiles based on 5-year kidney failure risk using the KFRE. We estimated conditional treatment effects within each quartile and compared them to the average treatment effect in the trial. The treatment effects of interest were the 7-year restricted-mean-survival-time (RMST) differences between intensive and standard glycemic control arms on (1) time-to-first development of severely elevated albuminuria or kidney failure and (2) all-cause mortality.Results: We found evidence that the effect of intensive glycemic control on kidney microvascular outcomes and all-cause mortality varies with baseline risk of kidney failure. Patients with elevated baseline risk of kidney failure benefitted the most from intensive glycemic control on kidney microvascular outcomes (7-year RMST difference of 115 v. 48 days in the entire trial population) However, this same patient group also experienced shorter times to death (7-year RMST difference of -57 v. -24 days).Conclusions: We found evidence of heterogenous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD as a function of predicted baseline risk of kidney failure. Patients with higher kidney failure risk experienced the most pronounced benefits of treatment on kidney microvascular outcomes but also experienced the highest risk of all-cause mortality.

  View details for DOI 10.1101/2023.06.14.23291396

  View details for PubMedID 37398349

• Metrologically Traceable Quantification of 3 Apolipoprotein E Isoforms in Cerebrospinal Fluid. Clinical chemistry Huynh, H., Kuch, K., Orquillas, A., Forrest, K., Barahona-Carrillo, L., Keene, D., Henderson, V. W., Wagner, A. D., Poston, K. L., Montine, T. J., Lin, A., Tian, L., MacCoss, M. J., Emrick, M. A., Hoofnagle, A. N. 2023

  Abstract

  BACKGROUND: APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies. Carefully validated and standardized assays could improve the interpretation of research findings, allow their replication in other laboratories, and generalize their application.METHODS: To evaluate this hypothesis, we aimed to develop, validate, and standardize a new measurement procedure using LC-MS/MS. Purified recombinant apoE protein standards (E2, E3, E4) were thoroughly characterized and used to assign the concentration of a matrix-matched calibration material that contained each apoE isoform, which ensured the metrological traceability of results.RESULTS: The assay of each isoform in human CSF was precise (≤11%CV) and of moderate throughput (approximately 80 samples per day). It demonstrated good linearity and parallelism for lumbar CSF, ventricular CSF, and bovine CSF. The use of an SI-traceable matrix-matched calibrator enabled precise and accurate measurements. There was no association observed between total apoE concentration and the number of Ɛ4 alleles in a cohort of 322 participants. However, the concentration of each isoform was significantly different in heterozygotes, with E4 > E3 > E2. Isoform concentrations were associated with cognitive and motor symptoms but contributed negligibly to a predictive model of cognitive impairment that included established CSF biomarkers.CONCLUSIONS: Our method simultaneously measures each apoE isoform in human CSF with excellent precision and accuracy. A secondary matrix-matched material has been developed and is available to other laboratories to improve interlaboratory agreement.

  View details for DOI 10.1093/clinchem/hvad056

  View details for PubMedID 37279935

• Using a Clinically Interpretable End Point Composed of Multiple Outcomes to Evaluate Totality of Treatment Effect in Comparative Oncology Studies. JAMA network open Wang, X., McCaw, Z. R., Tian, L., Stinchcombe, T. E., Vokes, E., Ludmir, E. B., Wei, L. J. 2023; 6 (6): e2319055

  View details for DOI 10.1001/jamanetworkopen.2023.19055

  View details for PubMedID 37342044

• Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy. Metabolites Zhang, Y., Sylvester, K. G., Jin, B., Wong, R. J., Schilling, J., Chou, C. J., Han, Z., Luo, R. Y., Tian, L., Ladella, S., Mo, L., Maric, I., Blumenfeld, Y. J., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Whitin, J. C., Cohen, H. J., McElhinney, D. B., Ling, X. B. 2023; 13 (6)

  Abstract

  Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.

  View details for DOI 10.3390/metabo13060715

  View details for PubMedID 37367874

• A frequentist approach to dynamic borrowing. Biometrical journal. Biometrische Zeitschrift Li, R., Lin, R., Huang, J., Tian, L., Zhu, J. 2023: e2100406

  Abstract

  There has been growing interest in leveraging external control data to augment a randomized control group data in clinical trials and enable more informative decision making. In recent years, the quality and availability of real-world data have improved steadily as external controls. However, information borrowing by directly pooling such external controls with randomized controls may lead to biased estimates of the treatment effect. Dynamic borrowing methods under the Bayesian framework have been proposed to better control the false positive error. However, the numerical computation and, especially, parameter tuning, of those Bayesian dynamic borrowing methods remain a challenge in practice. In this paper, we present a frequentist interpretation of a Bayesian commensurate prior borrowing approach and describe intrinsic challenges associated with this method from the perspective of optimization. Motivated by this observation, we propose a new dynamic borrowing approach using adaptive lasso. The treatment effect estimate derived from this method follows a known asymptotic distribution, which can be used to construct confidence intervals and conduct hypothesis tests. The finite sample performance of the method is evaluated through extensive Monte Carlo simulations under different settings. We observed highly competitive performance of adaptive lasso compared to Bayesian approaches. Methods for selecting tuning parameters are also thoroughly discussed based on results from numerical studies and an illustration example.

  View details for DOI 10.1002/bimj.202100406

  View details for PubMedID 37189217

• Assessment of Median and Mean Survival Time in Cancer Clinical Trials. JAMA network open Das, A., Lin, T. A., Lin, C., Meirson, T., McCaw, Z. R., Tian, L., Ludmir, E. B. 2023; 6 (4): e236498

  Abstract

  This cohort study assesses the relative stability of median and mean survival time estimates reported in cancer clinical trials.

  View details for DOI 10.1001/jamanetworkopen.2023.6498

  View details for PubMedID 37010873

• Mitochondrial Complex Abundance, Mitophagy Proteins, and Physical Performance in People With and Without Peripheral Artery Disease. Journal of the American Heart Association Picca, A., Wohlgemuth, S. E., McDermott, M. M., Saini, S. K., Dayanidhi, S., Zhang, D., Xu, S., Kosmac, K., Tian, L., Ferrucci, L., Sufit, R. L., Marzetti, E., Leeuwenburgh, C. 2023: e027088

  Abstract

  Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6-minute walk distance and 4-m gait speed were measured. Sixty-seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI] <0.60), 29 with mild PAD (ABI 0.60-0.90), and 23 without PAD (ABI 1.00-1.40). Abundance of all electron transport chain complexes was significantly higher in participants with lower ABI (eg, complex I: 0.66, 0.45, 0.48 arbitrary units [AU], respectively, P trend=0.043). Lower ABI values were associated with a higher LC3A/B II-to-LC3A/B I (microtubule-associated protein 1A/1B-light chain 3) ratio (2.54, 2.31, 2.15 AU, respectively, P trend=0.017) and reduced abundance of the autophagy receptor p62 (0.71, 0.69, 0.80 AU, respectively, P trend=0.033). The abundance of each electron transport chain complex was positively and significantly associated with 6-minute walk distance and 4-m gait speed at usual and fast pace only among participants without PAD (eg, complex I: r=0.541, P=0.008; r=0.477, P=0.021; r=0.628, P=0.001, respectively). Conclusions These results suggest that accumulation of electron transport chain complexes in gastrocnemius muscle of people with PAD may be because of impaired mitophagy in the setting of ischemia. Findings are descriptive, and further study in larger sample sizes is needed.

  View details for DOI 10.1161/JAHA.122.027088

  View details for PubMedID 36892048

• Illusory Responses across the Lewy Body Disease Spectrum ANNALS OF NEUROLOGY Shahid, M., Rawls, A., Ramirez, V., Ryman, S., Santini, V. E., Yang, L., Sha, S. J., Hall, J. N., Montine, T. J., Lin, A., Tian, L., Henderson, V. W., Cholerton, B., Yutsis, M., Poston, K. L. 2023

  View details for DOI 10.1002/ana.26574

  View details for Web of Science ID 000925056000001

• Improving the Robustness of Variable Selection and Predictive Performance of Regularized Generalized Linear Models and Cox Proportional Hazard Models MATHEMATICS Hong, F., Tian, L., Devanarayan, V. 2023; 11 (3)

  View details for DOI 10.3390/math11030557

  View details for Web of Science ID 000935700100001

• Quantifying and Interpreting the Prediction Accuracy of Models for the Time of a Cardiovascular Event-Moving Beyond C Statistic: A Review. JAMA cardiology Wang, X., Claggett, B. L., Tian, L., Malachias, M. V., Pfeffer, M. A., Wei, L. J. 2023

  Abstract

  For personalized or stratified medicine, it is critical to establish a reliable and efficient prediction model for a clinical outcome of interest. The goal is to develop a parsimonious model with fewer predictors for broad future application without compromising predictability. A general approach is to construct various empirical models via individual patients' specific baseline characteristics/biomarkers and then evaluate their relative merits. When the outcome of interest is the timing of a cardiovascular event, a commonly used metric to assess the adequacy of the fitted models is based on C statistics. These measures quantify a model's ability to separate those who develop events earlier from those who develop them later or not at all (discrimination), but they do not measure how closely model estimates match observed outcomes (prediction accuracy). Metrics that provide clinically interpretable measures to quantify prediction accuracy are needed.C statistics measure the concordance between the risk scores derived from the model and the observed event time observations. However, C statistics do not quantify the model prediction accuracy. The integrated Brier Score, which calculates the mean squared distance between the empirical cumulative event-free curve and its individual patient's counterparts, estimates the prediction accuracy, but it is not clinically intuitive. A simple alternative measure is the average distance between the observed and predicted event times over the entire study population. This metric directly quantifies the model prediction accuracy and has often been used to evaluate the goodness of fit of the assumed models in settings other than survival data. This time-scale measure is easier to interpret than the C statistics or the Brier score.This article enhances our understanding of the model selection/evaluation process with respect to prediction accuracy. A simple, intuitive measure for quantifying such accuracy beyond C statistics can improve the reliability and efficiency of the selected model for personalized and stratified medicine.

  View details for DOI 10.1001/jamacardio.2022.5279

  View details for PubMedID 36723915

• On assessing survival benefit of immunotherapy using long-term restricted mean survival time. Statistics in medicine Horiguchi, M., Tian, L., Uno, H. 2023

  Abstract

  The pattern of the difference between two survival curves we often observe in randomized clinical trials for evaluating immunotherapy is not proportional hazards; the treatment effect typically appears several months after the initiation of the treatment (ie, delayed difference pattern). The commonly used logrank test and hazard ratio estimation approach will be suboptimal concerning testing and estimation for those trials. The long-term restricted mean survival time (LT-RMST) approach is a promising alternative for detecting the treatment effect that potentially appears later in the study. A challenge in employing the LT-RMST approach is that it must specify a lower end of the time window in addition to a truncation time point that the RMST requires. There are several investigations and suggestions regarding the choice of the truncation time point for the RMST. However, little has been investigated to address the choice of the lower end of the time window. In this paper, we propose a flexible LT-RMST-based test/estimation approach that does not require users to specify a lower end of the time window. Numerical studies demonstrated that the potential power loss by adopting this flexibility was minimal, compared to the standard LT-RMST approach using a prespecified lower end of the time window. The proposed method is flexible and can offer higher power than the RMST-based approach when the delayed treatment effect is expected. Also, it provides a robust estimate of the magnitude of the treatment effect and its confidence interval that corresponds to the test result.

  View details for DOI 10.1002/sim.9662

  View details for PubMedID 36653933

• A Seasonality-Adjusted Sequential Test for Vaccine Safety Surveillance. Biometrics Shen, R., Moll, K., Lu, Y., Tian, L. 2023

  Abstract

  Post-market active safety monitoring is important for the timely capture of safety signals associated with exposure to a new vaccine or drug. The group sequential analysis is a common method employed in safety surveillance. Specifically, it compares the post-vaccination incidence of adverse event (AE) in a vaccinated population with a pre-specified reference level by sequentially conducting hypothesis testing during the surveillance. When the number of AEs is "too high", a safety signal is identified. If the null hypothesis is never rejected, the vaccine is considered safe. Such an approach doesn't account for either the variation in determining the reference risk from a control population or the seasonality effect. Furthermore, not rejecting the null could be due to a lack of power and cannot always be interpreted as proof of safety. In this paper, we proposed a new group sequential test procedure fully accounting for both seasonality and variation from the historical controls. More importantly, we proposed to construct a confidence interval for the relative AE risk between the exposed and control groups at the end of the study, which can be used to quantify the safety of the vaccine. The proposed method is illustrated via real data examples on anaphylaxis and examined by extensive simulationstudies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/biom.13829

  View details for PubMedID 36645553

• Exact inference for disease prevalence based on a test with unknown specificity and sensitivity. Journal of applied statistics Cai, B., Ioannidis, J. P., Bendavid, E., Tian, L. 2023; 50 (11-12): 2599-2623

  Abstract

  To make informative public policy decisions in battling the ongoing COVID-19 pandemic, it is important to know the disease prevalence in a population. There are two intertwined difficulties in estimating this prevalence based on testing results from a group of subjects. First, the test is prone to measurement error with unknown sensitivity and specificity. Second, the prevalence tends to be low at the initial stage of the pandemic and we may not be able to determine if a positive test result is a false positive due to the imperfect test specificity. The statistical inference based on a large sample approximation or conventional bootstrap may not be valid in such cases. In this paper, we have proposed a set of confidence intervals, whose validity doesn't depend on the sample size in the unweighted setting. For the weighted setting, the proposed inference is equivalent to hybrid bootstrap methods, whose performance is also more robust than those based on asymptotic approximations. The methods are used to reanalyze data from a study investigating the antibody prevalence in Santa Clara County, California in addition to several other seroprevalence studies. Simulation studies have been conducted to examine the finite-sample performance of the proposed method.

  View details for DOI 10.1080/02664763.2021.2019687

  View details for PubMedID 37529562

  View details for PubMedCentralID PMC10388830

• Medical therapies, comorbid conditions, and functional performance in people with peripheral artery disease enrolled in clinical trials between 2004 and 2021. Vascular medicine (London, England) Nayak, P., Polonsky, T., Tian, L., Greenland, P., Xu, S., Zhang, D., Zhao, L., Criqui, M. H., Kibbe, M. R., Gladders, B., Goodney, P., Ho, K., Guralnik, J. M., McDermott, M. M. 2023: 1358863X221145533

  View details for DOI 10.1177/1358863X221145533

  View details for PubMedID 36588397

• Cigarette smoking and mitochondrial dysfunction in peripheral artery disease. Vascular medicine (London, England) Guo, M., McDermott, M. M., Dayanidhi, S., Leeuwenburgh, C., Wohlgemuth, S., Ferrucci, L., Peterson, C. A., Kosmac, K., Tian, L., Zhao, L., Sufit, R., Ho, K., Criqui, M., Xu, S., Zhang, D., Greenland, P. 2022: 1358863X221143152

  Abstract

  BACKGROUND: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD).METHODS: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha) (mitochondrial biogenesis), and electron transport chain complexes I-V were measured with Western blot.RESULTS: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO2/s/mg, respectively [p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1alpha (p < 0.01), VDAC (p = 0.022), complex I (p = 0.021), and complex III (p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking (n = 5) and those not currently smoking (n = 63).CONCLUSIONS: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed.

  View details for DOI 10.1177/1358863X221143152

  View details for PubMedID 36567551

• Attendance at Supervised Exercise Sessions and Walking Outcomes in Peripheral Artery Disease: Results From 2 Randomized Clinical Trials. Journal of the American Heart Association Hammond, M. M., Tian, L., Zhao, L., Zhang, D., McDermott, M. M. 2022: e026136

  Abstract

  Background Supervised exercise therapy (SET) is the first-line therapy for walking impairment in peripheral artery disease (PAD). This study evaluated the association between attendance at SET and improved walking performance, compared with a control group, in PAD. Methods and Results Data from 2 randomized clinical trials of SET for PAD were combined. In each trial, participants were randomized to 3 times weekly supervised treadmill exercise or an attention control group for 6months (maximum, 77 exercise sessions). Participants randomized to SET were categorized into tertiles, according to the proportion of exercise sessions they attended. Results adjusted for age, sex, race, baseline walking performance, comorbidities, and other potential confounders. A total of 272 participants with PAD (mean age, 67.9±9.3years; 44% women; 61% Black race) were included. For participants randomized to SET, tertiles of attendance rates at exercise sessions were as follows: 11% to 68% (N=45), 69% to <85% (N=46), and ≥85% (N=46). Compared with control, mean improvement in 6-minute walk was significantly greater in each SET tertile: mean (95% CI) for tertile 1, 27.9m (1.3-54.4 m; P=0.04), tertile 2, 38.2m (12.2-64.2 m; P=0.001), and tertile 3, 56.9m (29.9-83.8 m; P<0.0001). Among participants randomized to SET, greater SET attendance was associated with greater improvement in 6-minute walk distance (overall P for trend=0.025). Compared with control, improvement in maximal treadmill walking time was greater in each SET attendance tertile: tertile 1 (3.3minutes [95% CI, 1.7-4.8minutes]; P<0.0001), tertile 2 (3.8minutes [95% CI, 2.3-5.3minutes]; P<0.0001), and tertile 3 (5.4minutes [95% CI, 3.9-7.0minutes]; P:<0.0001). Among participants randomized to SET, greater attendance at SET was not significantly associated with greater improvement in maximal treadmill walking time (overall P for trend=0.064). Conclusions Among people with PAD randomized to SET, better attendance at exercise sessions was associated with significantly greater 6-minute walk improvement. Among all participants with PAD, even relatively low SET attendance was associated with significantly greater improvement in walking performance, compared with a control group who did not exercise. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01408901. URL: https://clinicaltrials.gov/ct2/show/NCT00106327.

  View details for DOI 10.1161/JAHA.122.026136

  View details for PubMedID 36533626

• Causal inference for longitudinal data based on historical controls. Journal of biopharmaceutical statistics Liu, J., Zhang, J., Mitchell, A., Fang, M., Tian, L. 2022: 1-18

  Abstract

  Use of historical data has become a hot topic recently, considered to provide a way to reduce patient burden, lower drug development cost, and make innovative therapies available to patients earlier. In a single-arm study designed to examine the benefit of an experimental treatment, there is often a desire to compare the outcomes of patients receiving the new intervention with those receiving a control treatment, which can be extracted from sources such as historical trials or electronic medical records. Since the treatment is not randomly assigned, there is a need to adjust for the potential imbalance in key patient characteristics between the current study and historical controls. If the outcome of interest is measured longitudinally and subject to random missing, the required adjustment becomes more complicated. In this paper, we propose a doubly robust adjustment procedure specifically designed for longitudinal data analysis with missing data. The proposed method yields valid analysis results, if either the propensity score model or the mixed effects model for repeated measures (MMRM) regression model is correctly specified. An extensive numerical study is conducted to examine the performance of the proposed method. Data from a real clinical trial comparing with historical data are analyzed as an example applying the proposed procedure.

  View details for DOI 10.1080/10543406.2022.2148164

  View details for PubMedID 36469552

• The burden of cardiovascular disease attributable to high systolic blood pressure across China, 2005-18: a population-based study. The Lancet. Public health Cao, X., Zhao, Z., Kang, Y., Tian, Y., Song, Y., Wang, L., Zhang, L., Wang, X., Chen, Z., Zheng, C., Tian, L., Yin, P., Fang, Y., Zhang, M., He, Y., Zhang, Z., Weintraub, W. S., Zhou, M., Wang, Z. 2022; 7 (12): e1027-e1040

  Abstract

  Temporal trends and geographical variations in cardiovascular disease attributable to high systolic blood pressure in China are not yet fully understood. The aim of this study was to quantify the cardiovascular disease burden attributable to high systolic blood pressure at national and provincial levels in China.In this population-based study, we evaluated systolic blood pressure and estimated the number of deaths, age-standardised mortality rates, and years of life lost (YLLs) due to cardiovascular disease and its subcategories (including ischaemic heart disease, ischaemic stroke, haemorrhagic stroke, and other cardiovascular diseases) attributable to high systolic blood pressure, at the national level and by 31 provincial levels, in China, from 2005 to 2018. We pooled blood pressure data of 1·30 million adults aged 25 years and older from the China Chronic Disease and Risk Factor Surveillance project, the China National Nutrition Survey, and the China Hypertension Survey. We applied a temporal-spatial Bayesian hierarchical model to estimate age-specific, sex-specific, province-specific, and year-specific average systolic blood pressure, and a comparative risk assessment method to compute the cardiovascular disease burden attributable to high systolic blood pressure by age, sex, year, and province.Nationally, age-standardised mean systolic blood pressure was 132·5 mm Hg (95% uncertainty interval [UI] 124·6-140·3) in men and 129·4 mm Hg (121·7 to 137·2) in women. 2·67 million (95% UI 2·61 to 2·72) cardiovascular disease deaths in China were attributable to high systolic blood pressure, including 1·12 million deaths (1·07 to 1·16) due to ischaemic heart disease, 0·63 million deaths (0·60 to 0·65) due to ischaemic stroke, 0·58 million deaths (0·57 to 0·60) due to haemorrhagic stroke, and 0·34 million deaths (0·32 to 0·36) due to other cardiovascular disease. The age-standardised cardiovascular disease mortality rates associated with high systolic blood pressure were 268·99 per 100 000 people (95% UI 264·11 to 273·51) in 2005 and 220·84 per 100 000 people (216·30 to 224·76) in 2018, a percentage change of -17·90%; the rate changed by an average of -1·50% (95% UI -1·55% to -1·45%) per year from 2005 to 2018 nationally. YLL rates for total cardiovascular disease caused by high systolic blood pressure varied substantially across provinces, ranging from 3078·33 (95% UI 2807·40 to 3303·57) per 100 000 people in Beijing to 7189·98 (95% UI 6817·18 to 7507·99) per 100 000 people in Heilongjiang in 2018. Age-standardised YLL rates for ischaemic heart disease and ischaemic stroke attributable to high systolic blood pressure were particularly high in northeastern provinces, including Heilongjiang, Liaoning, and Jilin.The deaths and YLLs for cardiovascular disease attributable to high systolic blood pressure in China increased between 2005 and 2018, and age-standardised cardiovascular disease mortality rates decreased in the same timeframe. Our findings could help policy makers in promoting blood pressure control measures and implementing effective and locally adapted preventive interventions to reduce the prevalence of high systolic blood pressure and reduce the burden of systolic blood pressure-related cardiovascular disease in China.China National Key Research and Development Program, China National Science & Technology Pillar Program, and National Health Commission of the People's Republic of China.For the Chinese translation of the abstract see Supplementary Materials section.

  View details for DOI 10.1016/S2468-2667(22)00232-8

  View details for PubMedID 36462514

• The burden of cardiovascular disease attributable to high systolic blood pressure across China, 2005-18: a population-based study LANCET PUBLIC HEALTH Cao, X., Zhao, Z., Kang, Y., Tian, Y., Song, Y., Wang, L., Zhang, L., Wang, X., Chen, Z., Zheng, C., Tian, L., Yin, P., Fang, Y., Zhang, M., He, Y., Zhang, Z., Weintraub, W. S., Zhou, M., Wang, Z., China Burden Dis Attributable Risk 2022; 7 (12): E1027-E1040

  View details for Web of Science ID 000965673900012

• Characteristics of non-response to exercise therapy in people with peripheral artery disease: results from five randomized clinical trials Nayak, P., Zhang, D., Tian, L., Zhao, L., McDermott, M. M. SAGE PUBLICATIONS LTD. 2022: 628-629

  View details for Web of Science ID 000923957000057

• Using a surrogate with heterogeneous utility to test for a treatment effect. Statistics in medicine Parast, L., Cai, T., Tian, L. 2022

  Abstract

  The primary benefit of identifying a valid surrogate marker is the ability to use it in a future trial to test for a treatment effect with shorter follow-up time or less cost. However, previous work has demonstrated potential heterogeneity in the utility of a surrogate marker. When such heterogeneity exists, existing methods that use the surrogate to test for a treatment effect while ignoring this heterogeneity may lead to inaccurate conclusions about the treatment effect, particularly when the patient population in the new study has a different mix of characteristics than the study used to evaluate the utility of the surrogate marker. In this article, we develop a novel test for a treatment effect using surrogate marker information that accounts for heterogeneity in the utility of the surrogate. We compare our testing procedure to a test that uses primary outcome information (gold standard) and a test that uses surrogate marker information, but ignores heterogeneity. We demonstrate the validity of our approach and derive the asymptotic properties of our estimator and variance estimates. Simulation studies examine the finite sample properties of our testing procedure and demonstrate when our proposed approach can outperform the testing approach that ignores heterogeneity. We illustrate our methods using data from an AIDS clinical trial to test for a treatment effect using CD4 count as a surrogate marker for RNA.

  View details for DOI 10.1002/sim.9602

  View details for PubMedID 36372072

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• Dysregulated Genes, MicroRNAs, Biological Pathways, and Gastrocnemius Muscle Fiber Types Associated With Progression of Peripheral Artery Disease: A Preliminary Analysis. Journal of the American Heart Association Saini, S. K., Perez-Cremades, D., Cheng, H. S., Kosmac, K., Peterson, C. A., Li, L., Tian, L., Dong, G., Wu, K. K., Bouverat, B., Wohlgemuth, S. E., Ryan, T., Sufit, R. L., Ferrucci, L., McDermott, M. M., Leeuwenburgh, C., Feinberg, M. W. 2022: e023085

  Abstract

  Background Peripheral artery disease (PAD) is associated with gastrocnemius muscle abnormalities. However, the biological pathways associated with gastrocnemius muscle dysfunction and their associations with progression of PAD are largely unknown. This study characterized differential gene and microRNA (miRNA) expression in gastrocnemius biopsies from people without PAD compared with those with PAD. Participants with PAD included those with and without PAD progression. Methods and Results mRNA and miRNA sequencing were performed to identify differentially expressed genes, differentially expressed miRNAs, mRNA-miRNA interactions, and associated biological pathways for 3 sets of comparisons: (1) PAD progression (n=7) versus non-PAD (n=7); (2) PAD no progression (n=6) versus non-PAD; and (3) PAD progression versus PAD no progression. Immunohistochemistry was performed to determine gastrocnemius muscle fiber types and muscle fiber size. Differentially expressed genes and differentially expressed miRNAs were more abundant in the comparison of PAD progression versus non-PAD compared with PAD with versus without progression. Among the top significant cellular pathways in subjects with PAD progression were muscle contraction or development, transforming growth factor-beta, growth/differentiation factor, and activin signaling, inflammation, cellular senescence, and notch signaling. Subjects with PAD progression had increased frequency of smaller Type 2a gastrocnemius muscle fibers in exploratory analyses. Conclusions Humans with PAD progression exhibited greater differences in the number of gene and miRNA expression, biological pathways, and Type 2a muscle fiber size compared with those without PAD. Fewer differences were observed between people with PAD without progression and control patients without PAD. Further study is needed to confirm whether the identified transcripts may serve as potential biomarkers for diagnosis and progression of PAD.

  View details for DOI 10.1161/JAHA.121.023085

  View details for PubMedID 36300658

• The effect of hyperoxia on ventilation during recovery from general anesthesia: A randomized pilot study for a parallel randomized controlled trial. Journal of clinical anesthesia Doufas, A. G., Tian, L., Kutscher, S., Finnsson, E., Ágústsson, J. S., Chung, B. I., Panousis, P. 2022; 83: 110982

  Abstract

  While supplemental O2 inhalation corrects hypoxemia, its effect on post-anesthesia ventilation remains unknown. This pilot trial tested the hypothesis that hyperoxia increases the time spent with a transcutaneous PCO2 (TcPCO2) > 45 mmHg, compared with standard O2 supplementation.Single-blinded, parallel two-arm randomized pilot trial.University hospital.20 patients undergoing robotic-assisted laparoscopic nephrectomy.After institutional approval and informed consent, patients were randomized to receive O2 titrated to arterial saturation (SpO2): 90-94% (Conservative O2, N =10), or to SpO2 > 96% (Liberal O2, N = 10) for up to 90 min after anesthesia. Continuous TcPCO2, respiratory inductance plethysmography (RIP), and SpO2, were recorded. We calculated the percentage of time at TcPCO2 > 45 mmHg for each patient and compared the two groups using analysis of covariance, adjusting for sex, age, and body mass index. We also estimated the sample size required to detect the between-group difference observed in this pilot trial. RIP signals were used to calculate apnea/hypopnea index (AHI), which was then compared between two groups.The mean percentage of time with a TcPCO2 > 45 mmHg was 80.6% for the Conservative O2 (N=9) and 61.2% for the Liberal O2 (N=10) group [between-group difference of 19.4% (95% CI: -18.7% to 57.6%), P = 0.140]. With an observed effect size of 0.73, we estimated that 30 participants per group are required, to demonstrate this difference with a power of 80% at a two-sided alpha of 5%. Means SpO2 were 94.5% and 99.9% for the Conservative O2 and the Liberal O2 groups, respectively. AHI was significantly higher in the Conservative O2, compared with the Liberal O2 group (median AHI: 16 vs. 3; P = 0.0014).Hyperoxia in the post-anesthesia period reduced the time spent at TcPCO2 > 45 mmHg and significantly decreased AHI, while mean SpO2 ranged inside the a priori defined limits.ClinicalTrials.gov identifier: NCT04723433.

  View details for DOI 10.1016/j.jclinane.2022.110982

  View details for PubMedID 36265267

• Effect of Telmisartan on Walking Performance in Patients With Lower Extremity Peripheral Artery Disease The TELEX Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION McDermott, M. M., Bazzano, L., Peterson, C. A., Sufit, R., Ferrucci, L., Domanchuk, K., Zhao, L., Polonsky, T. S., Zhang, D., Lloyd-Jones, D., Leeuwenburgh, C., Guralnik, J. M., Kibbe, M. R., Kosmac, K., Criqui, M. H., Tian, L. 2022; 328 (13): 1315-1325

  View details for DOI 10.1001/jama.202216797

  View details for Web of Science ID 000866412700012

• Effect of Telmisartan on Walking Performance in Patients With Lower Extremity Peripheral Artery Disease: The TELEX Randomized Clinical Trial. JAMA McDermott, M. M., Bazzano, L., Peterson, C. A., Sufit, R., Ferrucci, L., Domanchuk, K., Zhao, L., Polonsky, T. S., Zhang, D., Lloyd-Jones, D., Leeuwenburgh, C., Guralnik, J. M., Kibbe, M. R., Kosmac, K., Criqui, M. H., Tian, L. 2022; 328 (13): 1315-1325

  Abstract

  Importance: Patients with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan (an angiotensin receptor blocker) has properties that reverse these abnormalities.Objective: To determine whether telmisartan improves 6-minute walk distance, compared with placebo, in patients with lower extremity PAD at 6-month follow-up.Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 2 US sites and involving 114 participants. Enrollment occurred between December 28, 2015, and November 9, 2021. Final follow-up occurred on May 6, 2022.Interventions: The trial randomized patients using a 2*2 factorial design to compare the effects of telmisartan plus supervised exercise vs telmisartan alone and supervised exercise alone and to compare telmisartan alone vs placebo. Participants with PAD were randomized to 1 of 4 groups: telmisartan plus exercise (n=30), telmisartan plus attention control (n=29), placebo plus exercise (n=28), or placebo plus attention control (n=27) for 6 months. The originally planned sample size was 240 participants. Due to slower than anticipated enrollment, the primary comparison was changed to the 2 combined telmisartan groups vs the 2 combined placebo groups and the target sample size was changed to 112 participants.Main Outcomes and Measures: The primary outcome was the 6-month change in 6-minute walk distance (minimum clinically important difference, 8-20 m). The secondary outcomes were maximal treadmill walking distance; Walking Impairment Questionnaire scores for distance, speed, and stair climbing; and the 36-Item Short-Form Health Survey physical functioning score. The results were adjusted for study site, baseline 6-minute walk distance, randomization to exercise vs attention control, sex, and history of heart failure at baseline.Results: Of the 114 randomized patients (mean age, 67.3 [SD, 9.9] years; 46 were women [40.4%]; and 81 were Black individuals [71.1%]), 105 (92%) completed 6-month follow-up. At 6-month follow-up, telmisartan did not significantly improve 6-minute walk distance (from a mean of 341.6 m to 343.0 m; within-group change: 1.32 m) compared with placebo (from a mean of 352.3 m to 364.8 m; within-group change: 12.5 m) and the adjusted between-group difference was -16.8 m (95% CI, -35.9 m to 2.2 m; P=.08). Compared with placebo, telmisartan did not significantly improve any of the 5 secondary outcomes. The most common serious adverse event was hospitalization for PAD (ie, lower extremity revascularization, amputation, or gangrene). Three participants (5.1%) in the telmisartan group and 2 participants (3.6%) in the placebo group were hospitalized for PAD.Conclusions and Relevance: Among patients with PAD, telmisartan did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support telmisartan for improving walking performance in patients with PAD.Trial Registration: ClinicalTrials.gov Identifier: NCT02593110.

  View details for DOI 10.1001/jama.2022.16797

  View details for PubMedID 36194220

• BOUNDS ON THE CONDITIONAL AND AVERAGE TREATMENT EFFECT WITH UNOBSERVED CONFOUNDING FACTORS ANNALS OF STATISTICS Yadlowsky, S., Namkoong, H., Basu, S., Duchi, J., Tian, L. 2022; 50 (5): 2587-2615

  View details for DOI 10.1214/22-AOS2195

  View details for Web of Science ID 000964342400006

• Quantifying Treatment Effects in Trials with Multiple Event-Time Outcomes. NEJM evidence Claggett, B. L., McCaw, Z. R., Tian, L., McMurray, J. J., Jhund, P. S., Uno, H., Pfeffer, M. A., Solomon, S. D., Wei, L. 2022; 1 (10)

  Abstract

  BACKGROUND: Data on the occurrence times of multiple outcomes, reflecting the temporal profile of disease burden/progression, have been used to estimate treatment effects in various recent randomized trials. Most procedures for analyzing these data require specific model assumptions. When the assumptions are not met, the results may be misleading. Robust, model-free procedures for study design and analysis that enable clinically meaningful interpretations are warranted.METHODS: For each treatment group, we constructed and summarized the estimated mean cumulative count of events over time by the area under the curve (AUC), which can be interpreted as the mean total event-free time lost from multiple undesirable outcomes. A higher curve, and resulting larger AUC, implies a worse treatment. The treatment effect is quantified by the ratio and/or difference of AUCs. The timing and occurrence of recurrent heart failure hospitalizations (HFHs) and cardiovascular (CV) death from Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF), comparing sacubitril/valsartan with valsartan, are presented for illustration. We also discuss the design of future studies on the basis of the proposed method.RESULTS: With 48 months of follow-up, estimated AUCs, representing the total event-free time lost to HFHs and CV death, were 11.3 and 13.1 event-months for sacubitril/valsartan and valsartan, respectively. The ratio of these AUCs was 0.86 (95% confidence interval, 0.75 to 1.00; P=0.049), a 14% reduction of disease burden favoring combination therapy. A future study, similar to PARAGON-HF, designed using the new proposal would require fewer patients would than a conventional time-to-first-event analysis.CONCLUSIONS: The proposed method is robust and model-free and provides a clinically interpretable, time-scale summary of the treatment effect. (Funded by National Institutes of Health.).

  View details for DOI 10.1056/evidoa2200047

  View details for PubMedID 37645407

• Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, and Acupuncture in Chronic Low Back Pain: Protocol for Two Linked Randomized Controlled Trials. JMIR research protocols Mackey, S., Gilam, G., Darnall, B., Goldin, P., Kong, J., Law, C., Heirich, M., Karayannis, N., Kao, M., Tian, L., Manber, R., Gross, J. 2022; 11 (9): e37823

  Abstract

  BACKGROUND: Nonpharmacologic mind-body therapies have demonstrated efficacy in low back pain. However, the mechanisms underlying these therapies remain to be fully elucidated.OBJECTIVE: In response to these knowledge gaps, the Stanford Center for Low Back Pain-a collaborative, National Institutes of Health P01-funded, multidisciplinary research center-was established to investigate the common and distinct biobehavioral mechanisms of three mind-body therapies for chronic low back pain: cognitive behavioral therapy (CBT) that is used to treat pain, mindfulness-based stress reduction (MBSR), and electroacupuncture. Here, we describe the design and implementation of the center structure and the associated randomized controlled trials for characterizing the mechanisms of chronic low back pain treatments.METHODS: The multidisciplinary center is running two randomized controlled trials that share common resources for recruitment, enrollment, study execution, and data acquisition. We expect to recruit over 300 chronic low back pain participants across two projects and across different treatment arms within each project. The first project will examine pain-CBT compared with MBSR and a wait-list control group. The second project will examine real versus sham electroacupuncture. We will use behavioral, psychophysical, physical measure, and neuroimaging techniques to characterize the central pain modulatory and emotion regulatory systems in chronic low back pain at baseline and longitudinally. We will characterize how these interventions impact these systems, characterize the longitudinal treatment effects, and identify predictors of treatment efficacy.RESULTS: Participant recruitment began on March 17, 2015, and will end in March 2023. Recruitment was halted in March 2020 due to COVID-19 and resumed in December 2021.CONCLUSIONS: This center uses a comprehensive approach to study chronic low back pain. Findings are expected to significantly advance our understanding in (1) the baseline and longitudinal mechanisms of chronic low back pain, (2) the common and distinctive mechanisms of three mind-body therapies, and (3) predictors of treatment response, thereby informing future delivery of nonpharmacologic chronic low back pain treatments.TRIAL REGISTRATION: ClinicalTrials.gov NCT02503475; https://clinicaltrials.gov/ct2/show/NCT02503475.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37823.

  View details for DOI 10.2196/37823

  View details for PubMedID 36166279

• BARRIERS TO PARTICIPATION IN SUPERVISED EXERCISE THERAPY REPORTED BY PEOPLE WITH PERIPHERAL ARTERY DISEASE. Journal of vascular surgery Cetlin, M. D., Polonsky, T., Ho, K., Zhang, D., Tian, L., Zhao, L., Greenland, P., Treat-Jacobson, D., Kibbe, M. R., Criqui, M. H., Guralnik, J. M., McDermott, M. M. 2022

  Abstract

  OBJECTIVE: This study identified barriers to participation in supervised exercise therapy covered by the Centers for Medicare and Medicaid Services (CMS), reported by people with lower extremity peripheral artery disease (PAD).METHODS: People with PAD participating in research studies of walking impairment due to PAD in the Chicagoland area were asked to complete a questionnaire between 03/15/2019 and 7/12/2022 assessing their experience and attitudes about supervised exercise therapy. Participants were identified using mailed postcards to people age 50 and older in Chicagoland, from medical centers in Chicago, and using bus and train advertisements. The questionnaire was developed based on focus group feedback from people with PAD.RESULTS: Of 516 participants with PAD approached, 489 (94.8%) completed the questionnaire (mean age 71.0 years (standard deviation (SD) 8.7), mean ankle-brachial index (ABI): 0.71 (SD: 0.25), 204 (41.7%) women and 261 (53.4%) Black). Of the 489 participants, 416 (85.1%) reported that their physician had never prescribed or recommended supervised exercise therapy. Overall, 357 (73.2%) reported willingness to travel three times weekly to the medical center for supervised exercise participation. However, of these, 214 (59.9%) reported that they were unwilling or unable to pay the $11 per exercise session co-pay required for supervised exercise covered by CMS. Of 51 people with PAD who reported prior participation in supervised exercise, only five (9.8%) completed the 12 weeks of supervised exercise therapy covered by CMS and 29 (56.9%) completed six or fewer weeks. Of 131 (26.8%) unwilling to travel three times weekly to a center for supervised exercise, the most common reasons for unwillingness to participate were "too time-consuming" (55.0%), "too inconvenient" (45.8%), and "lack of interest in treadmill exercise" (28.2%).CONCLUSIONS: Approximately two to four years after CMS began covering supervised exercise for PAD, most people with PAD in this study from a large urban area had not participated in supervised exercise therapy. Of those who participated, most completed fewer than half of the sessions covered by CMS. The required CMS co-payment was a common barrier to supervised exercise participation by people with PAD.

  View details for DOI 10.1016/j.jvs.2022.09.014

  View details for PubMedID 36150636

• Efficient Evaluation of Prediction Rules in Semi-Supervised Settings under Stratified Sampling. Journal of the Royal Statistical Society. Series B, Statistical methodology Gronsbell, J., Liu, M., Tian, L., Cai, T. 2022; 84 (4): 1353-1391

  Abstract

  In many contemporary applications, large amounts of unlabeled data are readily available while labeled examples are limited. There has been substantial interest in semi-supervised learning (SSL) which aims to leverage unlabeled data to improve estimation or prediction. However, current SSL literature focuses primarily on settings where labeled data is selected uniformly at random from the population of interest. Stratified sampling, while posing additional analytical challenges, is highly applicable to many real world problems. Moreover, no SSL methods currently exist for estimating the prediction performance of a fitted model when the labeled data is not selected uniformly at random. In this paper, we propose a two-step SSL procedure for evaluating a prediction rule derived from a working binary regression model based on the Brier score and overall misclassification rate under stratified sampling. In step I, we impute the missing labels via weighted regression with nonlinear basis functions to account for stratified sampling and to improve efficiency. In step II, we augment the initial imputations to ensure the consistency of the resulting estimators regardless of the specification of the prediction model or the imputation model. The final estimator is then obtained with the augmented imputations. We provide asymptotic theory and numerical studies illustrating that our proposals outperform their supervised counterparts in terms of efficiency gain. Our methods are motivated by electronic health record (EHR) research and validated with a real data analysis of an EHR-based study of diabetic neuropathy.

  View details for DOI 10.1111/rssb.12502

  View details for PubMedID 36275859

  View details for PubMedCentralID PMC9586151

• Illusory responses across the Lewy body disease spectrum Shahid, M., Rawls, A., Ramirez, V., Ryman, S., Santini, V., Yang, L., Sha, S., Hall, J., Montine, T., Lin, A., Tian, L., Henderson, V., Cholerton, B., Yutsis, M., Poston, K. WILEY. 2022: S364-S365

  Abstract

  To study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions.We studied illusory responses on the Noise Pareidolia Task in 300 participants [38 cognitively-impaired LB, 65 cognitively-unimpaired LB, 51 Alzheimer's disease-spectrum (AD-s), 146 Controls]. Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions.Cognitively-impaired LB participants were 12.3, 4.9, and 4.6 times more likely than Control, cognitively-unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex and education, the probability of endorsing one or more illusory response was 61% in the cognitively-impaired LB group, compared to 26% in AD-s, 25% in cognitively-unimpaired LB, and 12% in Control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least one illusory response.We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. This article is protected by copyright. All rights reserved.

  View details for Web of Science ID 000859942301355

  View details for PubMedID 36511519

• Predictive signature development based on maximizing the area between receiver operating characteristic curves. Statistics in medicine Huang, X., Tian, L., Sun, Y., Chatterjee, S., Devanarayan, V. 2022

  Abstract

  Development of marker signatures to predict treatment benefits for a new therapeutic is an important scientific component in advancing the drug discovery and is an important first step toward the goal of precision medicine. In this article, we focus on developing an algorithm to search for optimal linear combination of markers that maximizes the area between two receiver operating characteristic curves of the new therapeutic and the control groups without assuming any parametric model. We further generalize the proposed algorithm for predictive signature development to maximize the difference of Harrel's C-index of the new therapeutic and the control groups when the outcome of interest is time-to-event. The performance of this proposed method is evaluated and compared to existing methods via simulations and real clinical trial data.

  View details for DOI 10.1002/sim.9565

  View details for PubMedID 36053782

• Thalamic nuclei atrophy at high and heterogenous rates during cognitively unimpaired human aging. NeuroImage Choi, E. Y., Tian, L., Su, J. H., Radovan, M. T., Tourdias, T., Tran, T. T., Trelle, A. N., Mormino, E., Wagner, A. D., Rutt, B. K. 2022: 119584

  Abstract

  The thalamus is a central integration structure in the brain, receiving and distributing information among the cerebral cortex, subcortical structures, and the peripheral nervous system. Prior studies clearly show that the thalamus atrophies in cognitively unimpaired aging. However, the thalamus is comprised of multiple nuclei involved in a wide range of functions, and the age-related atrophy of individual thalamic nuclei remains unknown. Using a recently developed automated method of identifying thalamic nuclei (3T or 7T MRI with white-matter-nulled MPRAGE contrast and THOMAS segmentation) and a cross-sectional design, we evaluated the age-related atrophy rate for 10 thalamic nuclei (AV, CM, VA, VLA, VLP, VPL, pulvinar, LGN, MGN, MD) and an epithalamic nucleus (habenula). We also used T1-weighted images with the FreeSurfer SAMSEG segmentation method to identify and measure age-related atrophy for 11 extra-thalamic structures (cerebral cortex, cerebral white matter, cerebellar cortex, cerebellar white matter, amygdala, hippocampus, caudate, putamen, nucleus accumbens, pallidum, and lateral ventricle). In 198 cognitively unimpaired participants with ages spanning 20-88 years, we found that the whole thalamus atrophied at a rate of 0.45% per year, and that thalamic nuclei had widely varying age-related atrophy rates, ranging from 0.06% to 1.18% per year. A functional grouping analysis revealed that the thalamic nuclei involved in cognitive (AV, MD; 0.53% atrophy per year), visual (LGN, pulvinar; 0.62% atrophy per year), and auditory/vestibular (MGN; 0.64% atrophy per year) functions atrophied at significantly higher rates than those involved in motor (VA, VLA, VLP, and CM; 0.37% atrophy per year) and somatosensory (VPL; 0.32% atrophy per year) functions. A proximity-to-CSF analysis showed that the group of thalamic nuclei situated immediately adjacent to CSF atrophied at a significantly greater atrophy rate (0.59% atrophy per year) than that of the group of nuclei located farther from CSF (0.36% atrophy per year), supporting a growing hypothesis that CSF-mediated factors contribute to neurodegeneration. We did not find any significant hemispheric differences in these rates of change for thalamic nuclei. Only the CM thalamic nucleus showed a sex-specific difference in atrophy rates, atrophying at a greater rate in male versus female participants. Roughly half of the thalamic nuclei showed greater atrophy than all extra-thalamic structures examined (0% to 0.54% per year). These results show the value of white-matter-nulled MPRAGE imaging and THOMAS segmentation for measuring distinct thalamic nuclei and for characterizing the high and heterogeneous atrophy rates of the thalamus and its nuclei across the adult lifespan. Collectively, these methods and results advance our understanding of the role of thalamic substructures in neurocognitive and disease-related changes that occur with aging.

  View details for DOI 10.1016/j.neuroimage.2022.119584

  View details for PubMedID 36007822

• Handling Informative Premature Treatment or Study Discontinuation for Assessing Between-Group Differences in a Comparative Oncology Trial. JAMA oncology Huang, B., Sun, R., Claggett, B., Tian, L., Ludmir, E. B., Wei, L. 2022

  View details for DOI 10.1001/jamaoncol.2022.2394

  View details for PubMedID 35980612

• Overall and patient-level comparative effectiveness of dimethyl fumarate and fingolimod: A precision medicine application to the Observatoire Français de la Sclérose en Plaques registry. Multiple sclerosis journal - experimental, translational and clinical Simoneau, G., Jiang, X., Rollot, F., Tian, L., Copetti, M., Guéry, M., Ruiz, M., Vukusic, S., de Moor, C., Pellegrini, F. 2022; 8 (3): 20552173221116591

  Abstract

  Comparing real-world effectiveness and tolerability of therapies for relapsing-remitting multiple sclerosis is increasingly important, though average treatment effects fail to capture possible treatment effect heterogeneity. With the clinical course of the disease being highly heterogeneous across patients, precision medicine methods enable treatment response heterogeneity investigations.To compare real-world effectiveness and discontinuation profiles between dimethyl fumarate and fingolimod while investigating treatment effect heterogeneity with precision medicine methods.Adults initiating dimethyl fumarate or fingolimod as a second-line therapy were selected from a French registry. The primary outcome was annualized relapse rate at 12 months. Seven secondary outcomes relative to discontinuation and disease progression were considered. A precision medicine framework was used to characterize treatment effect heterogeneity.Annualized relapse rates at 12 months were similar for dimethyl fumarate and fingolimod. The odd of treatment persistence was 47% lower for patients treated with dimethyl fumarate relative to those treated with fingolimod (odds ratio: 0.53, 95% confidence interval: 0.39, 0.70). None of the five precision medicine scoring approaches identified treatment heterogeneity.These findings substantiated the similar effectiveness and different discontinuation profiles for dimethyl fumarate and fingolimod as a second-line therapy for relapsing-remitting multiple sclerosis, with no significant effect heterogeneity observed.

  View details for DOI 10.1177/20552173221116591

  View details for PubMedID 35959484

  View details for PubMedCentralID PMC9358343

• Effects of Walking Exercise at a Pace With Versus Without Ischemic Leg Symptoms on Functional Performance Measures in People With Lower Extremity Peripheral Artery Disease: The LITE Randomized Clinical Trial. Journal of the American Heart Association Hammond, M. M., Spring, B., Rejeski, W. J., Sufit, R., Criqui, M. H., Tian, L., Zhao, L., Xu, S., Kibbe, M. R., Leeuwenburgh, C., Manini, T., Forman, D. E., Treat-Jacobson, D., Polonsky, T. S., Bazzano, L., Ferrucci, L., Guralnik, J., Lloyd-Jones, D. M., McDermott, M. M. 2022: e025063

  Abstract

  Background In people with peripheral artery disease, post hoc analyses of the LITE (Low Intensity Exercise Intervention in Peripheral Artery Disease) randomized trial were conducted to evaluate the effects of walking exercise at a pace inducing ischemic leg symptoms on walking velocity and the Short Physical Performance Battery, compared with walking exercise without ischemic leg symptoms and compared with a nonexercising control group. Methods and Results Participants with peripheral artery disease were randomized to: home-based walking exercise that induced ischemic leg symptoms; home-based walking exercise conducted without ischemic leg symptoms; or a nonexercising control group for 12months. Outcomes were change of walking velocity over 4m and change of the Short Physical Performance Battery (0-12, with 12=best) at 6- and 12-month follow-up. A total of 264 participants (48% women, 61% Black race) were included. Compared with walking exercise without ischemic symptoms, walking exercise that induced ischemic symptoms improved change in usual-paced walking velocity over 4m at 6-month (0.056 m/s [95% CI, 0.019-0.094 m/s]; P<0.01) and 12-month follow-up (0.084 m/s [95% CI, 0.049-0.120 m/s]; P<0.01), change in fast-paced of walking velocity over 4m at 6-month follow-up (P=0.03), and change in the Short Physical Performance Battery at 12-month follow-up (0.821 [95% CI, 0.309-1.334]; P<0.01). Compared with control, walking exercise at a pace inducing ischemic symptoms improved change in usual-paced walking velocity over 4m at 6-month follow-up (0.066 m/s [95% CI, 0.021-0.111 m/s]; P<0.01). Conclusions In people with peripheral artery disease, those who walked for exercise at a comfortable pace without ischemic leg symptoms slowed their walking speed during daily life and worsened the Short Physical Performance Battery score, a potentially harmful effect, compared with people who walked for exercise at a pace inducing ischemic leg symptoms. Compared with a control group who did not exercise, home-based walking exercise at a pace inducing ischemic leg symptoms significantly improved change of walking velocity over 4m at 6-month follow-up, but this benefit did not persist at 12-month follow-up. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02538900.

  View details for DOI 10.1161/JAHA.121.025063

  View details for PubMedID 35894088

• A Composite Endpoint for Treatment Benefit According to Patient Preference STATISTICS IN BIOPHARMACEUTICAL RESEARCH Lu, Y., Zhao, Q., Zou, J., Yan, S., Tamaresis, J. S., Nelson, L., Tu, X. M., Chen, J., Tian, L. 2022

  View details for DOI 10.1080/19466315.2022.2085783

  View details for Web of Science ID 000827504600001

• Association of Cognition and Dementia With Neuropathologic Changes of Alzheimer Disease and Other Conditions in the Oldest-Old. Neurology Montine, T. J., Corrada, M. M., Kawas, C., Bukhari, S., White, L., Tian, L., Cholerton, B. 2022

  Abstract

  BACKGROUND AND OBJECTIVES: Age is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals.METHODS: Participants were those enrolled in The 90+ Study, a longitudinal, population-based study of aging/dementia in the oldest-old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for prevalence of Alzheimer's disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNC/primary age-related tauopathy (PART). Resistance, or failure to develop ADNC/PART, and resilience, inferred from higher than expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features.RESULTS: The most common neuropathologic features in the sample (n=367) were ADNC/PART-related. Increased dementia odds were associated with elevated total neuropathologic burden (OR=1.5 [95% CI 1.3-1.7] p<0.0001), beta amyloid (OR=1.6 [95% CI 1.2-2.0] p<0.0001), neurofibrillary tangles (OR=2.6 [95% CI 1.7-4.1] p<0.0001), and LATE-NC (OR=2.3 [95% CI 1.7-3.1] p<0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR=6.1 [95% CI 2.0-18.7] p=0.002) and without (OR=5.0 [95% CI 2.6-9.7] p<0.0001) co-occurring HS, and increased the odds of dementia among participants with ADNC (OR=5.0 [95% CI 2.7-9.2] p<0.0001). Resistance to moderate/severe ADNC/PART was rare (3%), but resilience to ADNC/PART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderate/severe ADNC/PART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion: OR=2.4 [95% CI 1.3-4.5] p<0.005; 2 lesions: OR=5.9 [95% CI 2.8-12.3] p<0.0001).CONCLUSION: These results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest-old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals.

  View details for DOI 10.1212/WNL.0000000000200832

  View details for PubMedID 35705500

• Efficient evaluation of prediction rules in semi-supervised settings under stratified sampling JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY Gronsbell, J., Liu, M., Tian, L., Cai, T. 2022

  View details for DOI 10.1111/rssb.12502

  View details for Web of Science ID 000787247100001

• Robust approach to combining multiple markers to improve surrogacy. Biometrics Wang, X., Parast, L., Han, L., Tian, L., Cai, T. 2022

  Abstract

  Identifying effective and valid surrogate markers to make inference about a treatment effect on long-term outcomes is an important step in improving the efficiency of clinical trials. Replacing a long term outcome with short term and/or cheaper surrogate markers can potentially shorten study duration and reduce trial costs. There is a sizable statistical literature on methods to quantify the effectiveness of a single surrogate marker. Both parametric and nonparametric approaches have been well developed for different outcome types. However, when there are multiple markers available, methods for combining markers to construct a composite marker with improved surrogacy remain limited. In this paper, building on top of the optimal transformation framework of Wang etal. (2020), we propose a novel calibrated model fusion approach to optimally combine multiple markers to improve surrogacy. Specifically, we obtain two initial estimates of optimal composite scores of the markers based on two sets of models with one set approximating the underlying data distribution and the other directly approximating the optimal transformation function. We then estimate an optimal calibrated combination of the two estimated scores which ensures both validity of the final combined score and optimality with respect to the proportion of treatment effect explained (PTE) by the final combined score. This approach is unique in that it identifies an optimal combination of the multiple surrogates without strictly relying on parametric assumptions while borrowing modeling strategies to avoid fully non-parametric estimation which is subject to curse of dimensionality. Our identified optimal transformation can also be used to directly quantify the surrogacy of this identified combined score. Theoretical properties of the proposed estimators are derived and finite sample performance of the proposed method is evaluated through simulation studies. We further illustrate the proposed method using data from the Diabetes Prevention Program (DPP)study. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/biom.13677

  View details for PubMedID 35426444

• Nervous system drugs taken by future fathers and birth defects in offspring: a prospective registry-based cohort study. BMJ open Wensink, M., Lu, Y., Tian, L., Jensen, T. K., Skakkebak, N. E., Lindahl-Jacobsen, R., Eisenberg, M. 2022; 12 (3): e053946

  Abstract

  OBJECTIVES: To evaluate the association of paternal intake of antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, selective serotonin reuptake inhibitors (SSRIs) and (benzo)diazepines during the development of fertilising sperm with birth defects in offspring.DESIGN: Prospective registry-based cohort study.SETTING: Total Danish birth cohort 1997-2016 using Danish national registries.PARTICIPANTS: All 1201119 Danish liveborn singletons born 1997-2016 were eligible, 39803 (3.3%) of whom had at least one major birth defect.EXPOSURE: Offspring were considered exposed if their father had filled at least one prescription in the relevant drug category during development of fertilising sperm (the 3months prior to conception).PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the diagnosis, in the first year of life, of at least one major birth defect as categorised in the EUROCAT guidelines. Secondary outcome was the diagnosis, in the first year of life, of at least one major birth defect in any of the EUROCAT subcategories. Adjusted ORs (AORs) were calculated, along with their 95% CIs, adjusted for year, education, smoking status and age of the mother, and education, disposable income and age of the father.RESULTS: This study found weak or null associations between birth defects and selected drugs. Specifically, antidepressants (17827 exposed births) gave 3.5% birth defects (AOR 0.97 (0.89 to 1.05)). Diazepines, oxazepines, thiazepines and oxepines (as antipsychotics, 1633 offspring) gave 4.7% birth defects (AOR 1.22 (0.97 to 1.54)), attenuated to 1.13 when excluding by mothers' prescriptions. The study was well powered assuming 100% therapy adherence, while assuming 50% therapy adherence, the study remained well powered for the largest groups (SSRIs and antidepressants overall).CONCLUSIONS: Antipsychotics, anxiolytics, hypnotics and sedatives, antidepressants, SSRIs and benzodiazepine-derived anxiolytics, when taken by the father during development of fertilising sperm, are generally safe with regard to birth defects.

  View details for DOI 10.1136/bmjopen-2021-053946

  View details for PubMedID 35354621

• Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study. Annals of internal medicine Wensink, M. J., Lu, Y., Tian, L., Shaw, G. M., Rizzi, S., Jensen, T. K., Mathiesen, E. R., Skakkebæk, N. E., Lindahl-Jacobsen, R., Eisenberg, M. L. 2022

  Abstract

  Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.Nationwide prospective registry-based cohort study.Denmark from 1997 to 2016.All liveborn singletons from mothers without histories of diabetes or essential hypertension.Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).Information on underlying disease status was limited.Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.National Institutes of Health.

  View details for DOI 10.7326/M21-4389

  View details for PubMedID 35344380

• Utilizing restricted mean duration of response for efficacy evaluation of cancer treatments. Pharmaceutical statistics Huang, B., Tian, L. 2022

  Abstract

  In oncology clinical trials, response-based endpoints (time to response, objective response, duration of response [DOR]) are commonly used to detect therapeutic effect to support proof-of-concept or submission decisions. The restricted mean DOR (RMDOR) was recently proposed as a composite nonparametric method to efficiently quantify the treatment effect related to tumor reductions, which offers an intuitive way to perform statistical inference in cross-arm comparison and has since been applied in some Phase III studies. In this paper, we provide further technical details and asymptotic properties of the RMDOR method and discuss the selection of the truncation time. A simulation study is conducted comparing the performance of the proposed method with existing standard methods in hypothesis testing and quantification of treatment efficacy. We use two oncology Phase III examples to illustrate the method. An R package PBIR and a SAS macro are available to perform statistical inference based on the RMDOR.

  View details for DOI 10.1002/pst.2198

  View details for PubMedID 35191170

• Deviation from the precisely timed age-associated patterns revealed by blood metabolomics to find CRC patients at risk of relapse at the CRC diagnosis Thyparambil, S. P., Zhu, X., Zhang, Y., Sun, H., Peng, J., Cai, S., Li, Y., Fu, C., Bao, P., Hao, S., Li, Z., Ding, Y., Yao, X., Liao, W., Heaton, R., Han, Z., Tian, L., Schilling, J., Sylvester, K. G., Ling, X. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1200/JCO.2022.40.4_suppl.206

  View details for Web of Science ID 000770995900202

• Evaluating Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma. JAMA surgery Sun, R., Tian, L., Wei, L. 1800

  View details for DOI 10.1001/jamasurg.2021.7113

  View details for PubMedID 35080625

• Weighted Approach for Estimating Effects in Principal Strata With Missing Data for a Categorical Post-Baseline Variable in Randomized Controlled Trials STATISTICS IN BIOPHARMACEUTICAL RESEARCH Kong, S., Heinzmann, D., Lauer, S., Tian, L. 2022

  View details for DOI 10.1080/19466315.2021.2009020

  View details for Web of Science ID 000750901900001

• Exact inference for disease prevalence based on a test with unknown specificity and sensitivity JOURNAL OF APPLIED STATISTICS Cai, B., Ioannidis, J. A., Bendavid, E., Tian, L. 2022

  View details for DOI 10.1080/02664763.2021.2019687

  View details for Web of Science ID 000738502700001

• Corrigendum: Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells. Frontiers in immunology Hu, B., Jadhav, R. R., Gustafson, C. E., Le Saux, S., Ye, Z., Li, X., Tian, L., Weyand, C. M., Goronzy, J. J. 2022; 13: 911132

  Abstract

  [This corrects the article DOI: 10.3389/fimmu.2020.585168.].

  View details for DOI 10.3389/fimmu.2022.911132

  View details for PubMedID 35572522

• Effects of emollient therapy with sunflower seed oil on neonatal growth and morbidity in Uttar Pradesh, India: a cluster-randomized, open-label, controlled trial. The American journal of clinical nutrition Kumar, V., Kumar, A., Mishra, S., Kan, P., Ashraf, S., Singh, S., Blanks, K. J., Baiocchi, M., Limcaoco, M., Ghosh, A. K., Kumar, A., Krishna, R., Stevenson, D. K., Tian, L., Darmstadt, G. L. 2022

  Abstract

  Newborn oil massage is a widespread practice. Vigorous massage with potentially harmful products and forced removal of vernix may disrupt skin barrier integrity. Hospitalized, very preterm infants treated with sunflower seed oil (SSO) have demonstrated improved growth but community-based data on growth and health outcomes are lacking.We aimed to test whether SSO therapy enhances neonatal growth and reduces morbidity at population-level.We conducted an open-label, controlled trial in rural Uttar Pradesh, India, randomly allocating 276 village clusters equally to comparison (usual care) and intervention comprised of promotion of improved massage practices exclusively with SSO, using intention-to-treat and per-protocol mixed-effects regression analysis.We enrolled 13,478 and 13,109 newborn infants in demographically similar intervention and comparison arms, respectively. Adherence to exclusive SSO increased from 22.6% of intervention infants enrolled in the first study quartile to 37.2% in the last quartile. Intervention infants gained significantly more weight by 0.94 grams/kilogram/day (g/kg/d) [95% confidence interval (CI): 0.07, 1.82, p = 0.03] than comparison infants by intention-to-treat analysis. Restricted cubic spline regression revealed the largest benefits in weight gain (2-4 g/kg/day) occurred in infants <2000 g. Weight gain in intervention infants was higher by 1.31 g/kg/d (95% CI: 0.17, 2.46, p = 0.02) by per-protocol analysis. Morbidities were similar by intention-to-treat analysis but in per-protocol analysis rates of hospitalization and of any illness were reduced by 36% [odds ratio (OR): 0.64; 95% CI: 0.44, 0.94, p = 0.02] and 44% (OR: 0.56; 95% CI: 0.40, 0.77, p<0.001), respectively, in treated infants.SSO therapy improved neonatal growth, and reduced morbidities when applied exclusively, across the facility-community continuum of care at population-level. Further research is needed to improve demand for recommended therapy inside hospital as well as in community settings, and to confirm these results in other settings. Clinical Trial Registry: The trial was registered at the ISRCTN (ISRCTN38965585) and CTRI (CTRI/2014/12/005282) registries with WHO UTN # U1111-1158-4665.

  View details for DOI 10.1093/ajcn/nqab430

  View details for PubMedID 34982820

• Ways Forward in Preventing Severe Maternal Morbidity and Maternal Health Inequities: Conceptual Frameworks, Definitions, and Data, from a Population Health Perspective. Women's health issues : official publication of the Jacobs Institute of Women's Health Carmichael, S. L., Abrams, B., El Ayadi, A., Lee, H. C., Liu, C., Lyell, D. J., Lyndon, A., Main, E. K., Mujahid, M., Tian, L., Snowden, J. M. 1800

  View details for DOI 10.1016/j.whi.2021.11.006

  View details for PubMedID 34972599

• One-Year Change in Walking Performance and Subsequent Mobility Loss and Mortality Rates in Peripheral Artery Disease: Longitudinal Data From the WALCS. Journal of the American Heart Association Hammond, M. M., Tian, L., Zhao, L., Zhang, D., McDermott, M. M. 1800: e021917

  Abstract

  Background Associations of 1-year change in functional performance measures with subsequent mobility loss and mortality in people with lower extremity peripheral artery disease are unknown. Methods and Results Six-minute walk and 4-meter walking velocity (usual and fastest pace) were measured at baseline and 1year later in 612 people with peripheral artery disease (mean age 71±9years, 37% women). Participants were categorized into tertiles, based on 1-year changes in walking measures. Cox proportional hazards models were used to examine associations between 1-year change in each walking measure and subsequent mobility loss and mortality, respectively, adjusting for potential confounders. Compared with the best tertile, the worst tertile (ie, greatest decline) in 1-year change in each performance measure was associated with higher rates of mobility loss: 6-minute walk (Tertile 1 [T1] cumulative incidence rate [IR], 72/160; Tertile 3 [T3] IR, 47/160; hazard ratio [HR], 2.35; 95% CI, 1.47-3.74), usual-paced 4-meter walking velocity (T1 IR, 54/162; T3 IR, 57/162; HR, 2.21; 95% CI, 1.41-3.47), and fast-paced 4-meter walking velocity (T1 IR, 61/162; T3 IR, 58/162; HR, 1.81; 95% CI, 1.16-2.84). Compared with the best tertile, the worst tertiles in 1-year change in 6-minute walk (T1 IR, 66/163; T3 IR, 54/163; HR, 1.61; 95% CI, 1.07-2.43) and fast-paced 4-meter walking velocity (T1 IR, 63/166; T3 IR, 44/166; HR, 1.75; 95% CI, 1.16, 2.64) were associated with higher mortality. Conclusions In people with peripheral artery disease, greater 1-year decline in 6-minute walk or 4-meter walking velocity may help identify people with peripheral artery disease at highest risk for mobility loss and mortality.

  View details for DOI 10.1161/JAHA.121.021917

  View details for PubMedID 34913367

• Development and Validation of A Long-Term Incident Heart Failure Risk Model. Circulation research Khan, S. S., Ning, H., Allen, N. B., Carnethon, M., Yancy, C. W., Shah, S. J., Wilkins, J. T., Tian, L., Lloyd-Jones, D. 2021

  Abstract

  Background: Average lifetime risk for heart failure (HF) is high, but differs significantly across and within sex-race groups. No models for estimating long-term risk for HF exist, which would allow for earlier identification and interventions in high-risk subsets. The authors aim to derive 30-year HF risk equations. Methods: Adults between the ages of 20 to 59 years and free of cardiovascular disease at baseline from 5 population-based cohorts were included. Among 24,838 participants (55% women, 25% Black based on self-report), follow-up consisted of 599,551 person-years. Sex- and race-specific 30-year HF risk equations were derived and validated accounting for competing risk of non-HF death. HF was based on a clinical diagnosis. Model discrimation and calibration were assessed using 10-fold cross-validation. Finally, the model was applied to varying risk factor patterns for systematic examination. Results: The rate of incident HF was 4.0 per 1000 person-years. Harrell's c statistics were 0.82 (0.80-0.83) and 0.84 (0.82-0.85) in White and Black men, and 0.84 (0.82-0.85) and 0.85 (0.83-0.87) in White and Black women, respectively. Hosmer-Lemeshow calibration was acceptable, with x2 <30 in all subgroups. Risk estimation varied across sex-race groups: for example, in an average 40-year-old non-smoker with an untreated systolic blood pressure of 140 mm Hg and body mass index of 30 kg/m2, risk was estimated to be 22.8% in a Black man, 13.7% in a White man, 13.0% in a Black woman, and 12.1% in a White woman. Conclusions: Sex- and race-specific equations for prediction of long-term risk of HF demonstrated high discrimination and adequate calibration.

  View details for DOI 10.1161/CIRCRESAHA.121.319595

  View details for PubMedID 34886685

• Testing for heterogeneity in the utility of a surrogate marker. Biometrics Parast, L., Cai, T., Tian, L. 2021

  Abstract

  In studies that require long-term and/or costly follow-up of participants to evaluate a treatment, there is often interest in identifying and using a surrogate marker to evaluate the treatment effect. While several statistical methods have been proposed to evaluate potential surrogate markers, available methods generally do not account for or address the potential for a surrogate to vary in utility or strength by patient characteristics. Previous work examining surrogate markers has indicated that there may be such heterogeneity, that is, that a surrogate marker may be useful (with respect to capturing the treatment effect on the primary outcome) for some subgroups, but not for others. This heterogeneity is important to understand, particularly if the surrogate is to be used in a future trial to replace the primary outcome. In this paper, we propose an approach and estimation procedures to measure the surrogate strength as a function of a baseline covariate W and thus examine potential heterogeneity in the utility of the surrogate marker with respect to W. Within a potential outcome framework, we quantify the surrogate strength/utility using the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate. We propose testing procedures to test for evidence of heterogeneity, examine finite sample performance of these methods via simulation, and illustrate the methods using AIDS clinical trialdata.

  View details for DOI 10.1111/biom.13600

  View details for PubMedID 34874550

• Practical Recommendations on Quantifying and Interpreting Treatment Effects in the Presence of Terminal Competing Risks: A Review. JAMA cardiology McCaw, Z. R., Claggett, B. L., Tian, L., Solomon, S. D., Berwanger, O., Pfeffer, M. A., Wei, L. 2021

  Abstract

  Importance: In a comparative trial, the time to a clinical event is often a key end point. However, the occurrence of a terminal event, such as death or premature study discontinuation, may preclude observation of this outcome. Although various methods for handling competing risks are available, no specific recommendations have been made for scenarios encountered in practice, especially when the terminal event profiles of the study arms are dissimilar. Moreover, appropriate methods for a desirable outcome, such as live hospital discharge, have seldom been discussed.Observations: Several of the most commonly used methods are reviewed. The first regards the terminal event as censoring and applies standard survival analysis to the event of interest. The between-group difference is usually summarized by the cause-specific hazard ratio. This summary measure is inappropriate when the new therapy markedly prolongs time to the terminal event. Moreover, the corresponding Kaplan-Meier curve for the end point of interest is uninterpretable. The second method is to use the cumulative incidence curve, which is the probability of experiencing the event of interest by each time point, acknowledging that patients who have died will never experience the event. However, the resulting pseudo hazard ratio is difficult to interpret. With a proper alternative summary measure, this approach works well for a desirable outcome but may not for an undesirable outcome. The third method focuses on the event-free survival time by combining information from occurrences of the terminal event and the event of interest simultaneously. This clinically interpretable method naturally accounts for differences in terminal event rates when comparing treatments with respect to the time to an undesirable outcome.Conclusions and Relevance: This article enhances our understanding of each method's advantages and shortcomings and assists practitioners in choosing appropriate methods for handling competing risk problems in practice.

  View details for DOI 10.1001/jamacardio.2021.4932

  View details for PubMedID 34851356

• Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles. Annals of the rheumatic diseases Saper, V. E., Ombrello, M. J., Tremoulet, A. H., Montero-Martin, G., Prahalad, S., Canna, S., Shimizu, C., Deutsch, G., Tan, S. Y., Remmers, E. F., Monos, D., Hahn, T., Phadke, O. K., Cassidy, E., Ferguson, I., Mallajosyula, V., Xu, J., Rosa Duque, J. S., Chua, G. T., Ghosh, D., Szymanski, A. M., Rubin, D., Burns, J. C., Tian, L., Fernandez-Vina, M. A., Mellins, E. D., Hollenbach, J. A., Drug Hypersensitivity Consortium, INCHARGE Consortium, Aziz, R. A., Berard, R., Bingham, C. A., Bonaparth, A. D., Casey, A., Collins, K. P., Cidon, M., Goodman, S. I., Grom, A. A., Hazen, M., Hoftman, A., Ibarra, M., Jerath, R., Kingsbury, D. J., Klein-Gitelman, M. S., Lai, K., Lapidus, S., Mendoza-Londono, R., Onel, K., Perez, M., Radhakrishna, S. M., Reinhardt, A., Riskalla, M., Roth, J., Rosenwasser, N., Saad, N., Schulert, G. S., Shenoi, S., Smith, J. A., Soep, J., Stingl, C., Stoll, M. L., Tesher, M., Whitehead, B., Zemel, L., Anton, J., Bohnsack, J. F., Cobb, J., Demirkaya, E., Foell, D., Gattorno, M., Grom, A., Hilario, M. O., Ilowite, N. T., Haas, J., Hinks, A., Kastner, D. L., Langfeld, C. D., Martini, A., Mellins, E. D., Minden, K., Oliveira, S., Ombrello, M. J., Ozen, S., Prahalad, S., Rosen-Wolff, A., Rosenberg, A., Russo, R., Signa, S., Tachmazidou, I., Tenbrock, K., Thompson, S., Thomson, W., Wedderburn, L. R., Woo, P., Yeung, R. S., Zeft, A. S., Len, C. 2021

  Abstract

  OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.METHODS: In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied.RESULTS: Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2*10-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5*10-13) and versus self-identified, ancestry-matched Still's controls (p=6.3*10-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.CONCLUSIONS: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

  View details for DOI 10.1136/annrheumdis-2021-220578

  View details for PubMedID 34789453

• Identifying Gaps in Disease Knowledge among Patients with Peripheral Artery Disease. Journal of vascular surgery Byskosh, N., Pamulapati, V., Xu, S., Vavra, A. K., Hoel, A. W., Tian, L., McDermott, M. M., Butt, Z., Ho, K. J. 2021

  Abstract

  INTRODUCTION: An individual's understanding of disease risk factors and outcomes is important for the ability to make healthy lifestyle choices and decisions about disease treatment. Peripheral artery disease (PAD) is a condition with increasing global prevalence and high risk of adverse patient outcomes. This study seeks to understand the adequacy of disease understanding in patients with PAD.METHODS: This was an observational study of patients with PAD recruited from vascular surgery outpatient clinic and PAD clinical studies at a single academic medical center over an 8-month period. A 44-item paper survey assessed demographic and socioeconomic information, knowledge of personal medical history, PAD risk factors, consequences of PAD, and health education preferences. Patients with documented presence of PAD were offered the survey. Patients unable to complete the survey or provide informed consent were not considered eligible. Disease "awareness" was defined as correct acknowledgement of the presence or absence of a disease, including PAD, in the personal medical history. "PAD knowledge score" was the percentage of correct responses to questions on general PAD risk factors and consequences. Of 126 eligible patients, 109 participated. Bivariate analysis was used to study factors associated with awareness of PAD diagnosis. Factors associated with the PAD knowledge score were studied using the Pearson correlation coefficient, two-sample T-test, or one-way ANOVA. P value < .05 was considered statistically significant.RESULTS: Mean participant age was 69.4 ± 11.0 years and 39.4% (N=43) were female. Most participants (78.9%; N=86) had critical limb-threatening ischemia. Only 65.4% (N=70) of participants were aware of a diagnosis of PAD, which was less than their awareness of related comorbidities. Factors positively associated with PAD diagnosis awareness were female sex (81.4% vs. 54.7%; P=.004) and history of percutaneous leg revascularization (78.6% vs. 47.9%; p=.001). Among 17 patients who had undergone major leg amputation, 35% (N=6) were unaware of a diagnosis of PAD. PAD knowledge scores correlated positively with an awareness of PAD diagnosis (59.1% vs. 48.7%; P=.02) and negatively with a history of hypertension (53.4% vs. 68.1%; P=.001). Most participants (86.5%; N=90) expressed a desire to be further educated on PAD. The most popular education topics were dietary recommendations, causes, and treatment for PAD.CONCLUSION: Patients with PAD have deficits in their awareness of this diagnosis and general knowledge about PAD. Future research priorities should further define these deficits and their causes in order to inform new strategies that foster information-seeking behavior and effective educational programs for PAD.

  View details for DOI 10.1016/j.jvs.2021.11.036

  View details for PubMedID 34793926

• Analysis of Outcomes With Addition of Immunotherapy to Chemoradiation Therapy for Non-Small Cell Lung Cancer. JAMA oncology Tian, L., Huang, B., Wei, L. 2021

  View details for DOI 10.1001/jamaoncol.2021.5605

  View details for PubMedID 34734980

• Statistical Considerations for Sequential Analysis of the Restricted Mean Survival Time for Randomized Clinical Trials. Statistics in biopharmaceutical research Lu, Y., Tian, L. 2021; 13 (2): 210-218

  Abstract

  In this paper, we illustrate the method of designing a group-sequential randomized clinical trial based on the difference in restricted mean survival time (RMST). The procedure is based on theoretical formulations of Murray and Tsiatis (1999). We also present a numerical example in designing a cardiology surgical trial. Various practical considerations are discussed. R codes are provided in the Supplementary Materials. We conclude that the group-sequential design for RMST is a viable option in practice. A simulation study is performed to compare the proposed method to the Max-Combo and conventional log-rank tests. The simulation result shows that when there is a delayed treatment benefit and the proportional hazards assumption is untrue, the sequential design based on the RMST can be more efficient than that based on the log-rank test but less efficient than that based on the Max-Combo test. Compared with Max-Combo test, the RMST-based study design yield coherent estimand, statistical inference and result interpretation.

  View details for DOI 10.1080/19466315.2020.1816491

  View details for PubMedID 33927801

  View details for PubMedCentralID PMC8078843

• Chimeric Antigen Receptor-T Cell Therapy in Adults with B-Cell Acute Lymphoblastic Leukemia: A Systematic Review. Blood advances Grover, P., Veilleux, O., Tian, L., Sun, R., Previtera, M., Curran, E., Muffly, L. 2021

  Abstract

  Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase and Cochrane Library for prospective, interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥ 18 years. Risk of bias was assessed using a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean CR rate was 81% and MRD negative remission rate was 81% at 4 weeks post CAR-T infusion. With median follow-up across studies of 24 months the cumulative 12-month probability of PFS and OS were 37% (95% CI 26-48%) and 57% (95% CI 49-65%), respectively. Relapse occurred in 40.3%; target antigen was retained in 73.2% of relapses. Across studies, any grade of CRS occurred in 82% (95% CI 61-95%) and grade 3 or higher CRS in 27% (95% CI 18-36%). Neurotoxicity of any grade occurred in 34% (95% CI 24-47%) and grade 3 or higher in 14% (95% CI 1-25%). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.

  View details for DOI 10.1182/bloodadvances.2020003482

  View details for PubMedID 34610109

• Exercise characteristics associated with improved walking performance in peripheral artery disease: the lite randomized clinical trial Slysz, J., McDermott, M. M., Tian, L., Zhao, L. SAGE PUBLICATIONS LTD. 2021: NP7

  View details for Web of Science ID 000704017100026

• Quantifying the feasibility of shortening clinical trial duration using surrogate markers. Statistics in medicine Wang, X., Cai, T., Tian, L., Bourgeois, F., Parast, L. 2021

  Abstract

  The potential benefit of using a surrogate marker in place of a long-term primary outcome is very attractive in terms of the impact on study length and cost. Many available methods for quantifying the effectiveness of a surrogate endpoint either rely on strict parametric modeling assumptions or require that the primary outcome and surrogate marker are fully observed that is, not subject to censoring. Moreover, available methods for quantifying surrogacy typically provide a proportion of treatment effect explained (PTE) measure and do not directly address the important questions of whether and how the trial can be ended earlier using the surrogate marker. In this article, we specifically address these important questions by proposing a PTE measure to quantify the feasibility of ending trials early based on endpoint information collected at an earlier landmark point t 0 in a time-to-event outcome setting. We provide a framework for deriving an optimally predicted outcome for individual patients at t 0 based on a combination of surrogate marker and event time information in the presence of censoring. We propose a non-parametric estimator for the PTE measure and derive the asymptotic properties of our estimators. Finite sample performance of our estimators are illustrated via extensive simulation studies and a real data application examining the potential of hemoglobin A1c and fasting plasma glucose to predict treatment effects on long term diabetes risk based on the Diabetes Prevention Program study.

  View details for DOI 10.1002/sim.9185

  View details for PubMedID 34474500

• Chimeric Antigen Receptor T-Cell Therapy (CAR-T) in Adults with B-Cell Acute Lymphoblastic Leukemia (B-ALL): A Systematic Review and Meta-Analysis Grover, P., Veilleux, O., Tian, L., Sun, R., Previtera, M., Curran, E., Muffly, L. CIG MEDIA GROUP, LP. 2021: S454

  View details for Web of Science ID 000691910500446

• Macrophage-derived IL-6 trans-signaling as a novel target in the pathogenesis of bronchopulmonary dysplasia. The European respiratory journal Hirani, D., Alvira, C. M., Danopoulos, S., Milla, C., Donato, M., Tian, L., Mohr, J., Dinger, K., Vohlen, C., Selle, J., Koningsbruggen-Rietschel, S. V., Barbarino, V., Pallasch, C., Rose-John, S., Odenthal, M., Pryhuber, G. S., Mansouri, S., Savai, R., Seeger, W., Khatri, P., Al Alam, D., Dotsch, J., Alejandre Alcazar, M. A. 2021

  Abstract

  RATIONALE: Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.METHODS AND RESULTS: First, transcriptomic analysis with in-silico cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (Ccl2, Ccl7, Cxcl5) and markers (Il6, Il17A, Mmp12). Second, hyperoxia-activated IL-6/STAT3 signaling was measured in vivo and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. Il6 null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fiber assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signaling and IL-6 trans-signaling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly via Klf4; hyperoxia-conditioned medium of macrophages and IL-6 impaired ATII proliferation. Finally, clinical data demonstrate elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived IL6 and active STAT3 were related to loss of epithelial cells in BPD lungs.CONCLUSION: We present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis, and disrupts elastic fiber formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signaling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease.

  View details for DOI 10.1183/13993003.02248-2020

  View details for PubMedID 34446466

• Semantic fluency and processing speed are reduced in non-cognitively impaired participants with Parkinson's disease. Journal of clinical and experimental neuropsychology Cholerton, B. A., Poston, K. L., Yang, L., Rosenthal, L. S., Dawson, T. M., Pantelyat, A., Edwards, K. L., Tian, L., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S., Montine, T. J., Zabetian, C. P. 2021: 1-12

  Abstract

  Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B =-3.77, 95% CIs [-5.76 to -1.77], p <.001, and B =-2.02, 95% CIs [-3.12, -0.92], p <.001, respectively), even after excluding those with moderate to severe motor symptoms (B =-2.73, 95% CIs [-4.94 to -0.53], p =.015 and B =-2.11, 95% CIs [-3.32 to -0.91], p <.001, respectively) or longer disease duration (B =-3.89, 95% CIs [-6.14 to -1.63], p <.001 and B =-1.58, 95% CIs [-2.78 to -0.37], p =.010, respectively). Semantic verbal fluency remained significantly negatively associated with PD diagnosis after controlling for processing speed (B =-1.66, 95% CIs [-2.79 to -0.53], p =.004).Conclusions: Subtle decline in specific cognitive domains may be present among people diagnosed with PD but without evidence to support a formal cognitive diagnosis. These results suggest the importance of early awareness of the potential for diminishing aspects of cognition in PD even among those without mild cognitive impairment or dementia.

  View details for DOI 10.1080/13803395.2021.1927995

  View details for PubMedID 34355669

• Estimation and Validation of Ratio-based Conditional Average Treatment Effects Using Observational Data. Journal of the American Statistical Association Yadlowsky, S., Pellegrini, F., Lionetto, F., Braune, S., Tian, L. 2021; 116 (533): 335-352

  Abstract

  While sample sizes in randomized clinical trials are large enough to estimate the average treatment effect well, they are often insufficient for estimation of treatment-covariate interactions critical to studying data-driven precision medicine. Observational data from real world practice may play an important role in alleviating this problem. One common approach in trials is to predict the outcome of interest with separate regression models in each treatment arm, and estimate the treatment effect based on the contrast of the predictions. Unfortunately, this simple approach may induce spurious treatment-covariate interaction in observational studies when the regression model is misspecified. Motivated by the need of modeling the number of relapses in multiple sclerosis patients, where the ratio of relapse rates is a natural choice of the treatment effect, we propose to estimate the conditional average treatment effect (CATE) as the ratio of expected potential outcomes, and derive a doubly robust estimator of this CATE in a semiparametric model of treatment-covariate interactions. We also provide a validation procedure to check the quality of the estimator on an independent sample. We conduct simulations to demonstrate the finite sample performance of the proposed methods, and illustrate their advantages on real data by examining the treatment effect of dimethyl fumarate compared to teriflunomide in multiple sclerosis patients.

  View details for DOI 10.1080/01621459.2020.1772080

  View details for PubMedID 33767517

  View details for PubMedCentralID PMC7985957

• Supervised exercise therapy, blood pressure and heart rate during exercise, and functional impairment in Peripheral Artery Disease: results of a randomized clinical trial. Journal of vascular surgery Slysz, J. T., Tian, L., Zhao, L., Zhang, D., McDermott, M. M. 2021

  Abstract

  OBJECTIVE: Supervised exercise therapy (SET) improves walking ability in people with peripheral artery disease (PAD). However, the effects of SET on cardiovascular health in PAD remains unclear. Using data from a randomized clinical trial, this post-hoc study investigated the effects of a 6-month SET intervention, compared to a control group, on changes in blood pressure (BP) and heart rate (HR) during a graded treadmill exercise test (GXT) in people with PAD.METHODS: 210 participants with PAD were randomized to either SET (3X weekly) or control (1X weekly health lectures) for 6 months. A GXT, six-minute walk (6MW) test, and Walking Impairment Questionnaire (WIQ) were completed at baseline and 6-month follow-up. BP and HR were measured at the end of each 2-min stage of the GXT. Mixed-effects regression models compared the overall mean 6-month change in systolic BP, diastolic BP, pulse pressure (PP), and HR during the first 5 stages of the GXT between groups.RESULTS: Of 210 randomized, 176 participants with PAD (67±9 years, 72 (41%) female, 115 (65%) black) completed the GXT at baseline and 6-month follow-up. Compared to the control group at 6-month follow-up, SET significantly decreased overall mean systolic BP (-12mmHg; p<0.001), PP (-9mmHg; p<0.001), and HR (-7b/min; p< 0.01) during a GXT but not diastolic BP. Among participants randomized to SET, a greater reduction in systolic BP, PP, and HR during a GXT was significantly associated with greater improvement in 6MW distance (systolic BP: r=-0.19; p=0.03 & PP: r=-0.23; p<0.01 & HR: r=-0.21; p<0.01) and with maximal treadmill walking distance (systolic BP: r=-0.21; p<0.01 & PP: r=-0.17; p=0.03) at 6-month follow-up. A greater reduction in HR during a GXT was significantly associated with a better WIQ distance score (r=-0.27; p=0.03) at 6-month follow up.CONCLUSIONS: In people with PAD, compared to a control group, SET improved cardiovascular health, measured by changes in BP & HR during exercise. The degree of improvement in cardiovascular health correlated with the degree of improvement in walking performance in people with PAD.

  View details for DOI 10.1016/j.jvs.2021.05.033

  View details for PubMedID 34090987

• Perceived Versus Objective Change in Walking Ability in Peripheral Artery Disease: Results from 3 Randomized Clinical Trials of Exercise Therapy. Journal of the American Heart Association McDermott, M. M., Tian, L., Criqui, M. H., Ferrucci, L., Greenland, P., Guralnik, J. M., Kibbe, M. R., Li, L., Sufit, R., Zhao, L., Polonsky, T. S. 2021: e017609

  Abstract

  Background In people with lower-extremity peripheral artery disease, the effects of exercise on patient-reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6-minute walk and the Walking Impairment Questionnaire distance score (score 0-100, 100=best) at baseline and 6-month follow-up. Compared with the control group, exercise improved 6-minute walk distance by +39.8m (95% CI, 26.8-52.8, P<0.001) and the Walking Impairment Questionnaire distance score by +7.3 (95% CI, 2.4-12.1, P=0.003). In all, 2828 individual Walking Impairment Questionnaire distance score questions were completed at baseline and follow-up. Among participants who perceived no change in ability to walk 1 or more distances between baseline and follow-up, 6-minute walk improved in the exercise group and declined in the control group (+26.8 versus -6.5m, P<0.001). Among participants who perceived that their walking ability worsened for 1 or more distances between baseline and follow-up, the 6-minute walk improved in the exercise group and declined in the control group (+18.4 versus -27.3m, P<0.001). Among participants who reported worsening calf symptoms at follow-up, the exercise group improved and the control group declined (+28.9 versus -12.5m, P<0.01). Conclusions In 3 randomized trials, exercise significantly improved the 6-minute walk distance in people with peripheral artery disease, but many participants randomized to exercise reported no change or decline in walking ability. These findings suggest a significant discrepancy in objectively measured walking improvement relative to perceived walking improvement in people with peripheral artery disease. Registration Information clinicaltrials.gov. Identifiers: NCT00106327, NCT01408901.

  View details for DOI 10.1161/JAHA.120.017609

  View details for PubMedID 34075780

• Quantifying the Effect of Lower vs Higher Positive End-Expiratory Pressure on Ventilator-Free Survival in ICU Patients JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION McCaw, Z. R., Tian, L., Wei, L. 2021; 325 (15): 1566-+

  View details for Web of Science ID 000642636500028

• Quantifying the Effect of Lower vs Higher Positive End-Expiratory Pressure on Ventilator-Free Survival in ICU Patients. JAMA McCaw, Z. R., Tian, L., Wei, L. 2021; 325 (15): 1566–67

  View details for DOI 10.1001/jama.2021.1700

  View details for PubMedID 33877277

• Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial. Vascular medicine (London, England) Slysz, J. T., Rejeski, W. J., Treat-Jacobson, D., Bazzano, L. A., Forman, D. E., Manini, T. M., Criqui, M. H., Tian, L., Zhao, L., Zhang, D., Guralnik, J. M., Ferrucci, L., Kibbe, M. R., Polonsky, T. S., Spring, B., Sufit, R., Leeuwenburgh, C., McDermott, M. M. 2021: 1358863X21989430

  Abstract

  This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; p < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; p < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; p < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; p = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs. Clinicaltrials.gov ID: NCT02538900.

  View details for DOI 10.1177/1358863X21989430

  View details for PubMedID 33829920

• Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial. JAMA McDermott, M. M., Spring, B., Tian, L., Treat-Jacobson, D., Ferrucci, L., Lloyd-Jones, D., Zhao, L., Polonsky, T., Kibbe, M. R., Bazzano, L., Guralnik, J. M., Forman, D. E., Rego, A., Zhang, D., Domanchuk, K., Leeuwenburgh, C., Sufit, R., Smith, B., Manini, T., Criqui, M. H., Rejeski, W. J. 2021; 325 (13): 1266–76

  Abstract

  Importance: Supervised high-intensity walking exercise that induces ischemic leg symptoms is the first-line therapy for people with lower-extremity peripheral artery disease (PAD), but adherence is poor.Objective: To determine whether low-intensity home-based walking exercise at a comfortable pace significantly improves walking ability in people with PAD vs high-intensity home-based walking exercise that induces ischemic leg symptoms and vs a nonexercise control.Design, Setting, and Participants: Multicenter randomized clinical trial conducted at 4 US centers and including 305 participants. Enrollment occurred between September 25, 2015, and December 11, 2019; final follow-up was October 7, 2020.Interventions: Participants with PAD were randomized to low-intensity walking exercise (n=116), high-intensity walking exercise (n=124), or nonexercise control (n=65) for 12 months. Both exercise groups were asked to walk for exercise in an unsupervised setting 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. The low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. Accelerometer data were viewable to a coach who telephoned participants weekly for 12 months and helped them adhere to their prescribed exercise. The nonexercise control group received weekly educational telephone calls for 12 months.Main Outcomes and Measures: The primary outcome was mean change in 6-minute walk distance at 12 months (minimum clinically important difference, 8-20 m).Results: Among 305 randomized patients (mean age, 69.3 [SD, 9.5] years, 146 [47.9%] women, 181 [59.3%] Black patients), 250 (82%) completed 12-month follow-up. The 6-minute walk distance changed from 332.1 m at baseline to 327.5 m at 12-month follow-up in the low-intensity exercise group (within-group mean change, -6.4 m [95% CI, -21.5 to 8.8 m]; P=.34) and from 338.1 m to 371.2 m in the high-intensity exercise group (within-group mean change, 34.5 m [95% CI, 20.1 to 48.9 m]; P<.001) and the mean change for the between-group comparison was -40.9 m (97.5% CI, -61.7 to -20.0 m; P<.001). The 6-minute walk distance changed from 328.1 m at baseline to 317.5 m at 12-month follow-up in the nonexercise control group (within-group mean change, -15.1 m [95% CI, -35.8 to 5.7 m]; P=.10), which was not significantly different from the change in the low-intensity exercise group (between-group mean change, 8.7 m [97.5% CI, -17.0 to 34.4 m]; P=.44). Of 184 serious adverse events, the event rate per participant was 0.64 in the low-intensity group, 0.65 in the high-intensity group, and 0.46 in the nonexercise control group. One serious adverse event in each exercise group was related to study participation.Conclusions and Relevance: Among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise and was not significantly different from the nonexercise control for improving 6-minute walk distance. These results do not support the use of low-intensity home-based walking exercise for improving objectively measured walking performance in patients with PAD.Trial Registration: ClinicalTrials.gov Identifier: NCT02538900.

  View details for DOI 10.1001/jama.2021.2536

  View details for PubMedID 33821898

• Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. Journal of Alzheimer's disease : JAD Ryman, S. G., Yutsis, M., Tian, L., Henderson, V. W., Montine, T. J., Salmon, D. P., Galasko, D., Poston, K. L. 2021

  Abstract

  BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

  View details for DOI 10.3233/JAD-201187

  View details for PubMedID 33646154

• IFAA: Robust Association Identification and Inference for Absolute Abundance in Microbiome Analyses. Journal of the American Statistical Association Li, Z., Tian, L., O'Malley, A. J., Karagas, M. R., Hoen, A. G., Christensen, B. C., Madan, J. C., Wu, Q., Gharaibeh, R. Z., Jobin, C., Li, H. 2021; 116 (536): 1595-1608

  Abstract

  The target of inference in microbiome analyses is usually relative abundance (RA) because RA in a sample (e.g., stool) can be considered as an approximation of RA in an entire ecosystem (e.g., gut). However, inference on RA suffers from the fact that RA are calculated by dividing absolute abundances (AAs) over the common denominator (CD), the summation of all AA (i.e., library size). Because of that, perturbation in one taxon will result in a change in the CD and thus cause false changes in RA of all other taxa, and those false changes could lead to false positive/negative findings. We propose a novel analysis approach (IFAA) to make robust inference on AA of an ecosystem that can circumvent the issues induced by the CD problem and compositional structure of RA. IFAA can also address the issues of overdispersion and handle zero-inflated data structures. IFAA identifies microbial taxa associated with the covariates in Phase 1 and estimates the association parameters by employing an independent reference taxon in Phase 2. Two real data applications are presented and extensive simulations show that IFAA outperforms other established existing approaches by a big margin in the presence of unbalanced library size. Supplementary materials for this article are available online.

  View details for DOI 10.1080/01621459.2020.1860770

  View details for PubMedID 35241863

  View details for PubMedCentralID PMC8890673

• IFAA: Robust Association Identification and Inference for Absolute Abundance in Microbiome Analyses JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Li, Z., Tian, L., O'Malley, A., Karagas, M. R., Hoen, A. G., Christensen, B. C., Madan, J. C., Wu, Q., Gharaibeh, R. Z., Jobin, C., Li, H. 2021

  View details for DOI 10.1080/01621459.2020.1860770

  View details for Web of Science ID 000612450300001

• Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ. Parkinsonism & related disorders Zarifkar, P. n., Kim, J. n., La, C. n., Zhang, K. n., YorkWilliams, S. n., Levine, T. F., Tian, L. n., Borghammer, P. n., Poston, K. L. 2021; 83: 71–78

  Abstract

  To identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis.In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aβ-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments.LHC-RHC (F3,67 = 3.41,p=0.023) and CSF Aβ-42:40 (χ2(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment.We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.

  View details for DOI 10.1016/j.parkreldis.2021.01.002

  View details for PubMedID 33484978

• Comparison of a Single-Session Pain Management Skills Intervention With a Single-Session Health Education Intervention and 8 Sessions of Cognitive Behavioral Therapy in Adults With Chronic Low Back Pain: A Randomized Clinical Trial. JAMA network open Darnall, B. D., Roy, A., Chen, A. L., Ziadni, M. S., Keane, R. T., You, D. S., Slater, K., Poupore-King, H., Mackey, I., Kao, M. C., Cook, K. F., Lorig, K., Zhang, D., Hong, J., Tian, L., Mackey, S. C. 2021; 4 (8): e2113401

  Abstract

  Chronic low back pain (CLBP), the most prevalent chronic pain condition, imparts substantial disability and discomfort. Cognitive behavioral therapy (CBT) reduces the effect of CLBP, but access is limited.To determine whether a single class in evidence-based pain management skills (empowered relief) is noninferior to 8-session CBT and superior to health education at 3 months after treatment for improving pain catastrophizing, pain intensity, pain interference, and other secondary outcomes.This 3-arm randomized clinical trial collected data from May 24, 2017, to March 3, 2020. Participants included individuals in the community with self-reported CLBP for 6 months or more and an average pain intensity of at least 4 (range, 0-10, with 10 indicating worst pain imaginable). Data were analyzed using intention-to-treat and per-protocol approaches.Participants were randomized to (1) empowered relief, (2) health education (matched to empowered relief for duration and format), or (3) 8-session CBT. Self-reported data were collected at baseline, before treatment, and at posttreatment months 1, 2, and 3.Group differences in Pain Catastrophizing Scale scores and secondary outcomes at month 3 after treatment. Pain intensity and pain interference were priority secondary outcomes.A total of 263 participants were included in the analysis (131 women [49.8%], 130 men [49.4%], and 2 other [0.8%]; mean [SD] age, 47.9 [13.8] years) and were randomized into 3 groups: empowered relief (n = 87), CBT (n = 88), and health education (n = 88). Empowered relief was noninferior to CBT for pain catastrophizing scores at 3 months (difference from CBT, 1.39 [97.5% CI, -∞ to 4.24]). Empowered relief and CBT were superior to health education for pain catastrophizing scores (empowered relief difference from health education, -5.90 [95% CI, -8.78 to -3.01; P < .001]; CBT difference from health education, -7.29 [95% CI, -10.20 to -4.38; P < .001]). Pain catastrophizing score reductions for empowered relief and CBT at 3 months after treatment were clinically meaningful (empowered relief, -9.12 [95% CI, -11.6 to -6.67; P < .001]; CBT, -10.94 [95% CI, -13.6 to -8.32; P < .001]; health education, -4.60 [95% CI, -7.18 to -2.01; P = .001]). Between-group comparisons for pain catastrophizing at months 1 to 3 were adjusted for baseline pain catastrophizing scores and used intention-to-treat analysis. Empowered relief was noninferior to CBT for pain intensity and pain interference (priority secondary outcomes), sleep disturbance, pain bothersomeness, pain behavior, depression, and anxiety. Empowered relief was inferior to CBT for physical function.Among adults with CLBP, a single-session pain management class resulted in clinically significant improvements in pain catastrophizing, pain intensity, pain interference, and other secondary outcomes that were noninferior to 8-session CBT at 3 months.ClinicalTrials.gov Identifier: NCT03167086.

  View details for DOI 10.1001/jamanetworkopen.2021.13401

  View details for PubMedID 34398206

• Moving beyond conventional stratified analysis to assess the treatment effect in a comparative oncology study. Journal for immunotherapy of cancer Sun, R., McCaw, Z., Tian, L., Uno, H., Hong, F., Kim, D. H., Wei, L. J. 2021; 9 (11)

  Abstract

  In a comparative oncology study with progression-free or overall survival as the endpoint, the primary or key secondary analysis is routinely stratified by patients' baseline characteristics when evaluating the treatment difference. The validity of a conventional strategy such as a stratified HR analysis depends on stringent model assumptions that are unlikely to be met in practice, especially in immunotherapy studies. Thus, the resulting summary is generally neither valid nor interpretable. This article discusses issues with conventional stratified analyses and presents alternatives using data from KEYNOTE-189, a recent immunotherapy trial for treating patients with metastatic, non-squamous, non-small-cell lung cancer.

  View details for DOI 10.1136/jitc-2021-003323

  View details for PubMedID 34799398

• How to Quantify and Interpret Treatment Effects in Comparative Clinical Studies of COVID-19. Annals of internal medicine Tian, L., Vassy, J. L., Ritchie, C. S., Lee, C., Kim, D. H. 2021; 174 (5): 731-732

  View details for DOI 10.7326/L20-1441

  View details for PubMedID 33999681

• Choosing clinically interpretable summary measures and robust analytic procedures for quantifying the treatment difference in comparative clinical studies. Statistics in medicine McCaw, Z. R., Tian, L., Wei, J., Claggett, B. L., Bretz, F., Fitzmaurice, G., Wei, L. J. 2021; 40 (28): 6235-6242

  View details for DOI 10.1002/sim.8971

  View details for PubMedID 34783094

• Histone deficiency and accelerated replication stress in T cell aging. The Journal of clinical investigation Kim, C., Jin, J., Ye, Z., Jadhav, R. R., Gustafson, C. E., Hu, B., Cao, W., Tian, L., Weyand, C. M., Goronzy, J. J. 2021; 131 (11)

  Abstract

  With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1-deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a-deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.

  View details for DOI 10.1172/JCI143632

  View details for PubMedID 34060486

• Effect of sunflower seed oil emollient therapy on newborn infant survival in Uttar Pradesh, India: A community-based, cluster randomized, open-label controlled trial. PLoS medicine Kumar, A., Mishra, S., Singh, S., Ashraf, S., Kan, P., Ghosh, A. K., Kumar, A., Krishna, R., Stevenson, D. K., Tian, L., Elias, P. M., Darmstadt, G. L., Kumar, V. 2021; 18 (9): e1003680

  Abstract

  Hospitalized preterm infants with compromised skin barrier function treated topically with sunflower seed oil (SSO) have shown reductions in sepsis and neonatal mortality rate (NMR). Mustard oil and products commonly used in high-mortality settings may possibly harm skin barrier integrity and enhance risk of infection and mortality in newborn infants. We hypothesized that SSO therapy may reduce NMR in such settings.This was a population-based, cluster randomized, controlled trial in 276 clusters in rural Uttar Pradesh, India. All newborn infants identified through population-based surveillance in the study clusters within 7 days of delivery were enrolled from November 2014 to October 2016. Exclusive, 3 times daily, gentle applications of 10 ml of SSO to newborn infants by families throughout the neonatal period were recommended in intervention clusters (n = 138 clusters); infants in comparison clusters (n = 138 clusters) received usual care, such as massage practice typically with mustard oil. Primary analysis was by intention-to-treat with NMR and post-24-hour NMR as the primary outcomes. Secondary analysis included per-protocol analysis and subgroup analyses for NMR. Regression analysis was adjusted for caste, first-visit weight, delivery attendant, gravidity, maternal age, maternal education, sex of the infant, and multiple births. We enrolled 13,478 (52.2% male, mean weight: 2,575.0 grams ± standard deviation [SD] 521.0) and 13,109 (52.0% male, mean weight: 2,607.0 grams ± SD 509.0) newborn infants in the intervention and comparison clusters, respectively. We found no overall difference in NMR in the intervention versus the comparison clusters [adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.84 to 1.11, p = 0.61]. Acceptance of SSO in the intervention arm was high at 89.3%, but adherence to exclusive applications of SSO was 30.4%. Per-protocol analysis showed a significant 58% (95% CI 42% to 69%, p < 0.01) reduction in mortality among infants in the intervention group who were treated exclusively with SSO as intended versus infants in the comparison group who received exclusive applications of mustard oil. A significant 52% (95% CI 12% to 74%, p = 0.02) reduction in NMR was observed in the subgroup of infants weighing ≤1,500 g (n = 589); there were no statistically significant differences in other prespecified subgroup comparisons by low birth weight (LBW), birthplace, and wealth. No severe adverse events (SAEs) were attributable to the intervention. The study was limited by inability to mask allocation to study workers or participants and by measurement of emollient use based on caregiver responses and not actual observation.In this trial, we observed that promotion of SSO therapy universally for all newborn infants was not effective in reducing NMR. However, this result may not necessarily establish equivalence between SSO and mustard oil massage in light of our secondary findings. Mortality reduction in the subgroup of infants ≤1,500 g was consistent with previous hospital-based efficacy studies, potentially extending the applicability of emollient therapy in very low-birth-weight (VLBW) infants along the facility-community continuum. Further research is recommended to develop and evaluate therapeutic regimens and continuum of care delivery strategies for emollient therapy for newborn infants at highest risk of compromised skin barrier function.ISRCTN Registry ISRCTN38965585 and Clinical Trials Registry-India (CTRI/2014/12/005282) with WHO UTN # U1111-1158-4665.

  View details for DOI 10.1371/journal.pmed.1003680

  View details for PubMedID 34582448

• Examination of factors associated with lymph node metastases in lung carcinoids: Results from a single institution retrospective cohort study. Lung cancer (Amsterdam, Netherlands) Pathipati, M. P., Yohannan, T. K., Tian, L. n., Hornbacker, K. n., Benson, J. A., Berry, G. J., Lui, N. S., Kunz, P. L., Padda, S. K. 2021

  Abstract

  Well-differentiated lung neuroendocrine tumors (NETs), also known as typical and atypical carcinoids, have a decreased incidence of lymph node (LN) and distant metastases compared to poorly differentiated lung NETs. We aimed to (i) examine the clinicopathologic features associated with LN involvement in lung carcinoids and (ii) describe the postoperative management of patients with LN metastases.We identified 98 patients who underwent surgical resection and lymph node sampling at Stanford University. We assessed the following and used AJCC staging version 7: clinical features (age, sex, race, prior malignancy, smoking history), tumor features (functional syndrome, histology, size, location, laterality), pre-operative workup performed (imaging and suspicion of LN metastases), surgery (nodes and stations sampled, margin status, surgical approach, and type of surgery), and recurrence outcome. These features were examined between patients with and without LN metastases using the Wilcoxon test (continuous variables) and Fisher's exact test (categorical variables).87 patients (89%) had typical carcinoid and 11 patients (11%) had atypical carcinoid. 17 patients were found to have at least one positive lymph node, with 11 having N1 disease and 6 having N2 disease. In the univariable analysis, patients with lymph node disease were more likely to have recurrence of lung carcinoid (29% vs. 6%, p=0.01). In the multivariable logistic regression, there was a trend towards performance of preoperative SSTR imaging and lymph node involvement (OR = 3.06, p=0.07). No patients received adjuvant therapy.We found a trend for the performance of SSTR imaging and association of lymph node metastases in both univariable and multivariable analysis. A large proportion (41%) of patients with lymph node positive disease had < 2 cm tumors. This suggests the potential importance of incorporating SSTR imaging into routine practice and not restricting the use of this staging modality in patients with small tumors.

  View details for DOI 10.1016/j.lungcan.2021.01.017

  View details for PubMedID 33551175

• Low InTensity Exercise (LITE) Intervention to Improve Walking Performance in Peripheral Artery Disease: A Multi-centered Randomized Clinical Trial McDermott, M. M., Spring, B., Bazzano, L. A., Criqui, M. H., Domanchuk, K., Ferrucci, L., Forman, D. E., Guralnik, J., Kibbe, M. R., Leeuwenburgh, C., Lloyd-Jones, D. M., Manini, T., Polonsky, T. S., Rego, A., Smith, B., Sufit, R., Tian, L., Treat-Jacobson, D. J., Zhang, D., Zhao, L., Rejeski, W. LIPPINCOTT WILLIAMS & WILKINS. 2020: E487–E488

  View details for Web of Science ID 000598973900054

• Low InTensity Exercise (LITE) Intervention to Improve Walking Performance in Peripheral Artery Disease: A Multi-centered Randomized Clinical Trial McDermott, M. M., Spring, B., Bazzano, L. A., Criqui, M. H., Domanchuk, K., Ferrucci, L., Forman, D. E., Guralnik, J., Kibbe, M. R., Leeuwenburgh, C., Lloyd-Jones, D. M., Manini, T., Polonsky, T. S., Rego, A., Smith, B., Sufit, R., Tian, L., Treatjacobson, D. J., Zhang, D., Zhao, L., Rejeski, W. LIPPINCOTT WILLIAMS & WILKINS. 2020: E487–E488

  View details for Web of Science ID 000639226400054

• Maternal metabolic profiling to assess fetal gestational age and predict preterm delivery: a two-centre retrospective cohort study in the US. BMJ open Sylvester, K. G., Hao, S., You, J., Zheng, L., Tian, L., Yao, X., Mo, L., Ladella, S., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Whitin, J. C., McElhinney, D. B., Ling, X. B. 2020; 10 (12): e040647

  Abstract

  OBJECTIVES: The aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised that serial metabolic modelling of serum analytes throughout pregnancy could be used to describe fetal gestational age and project preterm birth with a high degree of precision.STUDY DESIGN: A retrospective cohort study.SETTING: Two medical centres from the USA.PARTICIPANTS: Thirty-six patients (20 full-term, 16 preterm) enrolled at Stanford University were used to develop gestational age and preterm birth risk algorithms, 22 patients (9 full-term, 13 preterm) enrolled at the University of Alabama were used to validate the algorithms.OUTCOME MEASURES: Maternal blood was collected serially throughout pregnancy. Metabolic datasets were generated using mass spectrometry.RESULTS: A model to determine gestational age was developed (R2=0.98) and validated (R2=0.81). 66.7% of the estimates fell within ±1week of ultrasound results during model validation. Significant disruptions from full-term pregnancy metabolic patterns were observed in preterm pregnancies (R2=-0.68). A separate algorithm to predict preterm birth was developed using a set of 10 metabolic pathways that resulted in an area under the curve of 0.96 and 0.92, a sensitivity of 0.88 and 0.86, and a specificity of 0.96 and 0.92 during development and validation testing, respectively.CONCLUSIONS: In this study, metabolic profiling was used to develop and test a model for determining gestational age during full-term pregnancy progression, and to determine risk of preterm birth. With additional patient validation studies, these algorithms may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights into the pathophysiology of preterm birth. Metabolic pathway-based pregnancy modelling is a novel modality for investigation and clinical application development.

  View details for DOI 10.1136/bmjopen-2020-040647

  View details for PubMedID 33268420

• A likelihood ratio test on temporal trends in age-period-cohort models with applications to the disparities of heart disease mortality among US populations and comparison with Japan. Statistics in medicine Fu, W., Ding, J., Gao, K., Ma, S., Tian, L. 2020

  Abstract

  In this article, we introduce the recently developed intrinsic estimator method in the age-period-cohort (APC) models in examining disease incidence and mortality data, further develop a likelihood ratio (L-R) test for testing differences in temporal trends across populations, and apply the methods to examining temporal trends in the age, period or calendar time, and birth cohort of the US heart disease mortality across racial and sex groups. The temporal trends are estimated with the intrinsic estimator method to address the model identification problem, in which multiple sets of parameter estimates yield the same fitted values for a given dataset, making it difficult to conduct comparison of and hypothesis testing on the temporal trends in the age, period, and cohort across populations. We employ a penalized profile log-likelihood approach in developing the L-R test to deal with the issues of multiple estimators and the diverging number of model parameters. The identification problem also induces overparametrization of the APC model, which requires a correction of the degree of freedom of the L-R test. Monte Carlo simulation studies demonstrate that the L-R test performs well in the Type I error calculation and is powerful to detect differences in the age or period trends. The L-R test further reveals disparities of heart disease mortality among the US populations and between the US and Japanese populations.

  View details for DOI 10.1002/sim.8796

  View details for PubMedID 33210329

• Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception. BMC research notes Rizzi, S., Wensink, M. J., Lindahl-Jacobsen, R., Tian, L., Lu, Y., Eisenberg, M. L. 2020; 13 (1): 509

  Abstract

  OBJECTIVE: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.RESULTS: For azithromycin and naproxen, large numbers of offspring were exposed (>1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (<300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.

  View details for DOI 10.1186/s13104-020-05358-x

  View details for PubMedID 33160408

• Survival analysis of treatment efficacy in comparative COVID-19 studies. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America McCaw, Z. R., Tian, L., Kim, D. H., Localio, A. R., Wei, L. 2020

  Abstract

  For survival analysis in comparative COVID-19 trials, the routinely used hazard ratio may not provide a meaningful summary of the treatment effect. The mean survival time difference/ratio is an intuitive, assumption-free alternative. However, for short-term studies, landmark mortality rate differences/ratios are more clinically relevant and should be formally analyzed and reported.

  View details for DOI 10.1093/cid/ciaa1563

  View details for PubMedID 33053155

• Statistical Considerations for Sequential Analysis of the Restricted Mean Survival Time for Randomized Clinical Trials STATISTICS IN BIOPHARMACEUTICAL RESEARCH Lu, Y., Tian, L. 2020

  View details for DOI 10.1080/19466315.2020.1816491

  View details for Web of Science ID 000576654600001

• Evaluating multiple surrogate markers with censored data. Biometrics Parast, L., Cai, T., Tian, L. 2020

  Abstract

  The utilization of surrogate markers offers the opportunity to reduce the length of required follow-up time and/or costs of a randomized trial examining the effectiveness of an intervention or treatment. There are many available methods for evaluating the utility of a single surrogate marker including both parametric and nonparametric approaches. However, as the dimension of the surrogate marker increases, a completely nonparametric procedure becomes infeasible due to the curse of dimensionality. In this paper, we define a quantity to assess the value of multiple surrogate markers in a time-to-event outcome setting and propose a robust estimation approach for censored data. We focus on surrogate markers that are measured at some landmark time, t0 , which occurs earlier than the end of the study. Our approach is based on a dimension reduction procedure with an option to incorporate weights to guard against potential misspecification of the working model, resulting in three different proposed estimators, two of which can be shown to be double robust. We examine the finite sample performance of the estimators under various scenarios using a simulation study. We illustrate the estimation and inference procedures using data from the Diabetes Prevention Program(DPP) to examine multiple potential surrogate markers fordiabetes. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/biom.13370

  View details for PubMedID 32920821

• Selecting appropriate endpoints for assessing treatment effects in comparative clinical studies for COVID-19. Contemporary clinical trials McCaw, Z. R., Tian, L., Sheth, K. N., Hsu, W., Kimberly, W. T., Wei, L. 2020: 106145

  Abstract

  To evaluate the efficacy and safety of a new treatment for COVID-19 vs. standard care, certain key endpoints are related to the duration of a specific event, such as hospitalization, ICU stay, or receipt of supplemental oxygen. However, since patients may die in the hospital during study follow-up, using, for example, the duration of hospitalization to assess treatment efficacy can be misleading. If the treatment tends to prolong patients' survival compared with standard care, patients in the new treatment group may spend more time in hospital. This can lead to a "survival bias" issue, where a treatment that is effective for preventing death appears to prolong an undesirable outcome. On the other hand, by using hospital-free survival time as the endpoint, we can circumvent the survival bias issue. In this article, we use reconstructed data from a recent, large clinical trial for COVID-19 to illustrate the advantages of this approach. For the analysis of ICU stay or oxygen usage, where the initiating event is potentially an outcome of treatment, standard survival analysis techniques may not be appropriate. We also discuss issues with analyzing the durations of such events.

  View details for DOI 10.1016/j.cct.2020.106145

  View details for PubMedID 32927092

• Adjusting Coronavirus Prevalence Estimates for Laboratory Test Kit Error. American journal of epidemiology Sempos, C. T., Tian, L. 2020

  Abstract

  Testing representative populations to determine the prevalence or percent of the population with active SARS-Cov-2 infection and/or antibodies to infection is being recommended as essential for making public policy decisions to open-up or to continue enforcing national, state and local government rules to "shelter-in-place". However, all laboratory tests are imperfect and have estimates of sensitivity and specificity less than 100% - in some cases considerably less than 100%. That error will lead to biased prevalence estimates. If the true prevalence is low, possibly in the range of 1-5%, then testing error will lead to a constant background of bias that will most likely be larger and possibly much larger than the true prevalence itself. As a result, what is needed is a method for adjusting prevalence estimates for testing error. In this paper we outline methods for adjusting prevalence estimates for testing error both prospectively in studies being planned and retrospectively in studies that have been conducted. The methods if employed would also help to harmonize study results within countries and world-wide. Adjustment can lead to more accurate prevalence estimates and to better policy decisions. However, adjustment will not improve the accuracy of an individual test.

  View details for DOI 10.1093/aje/kwaa174

  View details for PubMedID 32803245

• Associations of Poly (ADP-Ribose) Polymerase1 abundance in calf skeletal muscle with walking performance in peripheral artery disease. Experimental gerontology Saini, S. K., Li, L., Peek, C. B., Kosmac, K., Polonsky, T. S., Tian, L., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Kibbe, M., Sufit, R. L., Leeuwenburgh, C., McDermott, M. M. 2020: 111048

  Abstract

  OBJECTIVE: This study investigated associations of markers of oxidative stress and mitochondrial function in calf muscle biopsies with walking performance in people with and without lower extremity peripheral artery disease (PAD).METHODS: Participants with PAD (ankle-brachial index (ABI) <0.90) and without PAD (ABI: 0.90-1.50) underwent calf muscle biopsy and measurement of 6-min walk and four-meter walking velocity. PARP1 (Poly (ADP-Ribose) Polymerase 1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), silent information regulator 1 (SIRT1) and 4-hydroxynonenal (4HNE) expression were measured in calf muscle using western blot.RESULTS: Among 15 participants with PAD mean age: 66.8 years (standard deviation (SD): 6.4) and six without PAD (age: 64.4 years, SD: 5.9), mean PARP1-abundance in calf muscle was 1.16 ± 0.92 AU and 0.96 ± 0.38 AU, respectively (P = 0.61). Among participants with PAD after adjustment with ABI, a greater abundance of PARP1 was associated with poorer 6-min walking distance (r = -0.65, P = 0.01), usual-paced 4-m walking velocity (r = -0.73, P = 0.003) and slower fast-paced four-meter walking velocity (r = -0.50, P = 0.07). Among participants with PAD, ABI was not associated with PARP1 abundance in calf muscle (r = 0.02, P = 0.93). Among participants without PAD, skeletal muscle PARP1 abundance was not significantly associated with 6-min walk distance (r = -0.58; P = 0.22), usual-paced walking velocity (r = -0.26; P = 0.62), or fast-paced walking velocity (r = -0.21; P = 0.70), perhaps due to lack of statistical power. There were no associations of remaining calf muscle measures with walking performance.CONCLUSIONS: These findings are consistent with the hypothesis that calf skeletal muscle characteristics are related to walking performance, independently of severity of lower extremity arterial obstruction in people with PAD.

  View details for DOI 10.1016/j.exger.2020.111048

  View details for PubMedID 32755612

• White Matter Hyperintensities Related to Parkinson's Disease Executive Function. Movement disorders clinical practice Linortner, P., McDaniel, C., Shahid, M., Levine, T. F., Tian, L., Cholerton, B., Poston, K. L. 2020; 7 (6): 629-638

  Abstract

  People with Parkinson's disease (PD) can develop multidomain cognitive impairments; however, it is unclear whether different pathologies underlie domain-specific cognitive dysfunction.We investigated the contribution of vascular copathology severity and location, as measured by MRI white matter hyperintensities (WMHs), to domain-specific cognitive impairment in PD.We studied 85 PD (66.6 ± 9.2 years) and 18 control (65.9 ± 6.6) participants. Using the Fazekas scale for rating the severity of WMH, we subdivided PD into 14 PD-WMH+ and 71 PD-WMH-. Participants underwent global, executive, visuospatial, episodic memory, and language testing. We performed nonparametric permutation testing to create WMH probability maps based on PD-WMH group and cognitive test performance.The PD-WMH+ group showed worse global and executive cognitive performance than the PD-WMH- group. On individual tests, the PD-WMH+ group showed worse Montreal Cognitive Assessment (MoCA), Stroop, Symbol Digit Modalities Test (SDMT), and Digit Span scores. WMH probability maps showed that in the PD-WMH+ group, worse Stroop was associated with lesions centered around the corticospinal tract (CST), forceps major, inferior-fronto-occipital fasciculus, and superior longitudinal fasciculus; worse SDMT with lesions around the CST, forceps major, and posterior corona radiata; worse Digit Span with lesions around the posterior corona radiata; and worse MoCA with lesions around the CST.We found that WMH severity was associated with PD executive dysfunction, including worse attention, working memory, and processing speed. Disruption of key white matter tracts in proximity to vascular lesions could contribute to these specific cognitive impairments. Early treatment of vascular disease might mitigate some executive dysfunction in a subset of patients with PD.

  View details for DOI 10.1002/mdc3.12956

  View details for PubMedID 32775508

  View details for PubMedCentralID PMC7396844

• Analysis of Response Data for Assessing Treatment Effects in Comparative Clinical Studies. Annals of internal medicine Huang, B., Tian, L., McCaw, Z. R., Luo, X., Talukder, E., Rothenberg, M., Xie, W., Choueiri, T. K., Kim, D. H., Wei, L. 2020

  Abstract

  In comparative studies, treatment effect is often assessed using a binary outcome that indicates response to the therapy. Commonly used summary measures for response include the cumulative and current response rates at a specific time point. The current response rate is sometimes called the probability of being in response (PBIR), which regards a patient as a responder only if they have achieved and remain in response at present. The methods used in practice for estimating these rates, however, may not be appropriate. Moreover, whereas an effective treatment is expected to achieve a rapid and sustained response, the response at a fixed time point does not provide information about the duration of response (DOR). As an alternative, a curve constructed from the current response rates over the entire study period may be considered, which can be used for visualizing how rapidly patients responded to therapy and how long responses were sustained. The area under the PBIR curve is the mean DOR. This connection between response and DOR makes this curve attractive for assessing the treatment effect. In contrast to the conventional method for analyzing the DOR data, which uses responders only, the above procedure includes all patients in the study. Although discussed extensively in the statistical literature, estimation of the current response rate curve has garnered little attention in the medical literature. This article illustrates how to construct and analyze such a curve using data from a recent study for treating renal cell carcinoma. Clinical trialists are encouraged to consider this robust and clinically interpretable procedure as an additional tool for evaluating treatment effects in clinical studies.

  View details for DOI 10.7326/M20-0104

  View details for PubMedID 32628533

• Estimation and Validation of Ratio-based Conditional Average Treatment Effects Using Observational Data JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Yadlowsky, S., Pellegrini, F., Lionetto, F., Braune, S., Tian, L. 2020

  View details for DOI 10.1080/01621459.2020.1772080

  View details for Web of Science ID 000547542500001

• Correlations of Calf Muscle Macrophage Content With Muscle Properties and Walking Performance in Peripheral Artery Disease. Journal of the American Heart Association Kosmac, K., Gonzalez-Freire, M., McDermott, M. M., White, S. H., Walton, R. G., Sufit, R. L., Tian, L., Li, L., Kibbe, M. R., Criqui, M. H., Guralnik, J. M., S Polonsky, T., Leeuwenburgh, C., Ferrucci, L., Peterson, C. A. 2020: e015929

  Abstract

  Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2-like macrophages positively correlated to satellite cell number (r=0.461 [P=0.023] and r=0.416 [P=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206- macrophages negatively correlated to 4-meter walk tests at normal (r=-0.447, P=0.036) and fast pace (r=-0.510, P=0.014). Extracellular matrix occupied more muscle area in PAD compared with non-PAD (8.72±2.19% versus 5.30±1.03%, P<0.001) and positively correlated with capillary density (r=0.656, P<0.001). Conclusions Among people with PAD, higher CD206+ M2-like macrophage abundance was associated with greater satellite cell numbers and muscle fiber size. Lower CD206- macrophage abundance was associated with better walking performance. Further study is needed to determine whether CD206+ macrophages are associated with ongoing reparative processes enabling skeletal muscle adaptation to damage with PAD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: NCT00693940, NCT01408901, NCT0224660.

  View details for DOI 10.1161/JAHA.118.015929

  View details for PubMedID 32390569

• Fulvestrant plus capivasertib for metastatic breast cancer LANCET ONCOLOGY Ludmir, E. B., McCaw, Z. R., Kim, D., Tian, L., Wei, L. 2020; 21 (5): E233

  View details for Web of Science ID 000540084200009

• White Matter Hyperintensities Related to Parkinson's Disease Executive Function MOVEMENT DISORDERS CLINICAL PRACTICE Linortner, P., McDaniel, C., Shahid, M., Levine, T. F., Tian, L., Cholerton, B., Poston, K. L. 2020

  View details for DOI 10.1002/mdc3.12956

  View details for Web of Science ID 000529623200001

• Association of six-minute walk distance with subsequent lower extremity events in peripheral artery disease. Vascular medicine (London, England) Nayak, P., Guralnik, J. M., Polonsky, T. S., Kibbe, M. R., Tian, L., Zhao, L., Criqui, M. H., Ferrucci, L., Li, L., Zhang, D., McDermott, M. M. 2020: 1358863X20901599

  Abstract

  The prognostic significance of the six-minute walk distance for lower extremity events in people with peripheral artery disease (PAD) is unknown. This longitudinal study assessed whether a poorer six-minute walk distance at baseline was associated with higher rates of subsequent lower extremity atherosclerotic disease events in PAD. A total of 369 patients (mean age 69.4 ± 10.0 years; mean ankle-brachial index (ABI) 0.67 ± 0.17; 31% women; 30% black individuals) from Chicago-area medical centers with PAD were enrolled. Participants underwent baseline six-minute walk testing and returned for annual study visits. Lower extremity events consisted of one or more of the following: ABI decline greater than 15% or medical record adjudicated lower extremity revascularization, critical limb ischemia, or amputation. At a mean follow-up of 33.3 months, lower extremity events occurred in 66/123 (53.7%) people in the first (worst) tertile of six-minute walk performance, 55/124 (44.4%) in the second tertile, and 56/122 (45.9%) in the third (best) tertile. After adjusting for age, sex, race, ABI, comorbidities, and other confounders, participants in the first (worst) tertile of six-minute walk distance at baseline had higher rates of lower extremity events during follow-up, compared to those in the best tertile at baseline (HR = 1.74, 95% CI 1.17-2.60, p = 0.0067). Among people with PAD, a poorer six-minute walk distance was associated with higher rates of subsequent lower extremity PAD-related events after adjusting for confounders. Further study is needed to determine whether interventions that improve six-minute walk distance can reduce lower extremity adverse events in people with PAD.

  View details for DOI 10.1177/1358863X20901599

  View details for PubMedID 32338582

• MEANINGFUL CHANGE IN SIX-MINUTE WALK IN PEOPLE WITH PERIPHERAL ARTERY DISEASE. Journal of vascular surgery McDermott, M. M., Tian, L., Criqui, M. H., Ferrucci, L., Conte, M. S., Zhao, L., Li, L., Sufit, R., Polonsky, T. S., Kibbe, M. R., Greenland, P., Leeuwenburgh, C., Guralnik, J. M. 2020

  Abstract

  OBJECTIVE: Six-minute walk is a common outcome in clinical trials of people with lower extremity peripheral artery disease (PAD). However, meaningful change in six-minute walk distance is not well defined in people with PAD. This study related change in six-minute walk distance corresponding to the degree of participant reported improvement or decline in six-minute walk distance, in order to define meaningful change in 6-minute walk distance in people with PAD.METHODS: PAD participants from three observational longitudinal studies completed the walking impairment questionnaire (WIQ) distance score and six-minute walk at baseline and one year later. The WIQ distance score measures participants' perceived difficulty walking seven different distances without stopping (ranging from walking around the home to five blocks) on a 0 to 4 Likert scale, where 0 represents inability to walk the distance and 4 represents no difficulty. Mean changes in six-minute walk distance corresponding to participant report of no change, one unit change, or two unit change, respectively, in the 0-4 Likert scale between baseline and one-year follow-up were calculated for each WIQ distance .RESULTS: 777 participants with PAD (mean age: 71.2 years (standard deviation (SD)=8.8) mean baseline six-minute walk: 350.1 meters (SD=118.1) completed 5,439 questions about difficulty walking each WIQ distance at baseline and follow-up. Participants with PAD who reported no change in difficulty walking each WIQ distance between baseline and follow-up declined by 7.2 meters (95% CI: -11.6, -2.8) in the six-minute walk test. Relative to people reporting no change in difficulty walking, people reporting one and two point improvements in walking ability (0-4 scale) had six-minute walk distance improvements of 7.8 meters (95% CI:-0.3, +15.9) and 20.1 meters (95% CI: +1.1, +39.2), respectively. Relative to people reporting no change in walking difficulty, those reporting one and two point declines in perceived walking difficulty corresponded to -11.2 meter (-95% CI:-19.0, -3.4) and -23.8 meter (95% CI:-37.4, -10.3) declines in six-minute walk distance.CONCLUSIONS: Among people with PAD, approximately 8 and 20 meter improvements in six-minute walk distance, respectively, represent small and large improvements in walking ability, respectively. People with PAD who reported no change in their ability to walk distances over one year simultaneously declined by a mean of seven meters in the six-minute walk test. These findings are useful for interpreting results of randomized trials of interventions to improve walking performance in people with PAD.

  View details for DOI 10.1016/j.jvs.2020.03.052

  View details for PubMedID 32335305

• Is the Log-Rank and Hazard Ratio Test/Estimation the Best Approach for Primary Analysis for All Trials? Journal of clinical oncology : official journal of the American Society of Clinical Oncology Uno, H., Tian, L. 2020: JCO1903097

  View details for DOI 10.1200/JCO.19.03097

  View details for PubMedID 32315272

• Associations of Peripheral Artery Disease With Calf Skeletal Muscle Mitochondrial DNA Heteroplasmy. Journal of the American Heart Association Gonzalez-Freire, M., Moore, A. Z., Peterson, C. A., Kosmac, K., McDermott, M. M., Sufit, R. L., Guralnik, J. M., Polonsky, T., Tian, L., Kibbe, M. R., Criqui, M. H., Li, L., Leeuwenburgh, C., Ferrucci, L. 2020; 9 (7): e015197

  Abstract

  Background Patients with peripheral artery disease (PAD) undergo frequent episodes of ischemia-reperfusion in lower extremity muscles that may negatively affect mitochondrial health and are associated with impaired mobility. We hypothesized that skeletal muscle from PAD patients will show high mitochondrial DNA heteroplasmy, especially in regions more susceptible to oxidative damage, such as the displacement loop, and that the degree of heteroplasmy will be correlated with the severity of ischemia and mobility impairment. Methods and Results Mitochondrial mutations and deletions and their relative abundance were identified by targeted mitochondrial DNA sequencing in biopsy specimens of gastrocnemius muscle from 33 PAD (ankle brachial index <0.9) and 9 non-PAD (ankle brachial index >0.9) subjects aged ≥60years. The probability of heteroplasmy per DNA base was significantly higher for PAD subjects than non-PAD within each region. In adjusted models, PAD was associated with higher heteroplasmy than non-PAD (P=0.003), but the association was limited to microheteroplasmy, that is heteroplasmy found in 1% to 5% of all mitochondrial genomes (P=0.004). Heteroplasmy in the displacement loop and coding regions were significantly higher for PAD than non-PAD subjects after adjustment for age, sex, race, and diabetes mellitus (P=0.037 and 0.004, respectively). Low mitochondrial damage, defined by both low mitochondrial DNA copy number and low microheteroplasmy, was associated with better walking performance. Conclusions People with PAD have higher "low frequency" heteroplasmy in gastrocnemius muscle compared with people without PAD. Among people with PAD, those who had evidence of least mitochondrial damage, had better walking performance than those with more mitochondrial damage. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02246660.

  View details for DOI 10.1161/JAHA.119.015197

  View details for PubMedID 32200714

• Assessing the value of a censored surrogate outcome LIFETIME DATA ANALYSIS Parast, L., Tian, L., Cai, T. 2020; 26 (2): 245–65

  View details for DOI 10.1007/s10985-019-09473-1

  View details for Web of Science ID 000521748000002

• Model-free approach to quantifying the proportion of treatment effect explained by a surrogate marker BIOMETRIKA Wang, X., Parast, L., Tian, L., Cai, T. 2020; 107 (1): 107–22

  View details for DOI 10.1093/biomet/asz065

  View details for Web of Science ID 000526004000007

• Model-free approach to quantifying the proportion of treatment effect explained by a surrogate marker. Biometrika Wang, X., Parast, L., Tian, L. U., Cai, T. 2020; 107 (1): 107-122

  Abstract

  In randomized clinical trials, the primary outcome, Y, often requires long-term follow-up and/or is costly to measure. For such settings, it is desirable to use a surrogate marker, S, to infer the treatment effect on Y, Δ. Identifying such an S and quantifying the proportion of treatment effect on Y explained by the effect on S are thus of great importance. Most existing methods for quantifying the proportion of treatment effect are model based and may yield biased estimates under model misspecification. Recently proposed nonparametric methods require strong assumptions to ensure that the proportion of treatment effect is in the range [0, 1]. Additionally, optimal use of S to approximate Δ is especially important when S relates to Y nonlinearly. In this paper we identify an optimal transformation of S, g opt(·), such that the proportion of treatment effect explained can be inferred based on g opt(S). In addition, we provide two novel model-free definitions of proportion of treatment effect explained and simple conditions for ensuring that it lies within [0, 1]. We provide nonparametric estimation procedures and establish asymptotic properties of the proposed estimators. Simulation studies demonstrate that the proposed methods perform well in finite samples. We illustrate the proposed procedures using a randomized study of HIV patients.

  View details for DOI 10.1093/biomet/asz065

  View details for PubMedID 32587413

  View details for PubMedCentralID PMC7315285

• Immune cell repertoires in breast cancer patients after adjuvant chemotherapy. JCI insight Gustafson, C. E., Jadhav, R., Cao, W., Qi, Q., Pegram, M., Tian, L., Weyand, C. M., Goronzy, J. J. 2020; 5 (4)

  Abstract

  Adjuvant chemotherapy in breast cancer patients causes immune cell depletion at an age when the regenerative capacity is compromised. Successful regeneration requires the recovery of both quantity and quality of immune cell subsets. Although immune cell numbers rebound within a year after treatment, it is unclear whether overall compositional diversity is recovered. We investigated the regeneration of immune cell complexity by comparing peripheral blood mononuclear cells from breast cancer patients ranging from 1-5 years after chemotherapy with those of age-matched healthy controls using mass cytometry and T cell receptor sequencing. These data reveal universal changes in patients' CD4+ T cells that persisted for years and consisted of expansion of Th17-like CD4 memory populations with incomplete recovery of CD4+ naive T cells. Conversely, CD8+ T cells fully recovered within a year. Mechanisms of T cell regeneration, however, were unbiased, as CD4+ and CD8+ T cell receptor diversity remained high. Likewise, terminal differentiated effector memory cells were not expanded, indicating that regeneration was not driven by recognition of latent viruses. These data suggest that, while CD8+ T cell immunity is successfully regenerated, the CD4 compartment may be irreversibly affected. Moreover, the bias of CD4 memory toward inflammatory effector cells may impact responses to vaccination and infection.

  View details for DOI 10.1172/jci.insight.134569

  View details for PubMedID 32102986

• Nonparametric estimation of risk tracking indices for longitudinal studies STATISTICAL METHODS IN MEDICAL RESEARCH Wu, C. O., Tian, X., Tian, L., Reis, J. P., Zhao, L., Allen, N. B., Bae, S., Liu, K. 2020; 29 (2): 481–97

  View details for DOI 10.1177/0962280219839427

  View details for Web of Science ID 000513264200011

• Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease. Pediatric pulmonology Robinson, T. E., Goris, M. L., Moss, R. B., Tian, L., Kan, P., Yilma, M., McCoy, K. S., Newman, B., de Jong, P. A., Long, F. R., Brody, A. S., Behrje, R., Yates, D. P., Cornfield, D. N. 2020

  Abstract

  OBJECTIVE: To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements.METHODS: Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1second (ppFEV1 ) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years.RESULTS: No significant changes were noted at 3-month for any variable except for decreased ppFEV1 . Mucus plugging score (MPS) and QATA1 and A2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1 , were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS.CONCLUSIONS: MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis.

  View details for DOI 10.1002/ppul.24646

  View details for PubMedID 31962004

• Fulvestrant plus capivasertib for metastatic breast cancer. The Lancet. Oncology Ludmir, E. B., McCaw, Z. R., Kim, D. H., Tian, L. n., Wei, L. J. 2020; 21 (5): e233

  View details for DOI 10.1016/S1470-2045(20)30228-X

  View details for PubMedID 32359498

• Multivariate prediction of dementia in Parkinson's disease. NPJ Parkinson's disease Phongpreecha, T., Cholerton, B., Mata, I. F., Zabetian, C. P., Poston, K. L., Aghaeepour, N., Tian, L., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S. C., Edwards, K. L., Montine, T. J. 2020; 6 (1): 20

  Abstract

  Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

  View details for DOI 10.1038/s41531-020-00121-2

  View details for PubMedID 34429432

• Cerebral Oxygenation and Autoregulation in Preterm Infants (Early NIRS Study). The Journal of pediatrics Chock, V. Y., Kwon, S. H., Ambalavanan, N. n., Batton, B. n., Nelin, L. D., Chalak, L. F., Tian, L. n., Van Meurs, K. P. 2020

  Abstract

  To determine if decreased cerebral oxygenation or altered cerebral autoregulation as measured by near-infrared spectroscopy (NIRS) in the first 96 postnatal hours is associated with an increased risk of death or severe neuroradiographic abnormalities in very preterm infants.The Early NIRS prospective, multi-center study enrolled very preterm infants with birth weight <1250 g from 6 tertiary neonatal intensive care units. Mean arterial blood pressure (MAP) and cerebral oxygen saturation (Csat) were continuously monitored using a neonatal sensor until 96 hours of age. Moving window correlations between Csat and MAP determined time periods with altered cerebral autoregulation, and percentiles of correlation were compared between infants with and without the adverse outcome of mortality or severe neuroradiographic abnormalities by early cranial ultrasound.Of 103 subjects with mean gestational age of 26 weeks, 21 (20%) died or had severe neuroradiographic abnormalities. Infants with adverse outcomes had a lower mean Csat (67 ± 9%) compared with those without adverse outcomes (72 ± 7%, P = .02). Csat <50% was identified as a cut-point for identifying infants with adverse outcome (AUC =0.76). Infants with adverse outcomes were more likely to have significant positive or negative correlations between Csat and MAP, indicating impaired cerebral autoregulation (p=0.006).Early NIRS monitoring may detect periods of lower cerebral oxygenation and altered cerebral autoregulation, identifying preterm infants at risk for mortality or neuroradiographic injury. Improved understanding of the relationship between altered hemodynamics and cerebral oxygenation may inform future strategies to prevent brain injury.

  View details for DOI 10.1016/j.jpeds.2020.08.036

  View details for PubMedID 32818482

• A data capture model and its associate study on the public web published COVID-19 data Liang, Z., Zhang, P., Liu, B., Xu, N., Tian, L., Lu, Y., Park, T., Cho, Y. R., Hu, Yoo, Woo, H. G., Wang, J., Facelli, J., Nam, S., Kang, M. IEEE COMPUTER SOC. 2020: 2005-2008

  View details for DOI 10.1109/BIBM49941.2020.9313399

  View details for Web of Science ID 000659487102011

• Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The Cocoa-Pad Pilot Randomized Clinical Trial. Circulation research McDermott, M. M., Criqui, M. H., Domanchuk, K. n., Ferrucci, L. n., Guralnik, J. M., Kibbe, M. n., Kosmac, K. n., Kramer, C. M., Leeuwenburgh, C. n., Li, L. n., Lloyd-Jones, D. M., Peterson, C. A., Polonsky, T. S., Stein, J. H., Sufit, R. n., Van Horn, L. V., Villarreal, F. J., Zhang, D. n., Zhao, L. n., Tian, L. n. 2020

  Abstract

  Rationale: Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD). Objective: In a phase II randomized clinical trial, to assess whether six months of cocoa improved walking performance in people with PAD, compared to placebo. Methods and Results: Six-month double blind randomized clinical trial in which participants with PAD were randomized to either cocoa beverage vs. placebo beverage. The cocoa beverage contained 15 grams of cocoa and 75 mgs of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The two primary outcomes were six-month change in six-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A one-sided P value <0.10 was considered statistically significant. Of 44 PAD participants randomized (mean age: 72.3 years (+7.1), mean ankle brachial index 0.66 (+0.15)), 40 (91%) completed follow-up. Adjusting for smoking, race, and body mass index, cocoa improved six-minute walk distance at 6-month follow-up by 42.6 meters (90% Confidence Interval (CI): +22.2,+∞, P=0.005) at 2.5 hours after a final study beverage and by 18.0 meters (90% CI:-1.7, +∞, P=0.12) at 24 hours after a study beverage, compared to placebo. In calf muscle biopsies, cocoa improved mitochondrial cytochrome c oxidase activity (P=0.013), increased capillary density (P=0.014), improved calf muscle perfusion (P=0.098), and reduced central nuclei (P=0.024), compared to placebo. Conclusions: These preliminary results suggest a therapeutic effect of cocoa on walking performance in people with PAD. Further study is needed to definitively determine whether cocoa significantly improves walking performance in people with PAD. Clinical Trial Registration: NCT02876887.

  View details for DOI 10.1161/CIRCRESAHA.119.315600

  View details for PubMedID 32078436

• Clinical Characteristics and Response to Supervised Exercise Therapy in People with Lower Extremity Peripheral Artery Disease. Journal of vascular surgery Patel, K. n., Polonsky, T. S., Kibbe, M. R., Guralnik, J. M., Tian, L. n., Ferrucci, L. n., Criqui, M. H., Sufit, R. n., Leeuwenburgh, C. n., Zhang, D. n., Zhao, L. n., McDermott, M. M. 2020

  Abstract

  Among people with lower extremity peripheral artery disease (PAD), little is known about variation in response to supervised exercise therapy (SET). Clinical characteristics associated with greater responsiveness to SET have not been identified.Data from participants with PAD in two randomized clinical trials comparing SET vs. non-exercising control were combined. The exercise intervention consisted of three times weekly supervised treadmill exercise. The control groups received lectures on health-related topics.Of 309 unique participants randomized (mean age 67.9 (standard deviation (SD) =9.3), 132 (42.7%) women, 185 (59.9%) black), 285 (92%) completed six-month follow-up. Compared to control, those randomized to SET improved six-minute walk distance by 35.6 meters (95% confidence interval (CI) = +21.4,+49.8, P<0.001). In the 95 (62.1%) participants who attended at least 70% of SET sessions, change in six-minute walk distance varied from -149.4 to +356.0 meters. Thirty-four (35.8%) had no six-minute walk distance improvement. Among all participants, age, sex, race, body mass index, prior lower extremity revascularization and other clinical characteristics did not affect the degree of improvement in six-minute walk distance after SET, relative to the control group. Participants with six-minute walk distance less than the median of 334 meters at baseline had greater percent improvement in six-minute walk distance compared to those with baseline six-minute walk distance above the median (+20.5% vs. +5.3%, P for interaction= 0.0107).Among people with PAD, substantial variability exists in walking improvement after SET. Shorter 6-minute walk distance at baseline was associated with greater improvement after SET, but other clinical characteristics, including age, sex, prior lower extremity revascularization, and disease severity, did not affect responsiveness to exercise therapy.

  View details for DOI 10.1016/j.jvs.2020.04.498

  View details for PubMedID 32416309

• Mitochondrial DNA damage in calf skeletal muscle and walking performance in people with peripheral artery disease. Free radical biology & medicine Saini, S. K., McDermott, M. M., Picca, A. n., Li, L. n., Wohlgemuth, S. E., Kosmac, K. n., Peterson, C. A., Tian, L. n., Ferrucci, L. n., Guralnik, J. M., Sufit, R. L., Leeuwenburgh, C. n. 2020

  Abstract

  Peripheral artery disease (PAD) is associated with mitochondrial dysfunction in calf skeletal muscle and a greater abundance of mitochondrial DNA (mtDNA) heteroplasmy. However, it is unknown whether calf skeletal muscle mtDNA of PAD participants harbors a greater abundance of mitochondrial DNA 4977-bp common deletion (mtDNA4977), strand breaks and oxidative damage (i.e., oxidized purines) compared to non-PAD participants and whether these mtDNA abnormalities are associated with poor walking performance in participants with PAD.Calf muscle biopsies were obtained from 50 PAD participants (ankle-brachial index (ABI) < 0.95) and 25 non-PAD participants (ABI = 0.99-1.40) matched by age, sex, and race. The abundance of mtDNA copy number, mtDNA4977 deletion, strand breaks, and oxidized purines in selected mtDNA regions coding for electron transport chain (ETC) constituents and the non-coding D-Loop region was determined in calf muscle. All participants completed measurement of six-minute walk and usual and fast-paced four-meter walking velocity test.Participants with PAD (mean age = 65.4 years, SD = 6.9; 14 (28%) women, 38 (76%) black) and without PAD (mean age = 65.2 years, SD = 6.7; 7 (28%) women, 16 (64%) black) did not differ in the abundance of calf muscle mtDNA4977 deletion, mtDNA strand breaks, and oxidized purines. Though, a greater abundance of mtDNA strand breaks within ND4/5 genes was significantly associated with poorer six-minute walk distance, lower usual-paced four-meter walking velocity, and lower fast-paced four-meter walking velocity in non-PAD participants. Significant associations were also found in the density of strand break damage (i.e., damage per mtDNA copy) within ND1/2, ND4/5 and COII/ATPase 6/8 region with six-minute walk distance, usual-paced four-meter walking velocity and fast-paced four-meter walking velocity in non-PAD participants. Significant interactions were found between PAD presence vs. absence and density of strand break damage within ND1/2, ND4/5, COII/ATPase 6/8 regions for the associations with six-minute walk distance, usual-paced four-meter walking velocity, fast-paced four-meter walking velocity. Conversely, of the three walking performance measures only the usual-paced four-meter walking velocity showed a significant, although modest, negative association with the abundance of oxidized purines in the D-Loop (P=0.031) and ND4/5 (P=0.033) regions in the calf skeletal muscle of people with PAD.Overall, these data suggest that the abundance of calf muscle mtDNA strand breaks and mtDNA4977 common deletion are not associated with walking performance in people with PAD and may not be directly involved in the pathophysiology of PAD. Conversely, strand breaks in specific mtDNA regions may contribute to poor walking performance in people without PAD. Further study is needed to confirm whether usual-paced four-meter walking velocity is associated significantly with a greater abundance of oxidized purines in the D-loop, a "mutational hotspot" for oxidative damage, and why this association may differ from the association with six-minute walk distance and fast-paced four-meter walking velocity.

  View details for DOI 10.1016/j.freeradbiomed.2020.09.004

  View details for PubMedID 32911084

• Response to the letter by Guogen Shan, Hua Zhang, and Tao Jiang. Statistics in medicine Gronsbell, J. n., Tian, L. n. 2020; 39 (22): 3024–25

  View details for DOI 10.1002/sim.8583

  View details for PubMedID 32914464

• Effect of Electroacupuncture vs Sham Treatment on Change in Pain Severity Among Adults With Chronic Low Back Pain: A Randomized Clinical Trial. JAMA network open Kong, J. T., Puetz, C. n., Tian, L. n., Haynes, I. n., Lee, E. n., Stafford, R. S., Manber, R. n., Mackey, S. n. 2020; 3 (10): e2022787

  Abstract

  Chronic low back pain has high societal and personal impact but remains challenging to treat. Electroacupuncture has demonstrated superior analgesia compared with placebo in animal studies but has not been extensively studied in human chronic pain conditions.To evaluate the treatment effect of real electroacupuncture vs placebo in pain and disability among adults with chronic low back pain and to explore psychophysical, affective, and demographic factors associated with response to electroacupuncture vs placebo in treating chronic low back pain.This double-blind randomized clinical trial was conducted between August 2, 2016, and December 18, 2018, at a single center in Stanford, California. Primary outcomes were collected at approximately 2 weeks before and after intervention. Participants included English-speaking adults with at least 6 months of chronic low back pain, pain intensity of at least 4 on a scale of 0 to 10, and no radiculopathy. Data analyses for this intent-to-treat study were conducted from June 2019 to June 2020.Twelve sessions of real or placebo (sham) electroacupuncture administered twice a week over 6 weeks.The main outcome was change in pain severity from baseline to 2 weeks after completion of treatment, measured by the National Institutes of Health PROMIS pain intensity scale. A secondary outcome was change in the Roland Morris Disability Questionnaire (RMDQ). Baseline factors potentially associated with these outcomes included psychophysical testing (ie, thermal temporal summation, conditioned pain modulation, pressure pain threshold), participant's self-report (ie, widespread pain, coping strategies, expectations, self-efficacy, and pain catastrophizing), and demographic characteristics (eg, age, sex, and race).A total of 121 adults were recruited to the study, among whom 59 participants (mean [SD] age, 46.8 [11.9] years; 36 [61.0%] women) were randomized to real electroacupuncture and 62 participants (mean [SD] age, 45.6 [12.8] years; 33 [53.2%] women) were randomized to sham electroacupuncture. At baseline, the mean (SD) PROMIS T-score was 50.49 (3.36) in the real electroacupuncture group and 51.71 (4.70) in the sham acupuncture group, and the mean (SD) RMDQ score was 10.16 (4.76) in the real electroacupuncture group and 10.03 (5.45) in the sham acupuncture group. After adjusting for baseline pain scores, there was no statistically significant difference between groups in change in T-scores 2 weeks after completion of treatment (real electroacupuncture: -4.33; 95% CI, -6.36 to -2.30; sham acupuncture: -2.90; 95% CI, -4.85 to -0.95; difference: -2.09; 95% CI, -4.27 to 0.09; P = .06). After adjusting for baseline RMDQ, there was a significantly greater reduction in RMDQ in the real electroacupuncture group (-2.77; 95% CI, -4.11 to -1.43) compared with the sham electroacupuncture group (-0.67; 95% CI, -1.88 to 0.55; difference: -2.11; 95% CI, -3.75 to -0.47; P = .01). Within the real electroacupuncture group, effective coping at baseline was associated with greater RMDQ reduction (r = -0.32; 95% CI, -0.54 to -0.05; P = .02), and White race was associated with worse outcomes in PROMIS score (β = 3.791; 95% CI, 0.616 to 6.965; P = .02) and RMDQ (β = 2.878; 95% CI, 0.506 to 5.250; P = .02).This randomized clinical trial found no statistically significant difference in change in PROMIS pain score in real electroacupuncture vs sham electroacupuncture. There was a statistically significant treatment effect for the secondary outcome of RMDQ compared with sham electroacupuncture. Effective coping skills and non-White race were associated with response to electroacupuncture.ClinicalTrials.gov Identifier: NCT02890810.

  View details for DOI 10.1001/jamanetworkopen.2020.22787

  View details for PubMedID 33107921

• On the empirical choice of the time window for restricted mean survival time. Biometrics Tian, L. n., Jin, H. n., Uno, H. n., Lu, Y. n., Huang, B. n., Anderson, K. M., Wei, L. J. 2020

  Abstract

  The t-year mean survival or restricted mean survival time (RMST) has been used as an appealing summary of the survival distribution within a time window [0, t]. RMST is the patient's life expectancy until time t and can be estimated nonparametrically by the area under the Kaplan-Meier curve up to t. In a comparative study, the difference or ratio of two RMSTs has been utilized to quantify the between-group-difference as a clinically interpretable alternative summary to the hazard ratio. The choice of the time window [0, t] may be pre-specified at the design stage of the study based on clinical considerations. On the other hand, after the survival data have been collected, the choice of time point t could be data-dependent. The standard inferential procedures for the corresponding RMST, which is also data-dependent, ignore this subtle yet important issue. In this paper, we clarify how to make inference about a random "parameter." Moreover, we demonstrate that under a rather mild condition on the censoring distribution, one can make inference about the RMST up to t, where t is less than or even equal to the largest follow-up time (either observed or censored) in the study. This finding reduces the subjectivity of the choice of t empirically. The proposal is illustrated with the survival data from a primary biliary cirrhosis study, and its finite sample properties are investigated via an extensive simulation study. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/biom.13237

  View details for PubMedID 32061098

• Risk of pre-term births and major birth defects resulting from paternal intake of COVID-19 medications prior to conception. Research square Rizzi, S. n., Wensink, M. J., Lindahl-Jacobsen, R. n., Tian, L. n., Lu, Y. n., Eisenberg, M. n. 2020

  Abstract

  With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the three months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). There is strong evidence that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. With some caution, the other drugs investigated can be considered safe.

  View details for DOI 10.21203/rs.3.rs-59420/v1

  View details for PubMedID 32869015

  View details for PubMedCentralID PMC7457584

• Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia. PloS one Hao, S. n., You, J. n., Chen, L. n., Zhao, H. n., Huang, Y. n., Zheng, L. n., Tian, L. n., Maric, I. n., Liu, X. n., Li, T. n., Bianco, Y. K., Winn, V. D., Aghaeepour, N. n., Gaudilliere, B. n., Angst, M. S., Zhou, X. n., Li, Y. M., Mo, L. n., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Mcelhinney, D. B., Sylvester, K. G., Ling, X. B. 2020; 15 (3): e0230000

  Abstract

  Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice.An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs.Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

  View details for DOI 10.1371/journal.pone.0230000

  View details for PubMedID 32126118

• Appropriate Analysis of Duration of Response Data in Cancer Trials. JAMA oncology McCaw, Z. R., Tian, L. n., Wei, L. J. 2020

  View details for DOI 10.1001/jamaoncol.2020.4657

  View details for PubMedID 33030502

• Multivariate prediction of dementia in Parkinson's disease. NPJ Parkinson's disease Phongpreecha, T. n., Cholerton, B. n., Mata, I. F., Zabetian, C. P., Poston, K. L., Aghaeepour, N. n., Tian, L. n., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S. C., Edwards, K. L., Montine, T. J. 2020; 6: 20

  Abstract

  Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

  View details for DOI 10.1038/s41531-020-00121-2

  View details for PubMedID 32885039

  View details for PubMedCentralID PMC7447766

• How to Quantify and Interpret Treatment Effects in Comparative Clinical Studies of COVID-19. Annals of internal medicine McCaw, Z. R., Tian, L. n., Vassy, J. L., Ritchie, C. S., Lee, C. C., Kim, D. H., Wei, L. J. 2020

  Abstract

  Clinical trials of treatments for coronavirus disease 2019 (COVID-19) draw intense public attention. More than ever, valid, transparent, and intuitive summaries of the treatment effects, including efficacy and harm, are needed. In recently published and ongoing randomized comparative trials evaluating treatments for COVID-19, time to a positive outcome, such as recovery or improvement, has repeatedly been used as either the primary or key secondary end point. Because patients may die before recovery or improvement, data analysis of this end point faces a competing risk problem. Commonly used survival analysis techniques, such as the Kaplan-Meier method, often are not appropriate for such situations. Moreover, almost all trials have quantified treatment effects by using the hazard ratio, which is difficult to interpret for a positive event, especially in the presence of competing risks. Using 2 recent trials evaluating treatments (remdesivir and convalescent plasma) for COVID-19 as examples, a valid, well-established yet underused procedure is presented for estimating the cumulative recovery or improvement rate curve across the study period. Furthermore, an intuitive and clinically interpretable summary of treatment efficacy based on this curve is also proposed. Clinical investigators are encouraged to consider applying these methods for quantifying treatment effects in future studies of COVID-19.

  View details for DOI 10.7326/M20-4044

  View details for PubMedID 32634024

• Distinct Age-Related Epigenetic Signatures in CD4 and CD8 T Cells. Frontiers in immunology Hu, B., Jadhav, R. R., Gustafson, C. E., Le Saux, S., Ye, Z., Li, X., Tian, L., Weyand, C. M., Goronzy, J. J. 2020; 11: 585168

  Abstract

  Healthy immune aging is in part determined by how well the sizes of naive T cell compartments are being maintained with advancing age. Throughout adult life, replenishment largely derives from homeostatic proliferation of existing naive and memory T cell populations. However, while the subpopulation composition of CD4 T cells is relatively stable, the CD8 T cell compartment undergoes more drastic changes with loss of naive CD8 T cells and accumulation of effector T cells, suggesting that CD4 T cells are more resilient to resist age-associated changes. To determine the epigenetic basis for these differences in behaviors, we compared chromatin accessibility maps of CD4 and CD8 T cell subsets from young and old individuals and related the results to the expressed transcriptome. The dominant age-associated signatures resembled hallmarks of differentiation, which were more pronounced for CD8 naive and memory than the corresponding CD4 T cell subsets, indicating that CD8 T cells are less able to keep cellular quiescence upon homeostatic proliferation. In parallel, CD8 T cells from old adults, irrespective of their differentiation state, displayed greater reduced accessibility to genes of basic cell biological function, including genes encoding ribosomal proteins. One possible mechanism is the reduced expression of the transcription factors YY1 and NRF1. Our data suggest that chromatin accessibility signatures can be identified that distinguish CD4 and CD8 T cells from old adults and that may confer the higher resilience of CD4 T cells to aging.

  View details for DOI 10.3389/fimmu.2020.585168

  View details for PubMedID 33262764

• Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells. Cell metabolism Wu, B. n., Qiu, J. n., Zhao, T. V., Wang, Y. n., Maeda, T. n., Goronzy, I. N., Akiyama, M. n., Ohtsuki, S. n., Jin, K. n., Tian, L. n., Goronzy, J. J., Weyand, C. M. 2020; 32 (6): 967–80.e5

  Abstract

  Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygen consumption and ATP production. Here, we identified suppression of the GDP-forming β subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficient T cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductive direction, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiated into pro-inflammatory effector cells. In AcCoAhi RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficient T cells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.

  View details for DOI 10.1016/j.cmet.2020.10.025

  View details for PubMedID 33264602

• Author Correction: In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls. Nature communications Jiang, W. n., Birtley, J. R., Hung, S. C., Wang, W. n., Chiou, S. H., Macaubas, C. n., Kornum, B. n., Tian, L. n., Huang, H. n., Adler, L. n., Weaver, G. n., Lu, L. n., Ilstad-Minnihan, A. n., Somasundaram, S. n., Ayyangar, S. n., Davis, M. M., Stern, L. J., Mellins, E. D. 2020; 11 (1): 242

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41467-019-13776-0

  View details for PubMedID 31913263

• Participant and Study Partner Reported Impact of Cognition on Functional Activities in Parkinson's Disease MOVEMENT DISORDERS CLINICAL PRACTICE Cholerton, B., Poston, K. L., Tian, L., Quinn, J. F., Chung, K. A., Hiller, A. L., Hu, S., Specketer, K., Montine, T. J., Edwards, K. L., Zabetian, C. P. 2020; 7 (1): 61–69

  Abstract

  Cognitive dysfunction is common in Parkinson's disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.Participants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.Although both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.For participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.

  View details for DOI 10.1002/mdc3.12870

  View details for Web of Science ID 000507324100010

  View details for PubMedID 31970213

  View details for PubMedCentralID PMC6962683

• Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau. Brain : a journal of neurology Wilson, E. N., Swarovski, M. S., Linortner, P. n., Shahid, M. n., Zuckerman, A. J., Wang, Q. n., Channappa, D. n., Minhas, P. S., Mhatre, S. D., Plowey, E. D., Quinn, J. F., Zabetian, C. P., Tian, L. n., Longo, F. M., Cholerton, B. n., Montine, T. J., Poston, K. L., Andreasson, K. I. 2020

  Abstract

  Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.

  View details for DOI 10.1093/brain/awaa021

  View details for PubMedID 32065223

• Exact inference for the random-effect model for meta-analyses with rare events. Statistics in medicine Gronsbell, J., Hong, C., Nie, L., Lu, Y., Tian, L. 2019

  Abstract

  Meta-analysis allows for the aggregation of results from multiple studies to improve statistical inference for the parameter of interest. In recent years, random-effect meta-analysis has been employed to synthesize estimates of incidence rates of adverse events across heterogeneous clinical trials to evaluate treatment safety. However, the validity of existing approaches relies on asymptotic approximation as the number of studies becomes large. In practice, a limited number of trials are typically available for analysis. Moreover, adverse events are typically rare; thus, study-specific incidence rate estimates may be unstable or undefined. In this paper, we present a method for construction of an exact confidence interval for the location parameter of the beta-binomial model through inversion of exact tests. The coverage level of the proposed confidence interval is guaranteed to achieve at least the nominal level, regardless of the number of studies or the with-in study sample size, making it particularly applicable to the study of rare-event data.

  View details for DOI 10.1002/sim.8396

  View details for PubMedID 31820458

• Assessing Clinical Equivalence in Oncology Biosimilar Trials With Time-to-Event Outcomes JNCI CANCER SPECTRUM Uno, H., Schrag, D., Kim, D., Tang, D., Tian, L., Rugo, H. S., Wei, L. 2019; 3 (4)

  View details for DOI 10.1093/jncics/pkz058

  View details for Web of Science ID 000503271700009

• Assessing Clinical Equivalence in Oncology Biosimilar Trials With Time-to-Event Outcomes. JNCI cancer spectrum Uno, H., Schrag, D., Kim, D. H., Tang, D., Tian, L., Rugo, H. S., Wei, L. J. 2019; 3 (4): pkz058

  Abstract

  A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product.

  View details for DOI 10.1093/jncics/pkz058

  View details for PubMedID 32337484

  View details for PubMedCentralID PMC7050006

• In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls. Nature communications Jiang, W., Birtley, J. R., Hung, S., Wang, W., Chiou, S., Macaubas, C., Kornum, B., Tian, L., Huang, H., Adler, L., Weaver, G., Lu, L., Ilstad-Minnihan, A., Somasundaram, S., Ayyangar, S., Davis, M. M., Stern, L. J., Mellins, E. D. 2019; 10 (1): 5247

  Abstract

  Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with thehuman leukocyte antigen (HLA)-DQ6 allele and T-cell receptor alpha (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer+/TRAJ24+/CD4+ T cells in DQ6+ individuals with and without narcolepsy. We identify related TRAJ24+ TCRalphabeta clonotypes encoded by identical alpha/beta gene regions from two patients and two controls. TRAJ24-G allele+ clonotypes only expand in the two patients, whereas a TRAJ24-C allele+ clonotype expands in a control. A representative tetramer+/G-allele+ TCR shows signaling reactivity to the epitope HCRT87-97. Clonally expanded G-allele+ T cells exhibit an unconventional effector phenotype. Our analysis of in vivo expansion of HCRT-reactive TRAJ24+ cells opens an avenue for further investigation of the autoimmune contribution to narcolepsy development.

  View details for DOI 10.1038/s41467-019-13234-x

  View details for PubMedID 31748512

• Trajectory analysis for postoperative pain using electronic health records: A nonparametric method with robust linear regression and K-medians cluster analysis. Health informatics journal Weng, Y., Tian, L., Tedesco, D., Desai, K., Asch, S. M., Carroll, I., Curtin, C., McDonald, K. M., Hernandez-Boussard, T. 2019: 1460458219881339

  Abstract

  Postoperative pain scores are widely monitored and collected in the electronic health record, yet current methods fail to fully leverage the data with fast implementation. A robust linear regression was fitted to describe the association between the log-scaled pain score and time from discharge after total knee replacement. The estimated trajectories were used for a subsequent K-medians cluster analysis to categorize the longitudinal pain score patterns into distinct clusters. For each cluster, a mixture regression model estimated the association between pain score and time to discharge adjusting for confounding. The fitted regression model generated the pain trajectory pattern for given cluster. Finally, regression analyses examined the association between pain trajectories and patient outcomes. A total of 3442 surgeries were identified with a median of 22 pain scores at an academic hospital during 2009-2016. Four pain trajectory patterns were identified and one was associated with higher rates of outcomes. In conclusion, we described a novel approach with fast implementation to model patients' pain experience using electronic health records. In the era of big data science, clinical research should be learning from all available data regarding a patient's episode of care instead of focusing on the "average" patient outcomes.

  View details for DOI 10.1177/1460458219881339

  View details for PubMedID 31621460

• Robust Alternatives to ANCOVA for Estimating the Treatment Effect via a Randomized Comparative Study JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Jiang, F., Tian, L., Fu, H., Hasegawa, T., Wei, L. J. 2019; 114 (528): 1854–64

  View details for DOI 10.1080/01621459.2018.1527226

  View details for Web of Science ID 000505405600035

• Loss-of-function of the DNA Repair Nuclease MRE11A Induces Mitochondrial Failure and Tissue Inflammation in Rheumatoid Arthritis Li, Y., Shen, Y., Jin, K., Wen, Z., Cao, W., Wu, B., Wen, R., Tian, L., Berry, G., Goronzy, J., Weyand, C. WILEY. 2019

  View details for Web of Science ID 000507466903359

• Comment on "Interpreting Clinical Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer (BRPC)'' ANNALS OF SURGERY Wei, L., McCaw, Z. R., Tian, L., Kim, D. 2019; 270 (2): E48–E50

  View details for DOI 10.1097/SLA.0000000000003115

  View details for Web of Science ID 000480739600034

• The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation. Cell metabolism Li, Y., Shen, Y., Jin, K., Wen, Z., Cao, W., Wu, B., Wen, R., Tian, L., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2019

  Abstract

  In the autoimmune disease rheumatoid arthritis (RA), CD4+ Tcells promote pro-inflammatory effector functions by shunting glucose away from glycolysis and ATP production. Underlying mechanisms remain unknown, and here we implicate the DNA repair nuclease MRE11A in the cells' bioenergetic failure. MRE11A deficiency in RA Tcells disrupted mitochondrial oxygen consumption and suppressed ATP generation. Also, MRE11A loss of function caused leakage of mitochondrial DNA (mtDNA) into the cytosol, triggering inflammasome assembly, caspase-1 activation, and pyroptotic cell death. Caspase-1 activation was frequent in lymph-node-residing Tcells in RA patients. Invivo, pharmacologic and genetic inhibition of MRE11A resulted in tissuedeposition of mtDNA, caspase-1 proteolysis, andaggressive tissue inflammation. Conversely, MRE11A overexpression restored mitochondrial fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondrial protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis.

  View details for DOI 10.1016/j.cmet.2019.06.016

  View details for PubMedID 31327667

• Associations of Weight Change With Changes in Calf Muscle Characteristics and Functional Decline in Peripheral Artery Disease. Journal of the American Heart Association Polonsky, T. S., Tian, L., Zhang, D., Bazzano, L. A., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Kibbe, M. R., Leeuwenburgh, C., Sufit, R. L., McDermott, M. M. 2019; 8 (13): e010890

  Abstract

  Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle-brachial index <0.90 were identified from Chicago-area hospitals in 2002-2004. Weight and 6-minute walk distance were measured annually. Weight change categories were weight loss or gain (≥5 pounds/year at ≥1 visit) or stable (weight change <5 pounds at each visit). Participants reported whether weight loss was "intentional" or "unintentional." Calf muscle area was measured with computed tomography every 2years. Associations of weight change with changes in calf muscle area and 6-minute walk distance were analyzed using mixed-effects models and adjusted for age, body mass index, ankle-brachial index, physical activity, and other confounders. Among 389 participants, mean ankle-brachial index was 0.63±0.16, mean age was 74.5±7.8, and mean body mass index was 28.1±5.1kg/m2. Over 3.23±1.37years, muscle area declined more in adults with intentional weight loss versus stable or gain (pair-wise comparisons, P<0.001). Intentional weight loss was associated with less annual decline in 6-minute walk distance than weight gain (intentional loss, 3.7m; stable, -14.0m; gain, -28.5m; unintentional loss, -20.8m; pair-wise comparison intentional loss versus gain, P=0.003). Conclusions Despite a greater loss of calf muscle area, adults with peripheral artery disease who intentionally lost ≥5 pounds experienced less functional decline than those who gained weight. A randomized trial is needed to establish whether benefits of weight loss in peripheral artery disease outweigh potential adverse effects.

  View details for DOI 10.1161/JAHA.118.010890

  View details for PubMedID 31257970

• An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF A beta 42 and an APOE epsilon 4 allele NEUROBIOLOGY OF DISEASE Shahid, M., Kim, J., Leaver, K., Hendershott, T., Zhu, D., Cholerton, B., Henderson, V. W., Tian, L., Poston, K. L. 2019; 127: 278–86

  View details for DOI 10.1016/j.nbd.2019.02.023

  View details for Web of Science ID 000472990100023

• Donor-Derived Cytokine-Induced Killer Cell Infusion as Consolidation after Nonmyeloablative Allogeneic Transplantation for Myeloid Neoplasms BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Narayan, R., Benjamin, J. E., Shah, O., Tian, L., Tate, K., Armstrong, R., Xie, B. J., Lowsky, R., Laport, G., Negrin, R. S., Meyer, E. H. 2019; 25 (7): 1293–1303

  View details for DOI 10.1016/j.bbmt.2019.03.027

  View details for Web of Science ID 000477092400003

• The ROC curve for regularly measured longitudinal biomarkers BIOSTATISTICS Michael, H., Tian, L., Ghebremichael, M. 2019; 20 (3): 433–51

  View details for DOI 10.1093/biostatistics/kxy010

  View details for Web of Science ID 000493040900005

• Transcription factor networks in aged naive CD4 T cells bias lineage differentiation. Aging cell Hu, B., Li, G., Ye, Z., Gustafson, C. E., Tian, L., Weyand, C. M., Goronzy, J. J. 2019: e12957

  Abstract

  With reducedthymic activity, the population of naive T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naive CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naive CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naive CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor beta (TGFbeta) stimulation is enhanced with age due to an upregulation of the TGFbetaR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naive CD4 T cells display altered transcription factor profiles in response to T-cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging-associated changes in the transcription factor profile favor TH9 commitment.

  View details for DOI 10.1111/acel.12957

  View details for PubMedID 31264370

• ON FEATURE ENSEMBLE OPTIMIZING THE SENSITIVITY AND PARTIAL ROC CURVE STATISTICA SINICA Zhang, Z., Lu, Y., Tian, L. 2019; 29 (3): 1395–1418

  View details for DOI 10.5705/ss.202014.0057

  View details for Web of Science ID 000474560000016

• Risk Factors of Ambulatory Central Line-Associated Bloodstream Infection in Pediatric Short Bowel Syndrome. JPEN. Journal of parenteral and enteral nutrition Seddik, T. B., Tian, L., Nespor, C., Kerner, J., Maldonado, Y., Gans, H. 2019

  Abstract

  BACKGROUND: Children with short bowel syndrome (SBS) receiving home parenteral nutrition (HPN) are predisposed to ambulatory central line-associated bloodstream infection (A-CLABSI). Data describing risk factors of this infection in children are limited.METHODS: Retrospective cohort, single-center, case-crossover study of children ≤18 years old with SBS receiving HPN from January 2012 to December 2016. Univariate and multivariate mixed effect Poisson regression identified the relative risk (RR) of A-CLABSI with proposed risk factors.RESULTS: Thirty-five children were identified; median follow-up was 30 months. A-CLABSI rate was 4.2 per 1000 central line (CL) days. Univariate analysis identified younger age (RR: 0.92 per 12-month increase [95% confidence interval {CI}: 0.85-0.99; P = 0.036]), shorter small intestine length (RR: 0.96 per 10-cm increase [95% CI: 0.92-0.99; P = 0.008]), lower citrulline level (RR: 0.86 per 5-nmol/mL increase [95% CI: 0.75-0.99; P = 0.036]), and recent CL break (RR: 1.55 [95% CI: 1.06-2.28; P = 0.024]) as risk factors for A-CLABSI. Multivariate analysis showed increased A-CLABSI with clinical diagnosis of small intestine bacterial overgrowth (SIBO) (RR: 1.87 [95% CI: 1.1-3.17; P = 0.021]) and CL breaks (RR: 1.49 [95% CI: 1-2.22; P = 0.024]).CONCLUSIONS: Factors influencing gut integrity increase A-CLABSI rate, supporting translocation as an important mechanism and target for prevention. Clinical diagnosis of SIBO increases A-CLABSI rate, but whether dysbiosis or diarrhea is responsible is an area for future research. CL maintenance is crucial, and prevention of breaks would likely decrease A-CLABSI rate.

  View details for DOI 10.1002/jpen.1667

  View details for PubMedID 31179578

• Exact inference on the random-effects model for meta-analyses with few studies BIOMETRICS Michael, H., Thornton, S., Xie, M., Tian, L. 2019; 75 (2): 485–93

  View details for DOI 10.1111/biom.12998

  View details for Web of Science ID 000483730600016

• Epicatechin-enriched cocoa to improve walking performance in older people with peripheral artery disease: The COCOA-PAD Randomized Clinical Trial McDermott, M. M., Domanchuk, K., Ferrucci, L., Guralnik, J. M., Kibbe, M. R., Kramer, C., Leeuwenburgh, C., Peterson, C., Sufit, R., Tian, L., Villarreal, F., Zhao, L., Polonsky, T. S. SAGE PUBLICATIONS LTD. 2019: 275–76

  View details for Web of Science ID 000469356500021

• Temporal changes in characteristics of patients with peripheral artery disease (PAD) relevant to treating PAD-related functional impairment Nayak, P., Guralnik, J. M., Polonsky, T. S., Kibbe, M. R., Tian, L., Zhao, L., Criqui, M. H., Ferrucci, L., Li, L., McDermott, M. M. SAGE PUBLICATIONS LTD. 2019: 273

  View details for Web of Science ID 000469356500017

• Response variability and associations of patient characteristics with improved response to supervised exercise therapy in peripheral artery disease Patel, K. H., Guralnik, J., Kibbe, M., Polonsky, T., Crique, M., Leeuwenburgh, C., Peterson, C., Sufit, R., Zhao, L., Ferruci, L., Tian, L., Li, L., McDermott, M. M. SAGE PUBLICATIONS LTD. 2019: 273–74

  View details for Web of Science ID 000469356500018

• Point Shear Wave Elastography Using Machine Learning to Differentiate Renal Cell Carcinoma and Angiomyolipoma. Ultrasound in medicine & biology Sagreiya, H., Akhbardeh, A., Li, D., Sigrist, R., Chung, B. I., Sonn, G. A., Tian, L., Rubin, D. L., Willmann, J. K. 2019

  Abstract

  The question of whether ultrasound point shear wave elastography can differentiate renal cell carcinoma (RCC) from angiomyolipoma (AML) is controversial. This study prospectively enrolled 51 patients with 52 renal tumors (42 RCCs, 10 AMLs). We obtained 10 measurements of shear wave velocity (SWV) in the renal tumor, cortex and medulla. Median SWV was first used to classify RCC versus AML. Next, the prediction accuracy of 4 machine learning algorithms-logistic regression, naive Bayes, quadratic discriminant analysis and support vector machines (SVMs)-was evaluated, using statistical inputs from the tumor, cortex and combined statistical inputs from tumor, cortex and medulla. After leave-one-out cross validation, models were evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Tumor median SWV performed poorly (AUC = 0.62; p = 0.23). Except logistic regression, all machine learning algorithms reached statistical significance using combined statistical inputs (AUC = 0.78-0.98; p < 7.1 * 10-3). SVMs demonstrated 94% accuracy (AUC = 0.98; p = 3.13 * 10-6) and clearly outperformed median SWV in differentiating RCC from AML (p = 2.8 * 10-4).

  View details for DOI 10.1016/j.ultrasmedbio.2019.04.009

  View details for PubMedID 31133445

• Using a surrogate marker for early testing of a treatment effect. Biometrics Parast, L., Cai, T., Tian, L. 2019

  Abstract

  The development of methods to identify, validate and use surrogate markers to test for a treatment effect has been an area of intense research interest given the potential for valid surrogate markers to reduce the required costs and follow-up times of future studies. Several quantities and procedures have been proposed to assess the utility of a surrogate marker. However, few methods have been proposed to address how one might use the surrogate marker information to test for a treatment effect at an earlier time point, especially in settings where the primary outcome and the surrogate marker are subject to censoring. In this paper, we propose a novel test statistic to test for a treatment effect using surrogate marker information measured prior to the end of the study in a time-to-event outcome setting. We propose a robust nonparametric estimation procedure and propose inference procedures. In addition, we evaluate the power for the design of a future study based on surrogate marker information. We illustrate the proposed procedure and relative power of the proposed test compared to a test performed at the end of the study using simulation studies and an application to data from the Diabetes Prevention Program. This article is protected by copyright. All rights reserved.

  View details for PubMedID 31009073

• Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis SCIENCE TRANSLATIONAL MEDICINE Burgener, E. B., Sweere, J. M., Bach, M. S., Secor, P. R., Haddock, N., Jennings, L. K., Marvig, R. L., Johansen, H., Rossi, E., Cao, X., Tian, L., Nedelec, L., Molin, S., Bollyky, P. L., Milla, C. E. 2019; 11 (488)

  View details for DOI 10.1126/scitranslmed.aau9748

  View details for Web of Science ID 000465116400003

• Assessing the value of a censored surrogate outcome. Lifetime data analysis Parast, L., Tian, L., Cai, T. 2019

  Abstract

  Assessing the potential of surrogate markers and surrogate outcomes for replacing a long term outcome is an active area of research. The interest in this topic is partly motivated by increasing pressure from stakeholders to shorten the time required to evaluate the safety and/or efficacy of a treatment or intervention such that treatments deemed safe and effective can be made available to those in need more quickly. Most existing methods in surrogacy evaluation either require strict model assumptions or that primary outcome and surrogate outcome information is available for all study participants. In this paper, we focus on a setting where the primary outcome is subject to censoring and the aim is to quantify the surrogacy of an intermediate outcome, which is also subject to censoring. We define the surrogacy as the proportion of treatment effect on the primary outcome that is explained by the intermediate surrogate outcome information and propose two robust methods to estimate this quantity. We propose both a nonparametric approach that uses a kernel smoothed Nelson-Aalen estimator of conditional survival, and a semiparametric method that derives conditional survival estimates from a landmark Cox proportional hazards model. Simulation studies demonstrate that both approaches perform well in finite samples. Our methodological development is motivated by our interest in investigating the use of a composite cardiovascular endpoint as a surrogate outcome in a randomized study of the effectiveness of angiotensin-converting enzyme inhibitors on survival. We apply the proposed methods to quantify the surrogacy of this potential surrogate outcome for the primary outcome, time to death.

  View details for PubMedID 30980316

• Nonparametric estimation of risk tracking indices for longitudinal studies. Statistical methods in medical research Wu, C. O., Tian, X., Tian, L., Reis, J. P., Zhao, L., Allen, N. B., Bae, S., Liu, K. 2019: 962280219839427

  Abstract

  Tracking a subject's risk factors or health status over time is an important objective in long-term epidemiological studies with repeated measurements. An important issue of time-trend tracking is to define appropriate statistical indices to quantitatively measure the tracking abilities of the targeted risk factors or health status over time. We present a number of local and global statistical tracking indices based on the rank-tracking probabilities, which are derived from the conditional distribution functions, and propose a class of kernel-based nonparametric estimation methods. Confidence intervals for the estimators of the tracking indices are constructed through a resampling subject bootstrap procedure. We demonstrate the application of the tracking indices using the body mass index and systolic blood pressure data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Statistical properties of the estimation methods and bootstrap inference are investigated through a simulation study and an asymptotic development.

  View details for PubMedID 30945590

• Cognitive Performance in Parkinson's Disease in the Brain Health Registry. Journal of Alzheimer's disease : JAD Cholerton, B., Weiner, M. W., Nosheny, R. L., Poston, K. L., Scott Mackin, R., Tian, L., Ashford, J. W., Montine, T. J. 2019

  Abstract

  The study of cognition in Parkinson's disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer's disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values <  0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies.

  View details for PubMedID 30909225

• CLONALITY: POINT ESTIMATION ANNALS OF APPLIED STATISTICS Tian, L., Liu, Y., Fire, A. Z., Boyd, S. D., Olshen, R. A. 2019; 13 (1): 113–31

  View details for DOI 10.1214/18-AOAS1197

  View details for Web of Science ID 000464000700005

• Examination of Factors Associated With Lymph Node Metastases in Lung Carcinoids Pathipati, M. P., Yohannan, T. K., Tian, L., Benson, J. A., Hornbacker, K., Berry, G. J., Lui, N., Kunz, P. L., Padda, S. K. LIPPINCOTT WILLIAMS & WILKINS. 2019: 447

  View details for Web of Science ID 000462541800096

• An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF ASS42 and an APOE epsilon4 allele. Neurobiology of disease Shahid, M., Kim, J., Leaver, K., Hendershott, T., Zhu, D., Cholerton, B., Henderson, V. W., Tian, L., Poston, K. L. 2019

  Abstract

  OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Abeta-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Abeta-42 compared to patients with normal levels.METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Abeta-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Abeta at baseline, PD participants with normal CSF Abeta, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education.RESULTS: 423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Abeta-42 (39 APOE epsilon4+, 64 APOE epsilon4-). Compared to participants with normal CSF Abeta-42, those with low CSF Abeta-42 declined faster on most cognitive tests. Within the low CSF Abeta-42 group, APOE epsilon4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72).DISCUSSION: PD patients with low CSF Abeta-42 and APOE epsilon4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Abeta-42 and APOE epsilon4 might interact to promote early cognitive changes in PD patients.

  View details for PubMedID 30826425

• N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation. Nature immunology Wen, Z., Jin, K., Shen, Y., Yang, Z., Li, Y., Wu, B., Tian, L., Shoor, S., Roche, N. E., Goronzy, J. J., Weyand, C. M. 2019

  Abstract

  N-myristoyltransferase (NMT) attaches the fatty acid myristate to the N-terminal glycine of proteins to sort them into soluble and membrane-bound fractions. Function of the energy-sensing AMP-activated protein kinase, AMPK, is myristoylation dependent. In rheumatoid arthritis (RA), pathogenic T cells shift glucose away from adenosine tri-phosphate production toward synthetic and proliferative programs, promoting proliferation, cytokine production, and tissue invasion. We found that RA T cells had a defect in NMT1 function, which prevented AMPK activation and enabled unopposed mTORC1 signaling. Lack of the myristate lipid tail disrupted the lysosomal translocation and activation of AMPK. Instead, myristoylation-incompetent RA T cells hyperactivated the mTORC1 pathway and differentiated into pro-inflammatory TH1 and TH17 helper T cells. In vivo, NMT1 loss caused robust synovial tissue inflammation, whereas forced NMT1 overexpression rescued AMPK activation and suppressed synovitis. Thus, NMT1 has tissue-protective functions by facilitating lysosomal recruitment of AMPK and dampening mTORC1 signaling.

  View details for PubMedID 30718913

• Racial Differences in the Effect of Granulocyte Macrophage Colony-Stimulating Factor on Improved Walking Distance in Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. Journal of the American Heart Association McDermott, M. M., Polonsky, T. S., Guralnik, J. M., Ferrucci, L., Tian, L., Zhao, L., Stein, J., Domanchuk, K., Criqui, M. H., Taylor, D. A., Li, L., Kibbe, M. R. 2019; 8 (2): e011001

  Abstract

  Background The effects of race on response to medical therapy in people with peripheral artery disease ( PAD ) are unknown. Methods and Results In the PROPEL (Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD) Trial, PAD participants were randomized to 1 of 4 groups for 6months: supervised treadmill exercise+granulocyte-macrophage colony-stimulating factor ( GM - CSF ) (Group 1), exercise+placebo (Group 2), attention control+ GM - CSF (Group 3), or attention control+placebo (Group 4). Change in 6-minute walk distance was measured at 12- and 26-week follow-up. In these exploratory analyses, groups receiving GM - CSF (Groups 1 and 3), placebo (Groups 2 and 4), exercise (Groups 1 and 2), and attention control (Groups 2 and 4) were combined, maximizing statistical power for studying the effects of race on response to interventions. Of 210 PAD participants, 141 (67%) were black and 64 (30%) were white. Among whites, GM - CSF improved 6-minute walk distance by +22.0m (95% CI : -4.5, +48.5, P=0.103) at 12 weeks and +44.4m (95% CI : +6.9, +82.0, P=0.020) at 26 weeks, compared with placebo. Among black participants, there was no effect of GM - CSF on 6-minute walk distance at 12-week ( P=0.26) or 26-week (-5.0m [-27.5, +17.5, P=0.66]) follow-up, compared with placebo. There was an interaction of race on the effect of GM - CSF on 6-minute walk change at 26-week follow-up ( P=0.018). Exercise improved 6-minute walk distance in black ( P=0.006) and white ( P=0.034) participants without interaction. Conclusions GM - CSF improved 6-minute walk distance in whites with PAD but had no effect in black participants. Further study is needed to confirm racial differences in GM - CSF efficacy in PAD . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01408901.

  View details for PubMedID 30661439

• Durability of Benefits From Supervised Treadmill Exercise in People With Peripheral Artery Disease. Journal of the American Heart Association McDermott, M. M., Kibbe, M. R., Guralnik, J. M., Ferrucci, L., Criqui, M. H., Domanchuk, K., Tian, L., Zhao, L., Li, L., Patel, K., Polonsky, T. S. 2019; 8 (1): e009380

  Abstract

  Background It is currently unknown whether 6months of supervised treadmill exercise has a durable benefit on 6-minute walk performance, even after exercise is completed, in people with peripheral artery disease. Methods and Results A total of 156 participants with peripheral artery disease were randomized to 1 of 3 groups: supervised treadmill exercise, supervised resistance training, or attention control. Participants received supervised sessions during months 1 to 6 and telephone contact during months 6 to 12. Primary outcomes were change in 6-minute walk distance and short physical performance battery at 6-month follow-up and have been reported previously. Secondary outcomes were change in 6-minute walk and short physical performance battery at 12-month follow-up and are reported here. A group of 134 participants (86%) completed the 12-month follow-up. At 6-month follow-up, compared with control, 6-minute walk distance improved in the treadmill exercise group (+36.1m, 95% CI =13.9-58.3, P=0.001). Between 6- and 12-month follow-up, 6-minute walk distance significantly declined (-28.6m, 95% CI=-52.6 to -4.5, P=0.020) and physical activity declined -272 activity units (95% CI =-546 to +2, P=0.052) in the treadmill exercise group compared with controls. At 12-month follow-up, 6months after completing supervised treadmill exercise, change in 6-minute walk distance was not different between the treadmill exercise and control groups (+7.5, 95% CI =-17.5 to +32.6, P=0.56). There were no differences in short physical performance battery change between either exercise group and control at 6-month or 12-month follow-up. Conclusions A 6-month supervised treadmill exercise intervention that improved 6-minute walk distance at 6-month follow-up did not have persistent benefit at 12-month follow-up. These results do not support a durable benefit of supervised treadmill exercise in peripheral artery disease. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Identifier: NCT 00106327.

  View details for PubMedID 30587066

• Comparing 6-minute walk versus treadmill walking distance as outcomes in randomized trials of peripheral artery disease. Journal of vascular surgery McDermott, M. M., Guralnik, J. M., Tian, L. n., Zhao, L. n., Polonsky, T. S., Kibbe, M. R., Criqui, M. H., Zhang, D. n., Conte, M. S., Domanchuk, K. n., Li, L. n., Sufit, R. n., Leeuwenburgh, C. n., Ferrucci, L. n. 2019

  Abstract

  Randomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD.Data from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol.Of 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (-10.2 m; 95% confidence interval, -18.2 to -2.2; P = .013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P = .010; difference between change in 6-minute walk versus maximal treadmill walking distance: -37.3 m; 95% CI, -56.4 to -18.2; P < .001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P = .048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P < .001), suggesting a benefit from treadmill training on the treadmill outcome.Maximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon.

  View details for DOI 10.1016/j.jvs.2019.05.058

  View details for PubMedID 31870756

• Determinants governing T cell receptor α/β-chain pairing in repertoire formation of identical twins. Proceedings of the National Academy of Sciences of the United States of America Tanno, H. n., Gould, T. M., McDaniel, J. R., Cao, W. n., Tanno, Y. n., Durrett, R. E., Park, D. n., Cate, S. J., Hildebrand, W. H., Dekker, C. L., Tian, L. n., Weyand, C. M., Georgiou, G. n., Goronzy, J. J. 2019

  Abstract

  The T cell repertoire in each individual includes T cell receptors (TCRs) of enormous sequence diversity through the pairing of diverse TCR α- and β-chains, each generated by somatic recombination of paralogous gene segments. Whether the TCR repertoire contributes to susceptibility to infectious or autoimmune diseases in concert with disease-associated major histocompatibility complex (MHC) polymorphisms is unknown. Due to a lack in high-throughput technologies to sequence TCR α-β pairs, current studies on whether the TCR repertoire is shaped by host genetics have so far relied only on single-chain analysis. Using a high-throughput single T cell sequencing technology, we obtained the largest paired TCRαβ dataset so far, comprising 965,523 clonotypes from 15 healthy individuals including 6 monozygotic twin pairs. Public TCR α- and, to a lesser extent, TCR β-chain sequences were common in all individuals. In contrast, sharing of entirely identical TCRαβ amino acid sequences was very infrequent in unrelated individuals, but highly increased in twins, in particular in CD4 memory T cells. Based on nucleotide sequence identity, a subset of these shared clonotypes appeared to be the progeny of T cells that had been generated during fetal development and had persisted for more than 50 y. Additional shared TCRαβ in twins were encoded by different nucleotide sequences, implying that genetic determinants impose structural constraints on thymic selection that favor the selection of TCR α-β pairs with entire sequence identities.

  View details for DOI 10.1073/pnas.1915008117

  View details for PubMedID 31879353

• Comparative Effectiveness of Cognitive Behavioral Therapy for Chronic Pain and Chronic Pain Self-Management within the Context of Voluntary Patient-Centered Prescription Opioid Tapering: The EMPOWER Study Protocol. Pain medicine (Malden, Mass.) Darnall, B. D., Mackey, S. C., Lorig, K. n., Kao, M. C., Mardian, A. n., Stieg, R. n., Porter, J. n., DeBruyne, K. n., Murphy, J. n., Perez, L. n., Okvat, H. n., Tian, L. n., Flood, P. n., McGovern, M. n., Colloca, L. n., King, H. n., Van Dorsten, B. n., Pun, T. n., Cheung, M. n. 2019

  Abstract

  Evidence to date, while sparse, suggests that patients taking long-term opioids require special considerations and protections to prevent potential iatrogenic harms from opioid de-prescribing, such as increased pain or suffering. Following this study protocol, the EMPOWER study seeks to address multiple unmet needs of patients with chronic pain who desire to reduce long-term opioid therapy, and provide the clinical evidence on effective methodology.EMPOWER applies patient-centered methods for voluntary prescription opioid reduction conducted within a comprehensive, multi-state, 3-arm randomized controlled comparative effectiveness study of three study arms (1) group cognitive behavioral therapy for chronic pain; (2) group chronic pain self-management; and (3) usual care (taper only). Specialized electronic data capture systems collect patient reported symptoms and satisfaction data weekly and monthly during the taper, with real-time clinical alerts and electronic feedback loops informing, documenting, and steering needed care actions.The EMPOWER study seeks to provide granular evidence on patient response to voluntary opioid tapering, and will provide evidence to inform clinical systems changes, clinical care, patient satisfaction, and patient outcomes for opioid reduction.

  View details for DOI 10.1093/pm/pnz285

  View details for PubMedID 31876947

• Trifluridine/tipiracil in metastatic gastric cancer. The Lancet. Oncology McCaw, Z. R., Kim, D. H., Tian, L., Fu, H., Wei, L. 2019; 20 (1): e8

  View details for PubMedID 30614483

• Donor-derived CIK Cell Infusion as Consolidation after Non-myeloablative Allogeneic Transplant for Myeloid Neoplasms. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Narayan, R. n., Benjamin, J. E., Shah, O. n., Tian, L. n., Tate, K. n., Armstrong, R. n., Xie, B. n., Lowsky, R. n., Laport, G. n., Negrin, R. S., Meyer, E. H. 2019

  Abstract

  Non-myeloablative conditioning, such as with total lymphoid irradiation and anti-thymocyte globulin (TLI-ATG), has allowed hematopoietic allotransplantation with curative potential for older patients and those with comorbid medical conditions with myeloid neoplasms. However, early achievement of full donor chimerism (FDC) and relapse remain challenges. Cytokine induced killer (CIK) cells have been shown to have anti-tumor cytotoxicity. Infusion of donor-derived CIK cells has been studied for hematologic malignancies relapsed after allotransplant but has not been evaluated as post-transplant consolidation. In this phase II study, we prospectively studied whether a one-time infusion of 1 × 108/kg CD3+ donor-derived CIK cells administered between Days +21-35 after TLI-ATG conditioning, could improve FDC achievement by Day +90 and 2-year clinical outcomes in patients with myeloid neoplasms. CIK cells were infused in 31 of 44 patients treated on study and contained predominantly CD3+CD8+NKG2D+ cells along with significantly expanded CD3+CD56+ cells. Outcomes were compared to a retrospective historical cohort of 100 patients. We found that this one-time CIK infusion did not increase the rate of FDC by Day +90. On an intention-to-treat analysis, 2-year non-relapse mortality (6.8%, 95%CI: 0-14.5%), event-free survival (27.3%, 95%CI: 16.8-44.2%), and overall survival (50.6%, 95%CI: 37.5-68.2%) were similar to our historical cohort. Cumulative incidence of grade II-IV acute graft versus host disease at 1-year was 25.1% (95%CI: 12-38.2%). On univariate analysis, the presence of monosomal or complex karyotype was adversely associated with relapse-free and overall survival. Given the favorable safety profile of CIK cell infusion, strategies such as repeat dosing or genetic modification are worth exploration. This trial was registered at clinicaltrials.gov (NCT01392989).

  View details for PubMedID 30951840

• Visuospatial functioning is associated with sleep disturbance and hallucinations in nondemented patients with Parkinson's disease. Journal of clinical and experimental neuropsychology Specketer, K. n., Zabetian, C. P., Edwards, K. L., Tian, L. n., Quinn, J. F., Peterson-Hiller, A. L., Chung, K. A., Hu, S. C., Montine, T. J., Cholerton, B. A. 2019: 1–11

  Abstract

  Introduction: Cognitive impairment is a common symptom of Parkinson's disease (PD) associated with reduced quality of life and a more severe disease state. Previous research has shown an association between visuospatial dysfunction and worse disease course; however, it is not clear whether this is separable from executive dysfunction and/or dementia. This study sought to determine whether distinct cognitive factors could be measured in a large PD cohort, and if those factors were differentially associated with other PD-related features, specifically to provide insight into visuospatial dysfunction. Methods: Non-demented participants with PD from the Pacific Udall Center were enrolled (n = 197). Co-participants (n = 104) completed questionnaires when available. Principal components factor analysis (PCFA) was utilized to group the neuropsychological test scores into independent factors by considering those with big factor loading (≥.40). Linear and logistic regression analyses were performed to examine the relationship between the cognitive factors identified in the PCFA and other clinical features of PD. Results: Six factors were extracted from the PCFA: 1) executive/processing speed, 2) visual learning & memory/visuospatial, 3) auditory working memory, 4) contextual verbal memory, 5) semantic learning & memory, and 6) visuospatial. Motor severity (p = 0.001), mood (p < 0.001), and performance on activities of daily living scores (informant: p < 0.001, patient: p = 0.009) were primarily associated with frontal and executive factors. General sleep disturbance (p < 0.006) and hallucinations (p = 0.002) were primarily associated with visuospatial functioning and visual learning/memory. Conclusions: Motor symptoms, mood, and performance on activities of daily living were primarily associated with frontal/executive factors. Sleep disturbance and hallucinations were associated with visuospatial functioning and visual learning/memory only, over and above executive functioning and regardless of cognitive disease severity. These findings support that visuospatial function in PD may indicate a more severe disease course, and that symptom management should be guided accordingly.

  View details for DOI 10.1080/13803395.2019.1623180

  View details for PubMedID 31177941

• Multivariate meta-analysis model for the difference in restricted mean survival times. Biostatistics (Oxford, England) Weir, I. R., Tian, L. n., Trinquart, L. n. 2019

  Abstract

  In randomized controlled trials (RCTs) with time-to-event outcomes, the difference in restricted mean survival times (RMSTD) offers an absolute measure of the treatment effect on the time scale. Computation of the RMSTD relies on the choice of a time horizon, $\tau$. In a meta-analysis, varying follow-up durations may lead to the exclusion of RCTs with follow-up shorter than $\tau$. We introduce an individual patient data multivariate meta-analysis model for RMSTD estimated at multiple time horizons. We derived the within-trial covariance for the RMSTD enabling the synthesis of all data by borrowing strength from multiple time points. In a simulation study covering 60 scenarios, we compared the statistical performance of the proposed method to that of two univariate meta-analysis models, based on available data at each time point and based on predictions from flexible parametric models. Our multivariate model yields smaller mean squared error over univariate methods at all time points. We illustrate the method with a meta-analysis of five RCTs comparing transcatheter aortic valve replacement (TAVR) with surgical replacement in patients with aortic stenosis. Over 12, 24, and 36 months of follow-up, those treated by TAVR live 0.28 [95% confidence interval (CI) 0.01 to 0.56], 0.46 (95% CI $-$0.08 to 1.01), and 0.79 (95% CI $-$0.43 to 2.02) months longer on average compared to those treated by surgery, respectively.

  View details for DOI 10.1093/biostatistics/kxz018

  View details for PubMedID 31175828

• Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis. Science translational medicine Burgener, E. B., Sweere, J. M., Bach, M. S., Secor, P. R., Haddock, N. n., Jennings, L. K., Marvig, R. L., Johansen, H. K., Rossi, E. n., Cao, X. n., Tian, L. n., Nedelec, L. n., Molin, S. n., Bollyky, P. L., Milla, C. E. 2019; 11 (488)

  Abstract

  Filamentous bacteriophage (Pf phage) contribute to the virulence of Pseudomonas aeruginosa infections in animal models, but their relevance to human disease is unclear. We sought to interrogate the prevalence and clinical relevance of Pf phage in patients with cystic fibrosis (CF) using sputum samples from two well-characterized patient cohorts. Bacterial genomic analysis in a Danish longitudinal cohort of 34 patients with CF revealed that 26.5% (n = 9) were consistently Pf phage positive. In the second cohort, a prospective cross-sectional cohort of 58 patients with CF at Stanford, sputum qPCR analysis showed that 36.2% (n = 21) of patients were Pf phage positive. In both cohorts, patients positive for Pf phage were older, and in the Stanford CF cohort, patients positive for Pf phage were more likely to have chronic P. aeruginosa infection and had greater declines in pulmonary function during exacerbations than patients negative for Pf phage presence in the sputum. Last, P. aeruginosa strains carrying Pf phage exhibited increased resistance to antipseudomonal antibiotics. Mechanistically, in vitro analysis showed that Pf phage sequesters these same antibiotics, suggesting that this mechanism may thereby contribute to the selection of antibiotic resistance over time. These data provide evidence that Pf phage may contribute to clinical outcomes in P. aeruginosa infection in CF.

  View details for PubMedID 30996083

• Cognitive Performance in Parkinson's Disease in the Brain Health Registry JOURNAL OF ALZHEIMERS DISEASE Cholerton, B., Weiner, M. W., Nosheny, R. L., Poston, K. L., Mackin, R., Tian, L., Ashford, J., Montine, T. J. 2019; 68 (3): 1029–38

  View details for DOI 10.3233/JAD-181009

  View details for Web of Science ID 000464031500013

• Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease NEUROIMAGE-CLINICAL La, C., Linortner, P., Bernstein, J. D., Cruadhlaoich, M., Fenesy, M., Deutsch, G. K., Rutt, B. K., Tian, L., Wagner, A. D., Zeineh, M., Kerchner, G. A., Poston, K. L. 2019; 23

  View details for DOI 10.1016/j.nicl.2019.101824

  View details for Web of Science ID 000485804400029

• Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease. NeuroImage. Clinical La, C. n., Linortner, P. n., Bernstein, J. D., Ua Cruadhlaoich, M. A., Fenesy, M. n., Deutsch, G. K., Rutt, B. K., Tian, L. n., Wagner, A. D., Zeineh, M. n., Kerchner, G. A., Poston, K. L. 2019; 23: 101824

  Abstract

  Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life.We studied 29 participants with PD (age 65.5 ± 7.8 years; disease duration 4.5 ± 3.0 years) and 8 matched-healthy controls (age 67.9 ± 6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD.In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05).In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

  View details for PubMedID 31054380

• Central mechanisms of real and sham electroacupuncture in the treatment of chronic low back pain: study protocol for a randomized, placebo-controlled clinical trial. Trials Kong, J., MacIsaac, B., Cogan, R., Ng, A., Law, C. S., Helms, J., Schnyer, R., Karayannis, N. V., Kao, M., Tian, L., Darnall, B. D., Gross, J. J., Mackey, S., Manber, R. 2018; 19 (1): 685

  Abstract

  BACKGROUND: Chronic low back pain (CLBP) is the most common chronic pain condition and is often resistant to conventional treatments. Acupuncture is a popular alternative for treating CLBP but its mechanisms of action remain poorly understood. Evidence suggests that pain regulatory mechanisms (particularly the ascending and secondarily the descending pain modulatory pathways) and psychological mechanisms (e.g., expectations, pain catastrophizing and self-efficacy) may be involved in the pathogenesis of CLBP and its response to treatments. We will examine these mechanisms in the treatment of CLBP by electroacupuncture (EA).METHODS: We present the aims and methods of a placebo-controlled, participant-blinded and assessor-blinded mechanistic study. Adult patients with CLBP will be randomized to receiving 16 sessions of real (active) or sham (placebo) EA over the course of 8weeks. The primary pain regulatory measure for which the study was powered is temporal summation (TS), which approximates ascending pain facilitation. Conditioned pain modulation (CPM), representing a descending pain modulatory pathway, will be our secondary pain regulatory measure. The primary psychological measure is expectations of benefit, and the secondary psychological measures are pain catastrophizing and self-efficacy in managing pain. Main clinical outcomes are back pain bothersomeness on a 0-100 visual analog scale (primary), Roland Morris Disability Questionnaire (secondary), and relevant items from the National Institutes of Health (NIH) Patient-Reported Outcome Measures Information System (secondary). We hypothesize that compared to sham, real EA will lead to greater reduction in TS after 8 treatment sessions (4weeks); and that reduction in TS (and secondarily, increase in CPM) after 8 treatment sessions will mediate reduction in back pain bothersomeness from baseline to week 10 (clinical response) to EA. We also hypothesize that the three psychological factors are moderators of clinical response. With 100 treatment completers, the study is designed to have 80% power to detect a medium-sized between-group effect (d=0.5) on temporal summation.DISCUSSION: To the best of our knowledge, this is the first appropriately powered, placebo-controlled clinical trial evaluating mechanisms of EA in the treatment of CLBP.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02503475 . Registered on 15 July 15 2015. Retrospectively registered.

  View details for PubMedID 30541586

• Interpreting Clinical Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer (BRPC). Annals of surgery McCaw, Z. R., Tian, L., Kim, D. H., Wei, L. 2018

  View details for PubMedID 30499804

• An Efficient Numerical Algorithm for Exact Inference in Meta Analysis. Journal of statistical computation and simulation Wang, Y., Tian, L. 2018; 88 (4): 646-656

  Abstract

  The performance of commonly used asymptotic inference procedures for the random effects model used in meta analysis relies on the number of studies. When the number of studies is moderate or small, the exact inference procedure is more reliable than the asymptotic counterparts. However, the related numerical computation may be demanding and an obstacle of routine use of the exact method. In this paper, we proposed a novel numerical algorithm for constructing the exact 95% confidence interval of the location parameter in the random effects model. The algorithm is much faster than the naive method and may greatly facilitate the use of the more appropriate exact inference procedure in meta analysis. Numerical studies and real data examples are used to illustrate the advantage of the proposed method.

  View details for DOI 10.1080/00949655.2017.1402331

  View details for PubMedID 31997838

  View details for PubMedCentralID PMC6988823

• Exact Inference on the Random-Effects Model for Meta-Analyses with Few Studies. Biometrics Michael, H., Thornton, S., Xie, M., Tian, L. 2018

  Abstract

  We describe an exact, unconditional, non-randomized procedure for producing confidence intervals for the grand mean in a normal-normal random effects meta-analysis. The procedure targets meta-analyses based on too few primary studies, ≤ 7; say, to allow for the conventional asymptotic estimators, e.g., DerSimonian and Laird 1986, or non-parametric resampling-based procedures, e.g., Liu, Lee, and Xie 2007. Meta-analyses with such few studies are common, with one recent sample of 22,453 heath-related meta-analsyes finding a median of 3 primary studies per meta-analysis (Davey et al. (2011)). Reliable and efficient inference procedures are therefore needed to address this setting. The coverage level of the resulting CI is guaranteed to be above the nominal level, up to Monte Carlo error, provided the meta-analysis contains more than 1 study and the model assumptions are met. After employing several techniques to accelerate computation, the new CI can be easily constructed on a personal computer. Simulations suggest that the proposed CI typically is not overly conservative. We illustrate the approach on several contrasting examples of meta-analyses investigating the effect of calcium intake on bone mineral density. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30430540

• Brachial artery intima-media thickness and grayscale texture changes in patients with peripheral artery disease receiving supervised exercise training in the PROPEL randomized clinical trial. Vascular medicine (London, England) Berroug, J., Korcarz, C. E., Mitchell, C. K., Weber, J. M., Tian, L., McDermott, M. M., Stein, J. H. 2018: 1358863X18804050

  Abstract

  We performed an exploratory analysis to evaluate the effects of a treadmill exercise program on brachial artery (BA) intima-media thickness (IMT) and three BA grayscale ultrasound measures that may indicate subclinical arterial injury. Data were from a clinical trial in individuals with peripheral artery disease who were randomly assigned to treadmill exercise training or attention control. B-mode ultrasonography was performed at baseline and after 26 weeks. BA IMT, grayscale median (GSM), entropy, and gray-level difference statistic-contrast (GLDS-CON) were measured by a single reader. The 184 participants were (mean (SD)) 66.7 (8.2) years old and had an ankle-brachial index of 0.70 (0.18). Exercise training was associated with a 0.01 (0.06) mm ( p = 0.025) reduction in BA IMT compared to 0.00 (0.05) mm ( p = 0.807) in the control group (between-group p = 0.061). BA GSM, entropy, and GLDS-CON did not change significantly with exercise. Improvements in the 6-minute walk distance correlated with increases in resting BA blood flow ( r = 0.23, p = 0.032), flow-mediated dilation ( r = 0.24, p = 0.022), diameter ( r = 0.29, p = 0.005), entropy ( r = 0.21, p = 0.047), and GLDS-CON ( r = 0.22, p = 0.041). In a post hoc analysis, BA IMT improved significantly with treadmill exercise training but did not change with attention control; however, the between-group difference did not reach statistical significance. With exercise, improvements in the 6-minute walk distance were associated with improved endothelial function, increased resting blood flow, and BA dilation, as well as higher grayscale entropy and GLDS-CON, indicating that lower extremity exercise is associated with salutary changes in upper-extremity arterial wall structure and function. ClinicalTrials.gov Identifier: NCT01408901.

  View details for PubMedID 30418100

• Quantifying the totality of treatment effect with multiple event-time observations in the presence of a terminal event from a comparative clinical study STATISTICS IN MEDICINE Claggett, B., Tian, L., Fu, H., Solomon, S. D., Wei, L. 2018; 37 (25): 3589–98

  Abstract

  To evaluate the totality of one treatment's benefit/risk profile relative to an alternative treatment via a longitudinal comparative clinical study, the timing and occurrence of multiple clinical events are typically collected during the patient's follow-up. These multiple observations reflect the patient's disease progression/burden over time. The standard practice is to create a composite endpoint from the multiple outcomes, the timing of the occurrence of the first clinical event, to evaluate the treatment via the standard survival analysis techniques. By ignoring all events after the composite outcome, this type of assessment may not be ideal. Various parametric or semiparametric procedures have been extensively discussed in the literature for the purposes of analyzing multiple event-time data. Many existing methods were developed based on extensive model assumptions. When the model assumptions are not plausible, the resulting inferences for the treatment effect may be misleading. In this article, we propose a simple, nonparametric inference procedure to quantify the treatment effect, which has an intuitive clinically meaningful interpretation. We use the data from a cardiovascular clinical trial for heart failure to illustrate the procedure. A simulation study is also conducted to evaluate the performance of the new proposal.

  View details for PubMedID 30047148

• Meta-analysis to Evaluate High-Dose Therapy Followed by Stem Cell Transplant in Patients With Multiple Myeloma JAMA ONCOLOGY Claggett, B., Tian, L., Wei, L. 2018; 4 (11): 1617–18

  View details for PubMedID 30098159

• Elafin Treatment Rescues EGFR-Klf4 Signaling and Lung Cell Survival in Ventilated Newborn Mice. American journal of respiratory cell and molecular biology Alejandre Alcazar, M. A., Kaschwich, M., Ertsey, R., Preuss, S., Milla, C., Mujahid, S., Masumi, J., Khan, S., Mokres, L. M., Tian, L., Mohr, J., Hirani, D. V., Rabinovitch, M., Bland, R. D. 2018; 59 (5): 623–34

  Abstract

  Mechanical ventilation with O2-rich gas (MV-O2) inhibits alveologenesis and lung growth. We previously showed that MV-O2 increased elastase activity and apoptosis in lungs of newborn mice, whereas elastase inhibition by elafin suppressed apoptosis and enabled lung growth. Pilot studies suggested that MV-O2 reduces lung expression of prosurvival factors phosphorylated epidermal growth factor receptor (pEGFR) and Kruppel-like factor 4 (Klf4). Here, we sought to determine whether apoptosis and lung growth arrest evoked by MV-O2 reflect disrupted pEGFR-Klf4 signaling, which elafin treatment preserves, and to assess potential biomarkers of bronchopulmonary dysplasia (BPD). Five-day-old mice underwent MV with air or 40% O2 for 8-24 hours with or without elafin treatment. Unventilated pups served as controls. Immunoblots were used to assess lung pEGFR and Klf4 proteins. Cultured MLE-12 cells were exposed to AG1478 (EGFR inhibitor), Klf4 siRNA, or vehicle to assess effects on proliferation, apoptosis, and EGFR regulation of Klf4. Plasma elastase and elafin levels were measured in extremely premature infants. In newborn mice, MV with air or 40% O2 inhibited EGFR phosphorylation and suppressed Klf4 protein content in lungs (vs. unventilated controls), yielding increased apoptosis. Elafin treatment inhibited elastase, preserved lung pEGFR and Klf4, and attenuated the apoptosis observed in lungs of vehicle-treated mice. In MLE-12 studies, pharmacological inhibition of EGFR and siRNA suppression of Klf4 increased apoptosis and reduced proliferation, and EGFR inhibition decreased Klf4. Plasma elastase levels were more than twofold higher, without a compensating increase of plasma elafin, in infants with BPD, compared to infants without BPD. These findings indicate that pEGFR-Klf4 is a novel prosurvival signaling pathway in lung epithelium that MV disrupts. Elafin preserves pEGFR-Klf4 signaling and inhibits apoptosis, thereby enabling lung growth during MV. Together, our animal and human data raise the question: would elastase inhibition prevent BPD in high-risk infants exposed to MV-O2?

  View details for PubMedID 29894205

• Change in Survival in Metastatic Breast Cancer with Treatment Advances: Meta-Analysis and Systematic Review. JNCI cancer spectrum Caswell-Jin, J. L., Plevritis, S. K., Tian, L., Cadham, C. J., Xu, C., Stout, N. K., Sledge, G. W., Mandelblatt, J. S., Kurian, A. W. 2018; 2 (4): pky062

  Abstract

  Metastatic breast cancer (MBC) treatment has changed substantially over time, but we do not know whether survival post-metastasis has improved at the population level.We searched for studies of MBC patients that reported survival after metastasis in at least two time periods between 1970 and the present. We used meta-regression models to test for survival improvement over time in four disease groups: recurrent, recurrent estrogen (ER)-positive, recurrent ER-negative, and de novo stage IV. We performed sensitivity analyses based on bias in some studies that could lead earlier cohorts to include more aggressive cancers.There were 15 studies of recurrent MBC (N = 18 678 patients; 3073 ER-positive and 1239 ER-negative); meta-regression showed no survival improvement among patients recurring between 1980 and 1990, but median survival increased from 21 (95% confidence interval [CI] = 18 to 25) months to 38 (95% CI = 31 to 47) months from 1990 to 2010. For ER-positive MBC patients, median survival increased during 1990-2010 from 32 (95% CI = 23 to 43) to 57 (95% CI = 37 to 87) months, and for ER-negative MBC patients from 14 (95% CI = 11 to 19) to 33 (95% CI = 21 to 51) months. Among eight studies (N = 35 831) of de novo stage IV MBC, median survival increased during 1990-2010 from 20 (95% CI = 16 to 24) to 31 (95% CI = 24 to 39) months. Results did not change in sensitivity analyses.By bridging studies over time, we demonstrated improvements in survival for recurrent and de novo stage IV MBC overall and across ER-defined subtypes since 1990. These results can inform patient-doctor discussions about MBC prognosis and therapy.

  View details for DOI 10.1093/jncics/pky062

  View details for PubMedID 30627694

  View details for PubMedCentralID PMC6305243

• Estimating and Interpreting the Overall Survival Benefit of Checkpoint Inhibitors via Meta-analysis JAMA ONCOLOGY Uno, H., Tian, L., Wei, L. 2018; 4 (8): 1137–38

  View details for PubMedID 29931103

• Sex as a predictor of response to cancer immunotherapy. The Lancet. Oncology Claggett, B., Tian, L., McCaw, Z. R., Takeuchi, M., Wei, L. J. 2018; 19 (8): e377

  View details for DOI 10.1016/S1470-2045(18)30517-5

  View details for PubMedID 30102227

• Sex as a predictor of response to cancer immunotherapy LANCET ONCOLOGY Claggett, B., Tian, L., McCaw, Z. R., Takeuchi, M., Wei, L. 2018; 19 (8): E377

  View details for Web of Science ID 000440573800012

• Peripheral artery disease, calf skeletal muscle mitochondrial DNA copy number, and functional performance VASCULAR MEDICINE McDermott, M. M., Peterson, C. A., Sufit, R., Ferrucci, L., Guralnik, J. M., Kibbe, M. R., Polonsky, T. S., Tian, L., Criqui, M. H., Zhao, L., Stein, J. H., Li, L., Leeuwenburgh, C. 2018; 23 (4): 340–48

  Abstract

  In people without lower extremity peripheral artery disease (PAD), mitochondrial DNA copy number declines with aging, and this decline is associated with declines in mitochondrial activity and functional performance. However, whether lower extremity ischemia is associated with lower mitochondrial DNA copy number and whether mitochondrial DNA copy number is associated with the degree of functional impairment in people with PAD is unknown. In people with and without PAD, age 65 years and older, we studied associations of the ankle-brachial index (ABI) with mitochondrial DNA copy number and associations of mitochondrial DNA copy number with functional impairment. Calf muscle biopsies were obtained from 34 participants with PAD (mean age: 73.5 years (SD 6.4), mean ABI: 0.67 (SD 0.15), mean 6-minute walk distance: 1191 feet (SD 223)) and 10 controls without PAD (mean age: 73.1 years (SD 4.7), mean ABI: 1.14 (SD 0.07), mean 6-minute walk distance: 1387 feet (SD 488)). Adjusting for age and sex, lower ABI values were associated with higher mitochondrial DNA copy number, measured in relative copy number (ABI<0.60: 914, ABI 0.60-0.90: 731, ABI 0.90-1.50: 593; p trend=0.016). The association of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity differed significantly between participants with versus without PAD ( p-value for interaction=0.001 and p=0.015, respectively). The correlation coefficient between mitochondrial DNA copy number and the 6-minute walk distance was 0.653 ( p=0.056) among people without PAD and -0.254 ( p=0.154) among people with PAD and ABI < 0.90. In conclusion, lower ABI values are associated with increased mitochondrial DNA copy number. Associations of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity significantly differed between people with versus without PAD, with stronger positive associations observed in people without PAD than in people with PAD. The cross-sectional and exploratory nature of the analyses precludes conclusions regarding causal inferences. ClinicalTrials.gov Identifier: NCT02246660.

  View details for PubMedID 29734865

• US Molecular Imaging of Acute Ileitis: Anti-Inflammatory Treatment Response Monitored with Targeted Microbubbles in a Preclinical Model. Radiology Wang, H., Hyvelin, J., Felt, S. A., Guracar, I., Vilches-Moure, J. G., Cherkaoui, S., Bettinger, T., Tian, L., Lutz, A. M., Willmann, J. K. 2018: 172600

  Abstract

  Purpose To evaluate whether dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in an acute terminal ileitis model in swine. Materials and Methods The Institutional Animal Care and Use Committee approved all animal studies. Fourteen swine with chemically induced acute terminal ileitis (day 0) were randomized into the following groups: (a) an anti-inflammatory treatment group (n = 8; meloxicam, 0.25 mg per kilogram of body weight; prednisone, 0.5 mg/kg) and (b) a control group (n = 6; saline). US molecular imaging was performed with a clinical US machine after intravenous injection of clinically translatable dual P- and E-selectin-targeted microbubbles (5 * 108/kg). Three inflamed bowel segments per swine were imaged at baseline, as well as on days 1, 3, and 6 after treatment initiation. At day 6, bowel segments were analyzed ex vivo for selectin expression levels by using quantitative immunofluorescence. Results After induction of inflammation, US molecular imaging signal increased at day 1 in both animal groups (P < .001). At day 3, signal in the treatment group decreased (P < .001 vs day 1), while signal in control animals did not significantly change (P = .18 vs day 1) and was higher (P = .001) compared with that in the treatment group. At day 6, signal in the treatment group further decreased and remained lower (P = .02) compared with that in the control group. Immunofluorescence confirmed significant (P ≤ .04) downregulation of both P- and E-selectin expression levels in treated versus control bowel segments. Conclusion Dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in a large-animal model of acute ileitis. This supports further clinical development of this quantitative and radiation-free technique for monitoring inflammatory bowel disease.

  View details for PubMedID 30040040

• Matrix Metalloprotease-9 (MMP-9)-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circulation research Watanabe, R., Maeda, T., Zhang, H., Berry, G. J., Zeisbrich, M., Brockett, R. D., Greenstein, A. E., Tian, L., Goronzy, J., Weyand, C. M. 2018

  Abstract

  Rationale: Giant cell arteritis (GCA), a primary vasculitis of medium and large arteries, is associated with vessel wall damage, elastic membrane fragmentation and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. Objective: The matrix metalloproteinase 9 (MMP-9), a type IV collagenase, is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. Methods and Results: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from GCA patients. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting recombinant MMP-9. Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates (p<0.001), reduced intramural neoangiogenesis (p<0.001) and prevented intimal layer hyperplasia (p<0.001). Recombinant MMP-9 amplified all domains of vasculitogenic activity, promoted assembly of T cell infiltrates (p<0.05), intensified formation of new microvessels (p<0.001) and worsened intimal thickening (p<0.001). Systemic delivery of N-acetyl-proline-glycine-proline (ac-PGP), a matrikine produced by MMP-9-mediated gelatinolysis, had limited vasculitogenic effects. Conclusions: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks and neointimal growth all require the enzymatic activity of MMP-9; identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

  View details for PubMedID 29970365

• Six-minute walk performance as a predictor of lower extremity events in people with peripheral artery disease Nayak, P., Criqui, M. H., Ferrucci, L., Guralnik, J., Kibbe, M., Polonsky, T., Tian, L., Zhao, L., McDermott, M. M. SAGE PUBLICATIONS LTD. 2018: 317

  View details for Web of Science ID 000433926000043

• Efficiency of two sample tests via the restricted mean survival time for analyzing event time observations BIOMETRICS Tian, L., Fu, H., Ruberg, S. J., Uno, H., Wei, L. 2018; 74 (2): 694–702

  Abstract

  In comparing two treatments with the event time observations, the hazard ratio (HR) estimate is routinely used to quantify the treatment difference. However, this model dependent estimate may be difficult to interpret clinically especially when the proportional hazards (PH) assumption is violated. An alternative estimation procedure for treatment efficacy based on the restricted means survival time or t-year mean survival time (t-MST) has been discussed extensively in the statistical and clinical literature. On the other hand, a statistical test via the HR or its asymptotically equivalent counterpart, the logrank test, is asymptotically distribution-free. In this article, we assess the relative efficiency of the hazard ratio and t-MST tests with respect to the statistical power under various PH and non-PH models theoretically and empirically. When the PH assumption is valid, the t-MST test performs almost as well as the HR test. For non-PH models, the t-MST test can substantially outperform its HR counterpart. On the other hand, the HR test can be powerful when the true difference of two survival functions is quite large at end but not the beginning of the study. Unfortunately, for this case, the HR estimate may not have a simple clinical interpretation for the treatment effect due to the violation of the PH assumption.

  View details for PubMedID 28901017

  View details for PubMedCentralID PMC5847424

• Quantification of Long-term Survival Benefit in a Comparative Oncology Clinical Study JAMA ONCOLOGY Horiguchi, M., Tian, L., Uno, H., Cheng, S., Kim, D., Schrag, D., Wei, L. 2018; 4 (6): 881–82

  View details for PubMedID 29801103

• Evaluating Treatment Effect Based on Duration of Response for a Comparative Oncology Study JAMA ONCOLOGY Huang, B., Tian, L., Talukder, E., Rothenberg, M., Kim, D., Wei, L. 2018; 4 (6): 874–76

  View details for PubMedID 29710201

• Changes in calf skeletal muscle characteristics and decline in walking performance in peripheral artery disease Ali, A., Ferrucci, L., Guralnik, J., Criqui, M. H., Polonsky, T., Zhao, L., Kibbe, M., Tian, L., McDermott, M. M. SAGE PUBLICATIONS LTD. 2018: 311

  View details for Web of Science ID 000433926000032

• Racial differences in granulocyte macrophage colony-stimulating factor (GM-CSF) effects on walking performance in peripheral artery disease: The PROPEL randomized clinical trial McDermott, M. M., Kibbe, M., Criqui, M., Ferrucci, L., Tian, L., Lloyd-Jones, D., Zhao, L., Domanchuk, K., Polonsky, T. SAGE PUBLICATIONS LTD. 2018: 309–10

  View details for Web of Science ID 000433926000030

• Durability of supervised treadmill exercise benefits in people with peripheral artery disease Patel, K. H., Kibbe, M., Guralnik, J., Leeuwenburgh, C., Sufit, R., Tian, L., Ferrucci, L., Polonsky, T., Criqui, M. H., McDermott, M. M. SAGE PUBLICATIONS LTD. 2018: 301–2

  View details for Web of Science ID 000433926000019

• Associations of weight change with calf muscle characteristics and functional decline in adults with peripheral artery disease Polonsky, T. S., Tian, L., Criqui, M., Ferrucci, L., Guralnick, J., Kibbe, M., Sufit, R., McDermott, M. M. SAGE PUBLICATIONS LTD. 2018: 317–18

  View details for Web of Science ID 000433926000044

• Longitudinal assessment of ultrasound-guided complementary microRNA therapy of hepatocellular carcinoma. Journal of controlled release : official journal of the Controlled Release Society Chowdhury, S. M., Lee, T., Bachawal, S. V., Devulapally, R., Abou-Elkacem, L., Yeung, T. A., Wischhusen, J., Tian, L., Dahl, J., Paulmurugan, R., Willmann, J. K. 2018

  Abstract

  Hepatocellular carcinoma (HCC) is the second-leading cause of cancer related deaths worldwide and new strategies to efficiently treat HCC are critically needed. The aim of this study was to assess the longitudinal treatment effects of two complementary miRNAs (miRNA-122 and antimiR-21) encapsulated in biodegradable poly lactic-co-glycolic acid (PLGA) - poly ethylene glycol (PEG) nanoparticles (PLGA-PEG-NPs), administered by an ultrasound-guided and microbubble-mediated delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Using in vitro assays, we show that repeated miRNA treatments resulted in gradual reduction of HCC cell proliferation and reversal of doxorubicin resistance. Optimized US parameters resulted in a 9-16 fold increase (p = 0.03) in miRNA delivery in vivo in HCC tumors after two US treatments compared to tumors without US treatment. Furthermore, when combined with doxorubicin (10 mg/kg), longitudinal miRNA delivery showed a significant inhibition of tumor growth in both resistant and non-resistant tumors compared to non-treated, and doxorubicin treated controls. We also found that ultrasound-guided miRNA therapy was not only effective in inhibiting HCC tumor growth but also allowed lowering the dose of doxorubicin needed to induce apoptosis. In conclusion, the results of this study suggest that ultrasound-guided and MB-mediated delivery of miRNA-122 and antimiR-21, when combined with doxorubicin, is a highly effective approach to treat resistant HCC while reducing doxorubicin doses needed for treating non-resistant HCC in longitudinal treatment experiments. Further refinement of this strategy could potentially lead to better treatment outcomes for patients with HCC.

  View details for PubMedID 29758233

• Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis CIRCULATION Zhang, H., Watanabe, R., Berry, G. J., Tian, L., Goronzy, J. J., Weyand, C. M. 2018; 137 (18): 1934–48

  Abstract

  Giant cell arteritis, a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells attract CD4+ T cells and macrophages to form prototypic granulomatous infiltrates. Vasculitic lesions contain a diverse array of effector T cells that persist despite corticosteroid therapy and sustain chronic, smoldering vasculitis. Transmural inflammation induces microvascular neoangiogenesis and results in lumen-occlusive intimal hyperplasia. We have examined whether persistent vessel wall inflammation is maintained by lesional T cells, including the newly identified tissue-resident memory T cells, and whether such T cells are sensitive to the cytokine-signaling inhibitor tofacitinib, a Janus kinase (JAK) inhibitor targeting JAK3 and JAK1.Vascular inflammation was induced in human arteries engrafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant cell arteritis. Mice carrying inflamed human arteries were treated with tofacitinib or vehicle. Vasculitic arteries were examined for gene expression (reverse transcription polymerase chain reaction), protein expression (immunohistochemistry), and infiltrating cell populations (flow cytometry).Tofacitinib effectively suppressed innate and adaptive immunity in the vessel wall. Lesional T cells responded to tofacitinib with reduced proliferation rates (<10%) and minimal production of the effector molecules interferon-γ, interleukin-17, and interleukin-21. Tofacitinib disrupted adventitial microvascular angiogenesis, reduced outgrowth of hyperplastic intima, and minimized CD4+CD103+ tissue-resident memory T cells.Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflammation of medium and large arteries. The JAK inhibitor tofacitinib effectively suppresses tissue-resident memory T cells and inhibits core vasculitogenic effector pathways.

  View details for PubMedID 29254929

  View details for PubMedCentralID PMC5930040

• Computed Tomography Features associated With the Eighth Edition TNM Stage Classification for Thymic Epithelial Tumors JOURNAL OF THORACIC IMAGING Padda, S. K., Terrone, D., Tian, L., Khuong, A., Neal, J. W., Riess, J. W., Berry, M. F., Hoang, C. D., Burt, B. M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. 2018; 33 (3): 176–83

  Abstract

  The eighth edition of the TNM classification of malignant tumors for the first time includes an official staging system for thymic epithelial tumors (TETs) recognized by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). Staging is critical for the management of TETs, and determining stage accurately from imaging has the potential to improve clinical outcomes. We examine preoperative computed tomography (CT) characteristics of TETs associated with AJCC/UICC pathologic TNM stage.In this retrospective study, patients were included if they met all the following criteria: (1) diagnosis of TET, (2) had primary curative intent surgery performed at Stanford University, and (3) had available preoperative CT imaging for review. Tumor pathology was staged according to the eighth edition TNM classification. Fifteen CT scan features were examined from each patient case according to the International Thymic Malignancy Interest Group standard report terms in a blinded manner. A Lasso-regularized multivariate model was used to produce a weighted scoring system predictive of pathologic TNM stage.Examining the 54 patients included, the following CT characteristics were associated with higher pathologic TNM stage when using the following scoring system: elevated hemidiaphragm (score of 6), vascular endoluminal invasion (score of 6), pleural nodule (score of 2), lobulated contour (score of 2), and heterogeneous internal density (score of 1). Area under the receiver operating characteristic curve was 0.76.TETs with clearly invasive or metastatic features seen on CT are associated with having higher AJCC/UICC pathologic TNM stage, as expected. However, features of lobulated contour and heterogeneous internal density are also associated with higher stage disease. These findings need to be validated in an independent cohort.

  View details for PubMedID 29219888

• Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone Coaching on Walking Performance in Peripheral Artery Disease The HONOR Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION McDermott, M. M., Spring, B., Berger, J. S., Treat-Jacobson, D., Conte, M. S., Creager, M. A., Criqui, M. H., Ferrucci, L., Gornik, H. L., Guralnik, J. M., Hahn, E. A., Henke, P., Kibbe, M. R., Kohlman-Trighoff, D., Li, L., Lloyd-Jones, D., McCarthy, W., Polonsky, T. S., Skelly, C., Tian, L., Zhao, L., Zhang, D., Rejeski, J. 2018; 319 (16): 1665–76

  Abstract

  Clinical practice guidelines support home-based exercise for patients with peripheral artery disease (PAD), but no randomized trials have tested whether an exercise intervention without periodic medical center visits improves walking performance.To determine whether a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching improves walking ability over 9 months in patients with PAD.Randomized clinical trial conducted at 3 US medical centers. Patients with PAD were randomized between June 18, 2015, and April 4, 2017, to home-based exercise vs usual care for 9 months. Final follow-up was on December 5, 2017.The exercise intervention group (n = 99) received 4 weekly medical center visits during the first month followed by 8 months of a wearable activity monitor and telephone coaching. The usual care group (n = 101) received no onsite sessions, active exercise, or coaching intervention.The primary outcome was change in 6-minute walk distance at 9-month follow-up (minimal clinically important difference [MCID], 20 m). Secondary outcomes included 9-month change in subcomponents of the Walking Impairment Questionnaire (WIQ) (0-100 score; 100, best), SF-36 physical functioning score, Patient-Reported Outcomes Measurement Information System (PROMIS) mobility questionnaire (higher = better; MCID, 2 points), PROMIS satisfaction with social roles questionnaire, PROMIS pain interference questionnaire (lower = better; MCID range, 3.5-4.5 points), and objectively measured physical activity.Among 200 randomized participants (mean [SD] age, 70.2 [10.4] years; 105 [52.5%] women), 182 (91%) completed 9-month follow-up. The mean change from baseline to 9-month follow-up in the 6-minute walk distance was 5.5 m in the intervention group vs 14.4 m in the usual care group (difference, -8.9 m; 95% CI, -26.0 to 8.2 m; P = .31). The exercise intervention worsened the PROMIS pain interference score, mean change from baseline to 9 months was 0.7 in the intervention group vs -2.8 in the usual care group (difference, 3.5; 95% CI, 1.3 to 5.8; P = .002). There were no significant between-group differences in the WIQ score, the SF-36 physical functioning score, or the PROMIS mobility or satisfaction with social roles scores.Among patients with PAD, a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching, compared with usual care, did not improve walking performance at 9-month follow-up. These results do not support home-based exercise interventions of wearable devices and telephone counseling without periodic onsite visits to improve walking performance in patients with PAD.clinicaltrials.gov Identifier: NCT02462824.

  View details for PubMedID 29710165

  View details for PubMedCentralID PMC5933394

• Somatic items on the Beck Depression Inventory-II do not affect self-reported depression severity in Parkinson's disease Ramirez, V., Hendershott, T. R., Faridi, N., Zhu, D., Tian, L., Poston, K. L. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090800073

• Estimating Treatment Effect With Clinical Interpretation From a Comparative Clinical Trial With an End Point Subject to Competing Risks JAMA CARDIOLOGY Zhao, L., Tian, D., Claggett, B., Pfeffer, M., Kim, D., Solomon, S., Wei, L. 2018; 3 (4): 357–58

  View details for PubMedID 29541747

  View details for PubMedCentralID PMC5875301

• The ROC curve for regularly measured longitudinal biomarkers. Biostatistics (Oxford, England) Michael, H., Tian, L., Ghebremichael, M. 2018

  Abstract

  The receiver operating characteristic (ROC) curve is a commonly used graphical summary of the discriminative capacity of a thresholded continuous scoring system for a binary outcome. Estimation and inference procedures for the ROC curve are well-studied in the cross-sectional setting. However, there is a paucity of research when both biomarker measurements and disease status are observed longitudinally. In a motivating example, we are interested in characterizing the value of longitudinally measured CD4 counts for predicting the presence or absence of a transient spike in HIV viral load, also time-dependent. The existing method neither appropriately characterizes the diagnostic value of observed CD4 counts nor efficiently uses status history in predicting the current spike status. We propose to jointly model the binary status as a Markov chain and the biomarkers levels, conditional on the binary status, as an autoregressive process, yielding a dynamic scoring procedure for predicting the occurrence of a spike. Based on the resulting prediction rule, we propose several natural extensions of the ROC curve to the longitudinal setting and describe procedures for statistical inference. Lastly, extensive simulations have been conducted to examine the small sample operational characteristics of the proposed methods.

  View details for PubMedID 29608649

• Guest Editorial for the 14th Asia Pacific Bioinformatics Conference IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS Tang, J., Tian, L., Chen, Y. 2018; 15 (2): 396–97

  View details for DOI 10.1109/TCBB.2018.2804960

  View details for Web of Science ID 000428936900006

• Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA neurology Sha, S. J., Deutsch, G. K., Tian, L. n., Richardson, K. n., Coburn, M. n., Gaudioso, J. L., Marcal, T. n., Solomon, E. n., Boumis, A. n., Bet, A. n., Mennes, M. n., van Oort, E. n., Beckmann, C. F., Braithwaite, S. P., Jackson, S. n., Nikolich, K. n., Stephens, D. n., Kerchner, G. A., Wyss-Coray, T. n. 2018

  Abstract

  Young mouse plasma restores memory in aged mice, but, to our knowledge, the effects are unknown in patients with Alzheimer disease (AD).To assess the safety, tolerability, and feasibility of infusions of young fresh frozen plasma (yFFP) from donors age 18 to 30 years in patients with AD.The Plasma for Alzheimer Symptom Amelioration (PLASMA) study randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed by a 6-week washout and crossover to 4 once-weekly infusions of an alternate treatment. Patients and informants were masked to treatment and subjective measurements. After an open-label amendment, 9 patients received 4 weekly yFFP infusions only and their subjective measurements were unmasked. Patients were enrolled solely at Stanford University, a tertiary academic medical center, from September 2014 to December 2016, when enrollment reached its target. Eighteen consecutive patients with probable mild to moderate AD dementia, a Mini-Mental State Examination (score of 12 to 24 inclusive), and an age of 50 to 90 years were enrolled. Thirty-one patients were screened and 13 were excluded: 11 failed the inclusion criteria and 2 declined to participate.One unit of yFFP from male donors/placebo infused once weekly for 4 weeks.The primary outcomes were the safety, tolerability, and feasibility of 4 weekly yFFP infusions. Safety end point analyses included all patients who received the study drug/placebo.There was no difference in the age (mean [SD], 74.17 [7.96] years), sex (12 women [67%]), or baseline Mini-Mental State Examination score (mean [SD], 19.39 [3.24]) between the crossover (n = 9) and open-label groups (n = 9). There were no related serious adverse events. One patient discontinued participation because of urticaria and another because of an unrelated stroke. There was no statistically significant difference between the plasma (17 [94.4%]) and placebo (9 [100.0%]) cohorts for other adverse events, which were mild to moderate in severity. The most common adverse events in the plasma group included hypertension (3 [16.7%]), dizziness (2 [11.1%]), sinus bradycardia (3 [16.7%]), headache (3 [16.7%]), and sinus tachycardia (3 [16.7%]). The mean visit adherence (n = 18) was 86% (interquartile range, 87%-100%) and adherence, accounting for a reduction in the total visit requirement due to early patient discontinuation, was 96% (interquartile range, 89%-100%).The yFFP treatment was safe, well tolerated, and feasible. The study's limitations were the small sample size, short duration, and change in study design. The results warrant further exploration in larger, double-blinded placebo-controlled clinical trials.ClinicalTrials.gov Identifier: NCT02256306.

  View details for PubMedID 30383097

• Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review JNCI Cancer Spectrum Caswell-Jin, J. L., Plevritis, S. K., Tian, L., Cadham, C. J., Xu, C., Stout, N. K., Sledge, G. W., Mandelblatt, J. S., Kurian, A. W. 2018; 2 (4)

  View details for DOI 10.1093/jncics/pky062

• An efficient numerical algorithm for exact inference in meta analysis JOURNAL OF STATISTICAL COMPUTATION AND SIMULATION Wang, Y., Tian, L. 2018; 88 (4): 646–56

  View details for DOI 10.1080/00949655.2017.1402331

  View details for Web of Science ID 000426934600003

• Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research Abou-Elkacem, L. n., Wang, H. n., Chowdhury, S. M., Kimura, R. H., Bachawal, S. V., Gambhir, S. S., Tian, L. n., Willmann, J. K. 2018

  Abstract

  To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble-enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC). Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MB Thy1-scFv. Thy1 binding of MB Thy1-scFv to Thy1-expressing cells was evaluated under flow shear stress conditions in flow-chamber experiments. MB scFv-scrambled and MB Non-targeted were used as negative controls. All microbubble types were tested in both orthotopic human PDAC xenografts and transgenic PDAC mice in vivo. Results: Thy1-scFv had a K D of 3.4±0.36 nM for human and 9.2±1.7 nM for murine Thy1 and showed binding to both soluble and cellularly expressed Thy1. MB Thy1-scFv attached to Thy1 with high affinity compared to negative control microbubbles P<0.01) as assessed by flow cytometry. Similarly, flow-chamber studies showed significantly (P<0.01) higher binding of MB Thy1-scFv (3.0±0.81 MB/cell) to Thy1-expressing cells than MB scFv-scrambled (0.57±0.53) and MB Non-targeted (0.43±0.53). In vivo ultrasound molecular imaging using MB Thy1-scFv demonstrated significantly higher signal (P<0.01) in both orthotopic (5.32±1.59 a.u.) and transgenic PDAC (5.68±2.5 a.u.) mice compared to chronic pancreatitis (0.84±0.6 a.u.) and normal pancreas (0.67±0.71 a.u.). Ex vivo immunofluorescence confirmed significantly (P<0.01) increased Thy1 expression in PDAC compared to chronic pancreatitis and normal pancreas tissue. Conclusions: A dual human and murine Thy1-binding scFv was designed to generate contrast microbubbles to allow PDAC detection with ultrasound.

  View details for PubMedID 29301827

• Anatomical Road Mapping Using CT and MR Enterography for Ultrasound Molecular Imaging of Small Bowel Inflammation in Swine. European radiology Wang, H. n., Felt, S. A., Guracar, I. n., Taviani, V. n., Zhou, J. n., Sigrist, R. M., Zhang, H. n., Liau, J. n., Vilches-Moure, J. G., Tian, L. n., Saenz, Y. n., Bettinger, T. n., Hargreaves, B. A., Lutz, A. M., Willmann, J. K. 2018; 28 (5): 2068–76

  Abstract

  To evaluate the feasibility and time saving of fusing CT and MR enterography with ultrasound for ultrasound molecular imaging (USMI) of inflammation in an acute small bowel inflammation of swine.Nine swine with ileitis were scanned with either CT (n = 3) or MR (n = 6) enterography. Imaging times to load CT/MR images onto a clinical ultrasound machine, fuse them to ultrasound with an anatomical landmark-based approach, and identify ileitis were compared to the imaging times without anatomical road mapping. Inflammation was then assessed by USMI using dual selectin-targeted (MBSelectin) and control (MBControl) contrast agents in diseased and healthy control bowel segments, followed by ex vivo histology.Cross-sectional image fusion with ultrasound was feasible with an alignment error of 13.9 ± 9.7 mm. Anatomical road mapping significantly reduced (P < 0.001) scanning times by 40%. Localising ileitis was achieved within 1.0 min. Subsequently performed USMI demonstrated significantly (P < 0.001) higher imaging signal using MBSelectin compared to MBControl and histology confirmed a significantly higher inflammation score (P = 0.006) and P- and E-selectin expression (P ≤ 0.02) in inflamed vs. healthy bowel.Fusion of CT and MR enterography data sets with ultrasound in real time is feasible and allows rapid anatomical localisation of ileitis for subsequent quantification of inflammation using USMI.• Real-time fusion of CT/MRI with ultrasound to localise ileitis is feasible. • Anatomical road mapping using CT/MRI significantly decreases the scanning time for USMI. • USMI allows quantification of inflammation in swine, verified with ex vivo histology.

  View details for PubMedID 29170798

• Granulocyte Macrophage Colony-Stimulating Factor With and Without Supervised Exercise to Improve Walking Performance in Peripheral Artery Disease: The PROPEL Randomized Clinical Trial McDermott, M. M., Criqui, M. H., Guralnik, J. M., Kibbe, M., Tian, L., Lloyd-Jones, D., Zhao, L., Domanchuk, K., Polonsky, T., Stein, J. H., Perlman, H., Skelly, C., Pearce, W., Taylor, D., Gao, Y., Sufit, R., Ferrucci, L. LIPPINCOTT WILLIAMS & WILKINS. 2017: E462–E463

  View details for Web of Science ID 000417682700032

• Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease The PROPEL Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION McDermott, M., Ferrucci, L., Tian, L., Guralnik, J. M., Lloyd-Jones, D., Kibbe, M. R., Polonsky, T. S., Domanchuk, K., Stein, J. H., Zhao, L., Taylor, D., Skelly, C., Pearce, W., Perlman, H., McCarthy, W., Li, L., Gao, Y., Sufit, R., Bloomfield, C. L., Criqui, M. H. 2017; 318 (21): 2089–98

  Abstract

  Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle.To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention.Randomized clinical trial with 2 × 2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control  + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The final follow-up visit was on August 15, 2017.Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 μg/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention.The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method.Of 827 persons evaluated, 210 participants with PAD were randomized (mean age, 67.0 [SD, 8.6] years; 141 [67%] black, 82 [39%] women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, -6.3 m [95% CI, -30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, -1.4 m [95% CI, -25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02).Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control + placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD.clinicaltrials.gov Identifier: NCT01408901.

  View details for PubMedID 29141087

  View details for PubMedCentralID PMC5820720

• Interpretability of Cancer Clinical Trial Results Using Restricted Mean Survival Time as an Alternative to the Hazard Ratio JAMA ONCOLOGY Pak, K., Uno, H., Kim, D., Tian, L., Kane, R. C., Takeuchi, M., Fu, H., Claggett, B., Wei, L. 2017; 3 (12): 1692–96

  Abstract

  In a comparative clinical study with progression-free survival (PFS) or overall survival (OS) as the end point, the hazard ratio (HR) is routinely used to design the study and to estimate the treatment effect at the end of the study. The clinical interpretation of the HR may not be straightforward, especially when the underlying model assumption is not valid. A robust procedure for study design and analysis that enables clinically meaningful interpretation of trial results is warranted.To discuss issues of conventional trial design and analysis and to present alternatives to the HR using a recent immunotherapy study as an illustrative example.By comparing 2 groups in a survival analysis, we discuss issues of using the HR and present the restricted mean survival time (RMST) as a summary measure of patients’ survival profile over time. We show how to use the difference or ratio in RMST between 2 groups as an alternative for designing and analyzing a clinical study with an immunotherapy study as an illustrative example.Overall survival or PFS. Group contrast measures included HR, RMST difference or ratio, and the event rate difference.For the illustrative example, the HR procedure indicates that nivolumab significantly prolonged patient OS and was numerically better than docetaxel for PFS. However, the median PFS time of docetaxel was significantly better than that of nivolumab. Therefore, it may be difficult to use median OS and/or PFS to interpret of the HR value clinically. On the other hand, using RMST difference, nivolumab was significantly better than docetaxel for both OS and PFS. We also provide details regarding design of a future study with RMST-based measures.The design and analysis of a conventional cancer clinical trial can be improved by adopting a robust statistical procedure that enables clinically meaningful interpretations of the treatment effect. The RMST-based quantitative method may be used as a primary tool for future cancer trials or to help us to better understand the clinical interpretation of the HR even when its model assumption is plausible.

  View details for PubMedID 28975263

  View details for PubMedCentralID PMC5824272

• A general statistical framework for subgroup identification and comparative treatment scoring BIOMETRICS Chen, S., Tian, L., Cai, T., Yu, M. 2017; 73 (4): 1199–1209

  Abstract

  Many statistical methods have recently been developed for identifying subgroups of patients who may benefit from different available treatments. Compared with the traditional outcome-modeling approaches, these methods focus on modeling interactions between the treatments and covariates while by-pass or minimize modeling the main effects of covariates because the subgroup identification only depends on the sign of the interaction. However, these methods are scattered and often narrow in scope. In this article, we propose a general framework, by weighting and A-learning, for subgroup identification in both randomized clinical trials and observational studies. Our framework involves minimum modeling for the relationship between the outcome and covariates pertinent to the subgroup identification. Under the proposed framework, we may also estimate the magnitude of the interaction, which leads to the construction of scoring system measuring the individualized treatment effect. The proposed methods are quite flexible and include many recently proposed estimators as special cases. As a result, some estimators originally proposed for randomized clinical trials can be extended to observational studies, and procedures based on the weighting method can be converted to an A-learning method and vice versa. Our approaches also allow straightforward incorporation of regularization methods for high-dimensional data, as well as possible efficiency augmentation and generalization to multiple treatments. We examine the empirical performance of several procedures belonging to the proposed framework through extensive numerical studies.

  View details for PubMedID 28211943

  View details for PubMedCentralID PMC5561419

• Femoral artery plaque characteristics, lower extremity collaterals, and mobility loss in peripheral artery disease VASCULAR MEDICINE McDermott, M. M., Carroll, T., Carr, J., Yuan, C., Ferrucci, L., Guralnik, J. M., Kibbe, M., Criqui, M. H., Tian, L., Polonsky, T., Zhao, L., Gao, Y., Hippe, D. S., Xu, D., McCarthy, W., Kramer, C. M. 2017; 22 (6): 473–81

  Abstract

  Little is known about the prognostic significance of specific characteristics of magnetic resonance imaging (MRI) measured plaque in the superficial femoral artery (SFA). Associations of MRI-measured plaque quantity, lumen area, and plaque composition in the SFA with subsequent mobility loss were studied in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 1.00 were identified from Chicago medical centers and underwent direct visualization of atherosclerotic plaque in the SFA using MRI. Participants were followed annually for up to 4 years. Mobility loss was defined as becoming unable to walk up and down a flight of stairs or walk one-quarter of a mile without assistance among participants without mobility impairment at baseline. Analyses adjusted for age, sex, race, comorbidities, ABI, physical activity, and other confounders. Of 308 PAD participants without baseline mobility impairment, 100 (32.5%) developed mobility loss during follow-up. Compared to the lowest mean plaque area tertile at baseline, participants in the highest (worst) plaque area tertile had a higher rate of mobility loss (hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.14-3.79, p = 0.018). Compared to the highest mean lumen area tertile, the smallest (worst) mean lumen area tertile was associated with greater mobility loss (HR = 2.18, 95% CI = 1.20-3.96, p = 0.011). Neither lipid rich necrotic core nor calcium in the SFA were associated with mobility loss. In conclusion, greater plaque quantity and smaller lumen area in the proximal SFA, but not lipid rich necrotic core or calcium, were associated with higher mobility loss in people with PAD.

  View details for PubMedID 28965473

• Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging ANGIOGENESIS Zhou, J., Zhang, H., Wang, H., Lutz, A. M., El Kaffas, A., Tian, L., Hristov, D., Willmann, J. K. 2017; 20 (4): 547–55

  Abstract

  Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment (P = 0.005), but not in CT26 tumors (P > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors (P < 0.001), but not in treated versus control CT26 tumors (P = 0.796). Early decrease in both PE and AUC by 45-50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes.

  View details for PubMedID 28721500

  View details for PubMedCentralID PMC5660665

• Association of the von Willebrand Factor-ADAMTS13 Ratio With Incident Cardiovascular Events in Patients With Peripheral Arterial Disease CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS Green, D., Tian, L., Greenland, P., Liu, K., Kibbe, M., Tracy, R., Shah, S., Wilkins, J. T., Huffman, M. D., Liao, Y., Jones, D., McDermott, M. M. 2017; 23 (7): 807–13

  Abstract

  Platelet adhesion is mediated by von Willebrand factor (vWF), and disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13 (ADAMTS13) is a protease that cleaves vWF. A change in the balance between vWF and ADAMTS13 in favor of thrombosis might occur shortly before ischemic cardiovascular (CV) events.To determine whether vWF, ADAMTS13, and the ratio of vWF and ADAMTS13 change during the months preceding an acute CV event.Prospective longitudinal observational study.Outpatient.A total of 595 participants with peripheral artery disease (PAD).Blood samples were obtained every 2 months for up to 3 years and hemostatic factors examined at intervals preceding events.Sixty-one participants (cases) experienced events and were matched to 122 PAD controls. During the 2-month interval prior to an event, cases (n = 48) had higher levels of the vWF and ADAMTS13 than controls (n = 95; P = .05), but significance was lost after adjusting for the baseline differences in myocardial infarction, unstable angina, and stroke. During the 10 months prior to an event, median values for vWF and the ratio of vWF and ADAMTS13 were higher in cases than in controls, but the differences were not statistically significant. However, in a subset of 20 patients with complete bimonthly data, there was a trend toward an increase in the ratio in the 10 months prior to a CV event ( P = .04).In patients with PAD experiencing an ischemic CV event, a significant increase in the ratio of vWF to ADAMTS13 prior to the event could not be confirmed, although there was a weak trend in this direction.

  View details for PubMedID 27317583

• Plaque Composition in the Proximal Superficial Femoral Artery and Peripheral Artery Disease Events JACC-CARDIOVASCULAR IMAGING McDermott, M. M., Kramer, C. M., Tian, L., Carr, J., Guralnik, J. M., Polonsky, T., Carroll, T., Kibbe, M., Criqui, M. H., Ferrucci, L., Zhao, L., Hippe, D. S., Wilkins, J., Xu, D., Liao, Y., McCarthy, W., Yuan, C. 2017; 10 (9): 1003–12

  Abstract

  The aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the proximal superficial femoral artery (SFA) with lower extremity peripheral artery disease (PAD) event rates and systemic cardiovascular event rates.LRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied previously in lower extremity arteries.Participants with ankle-brachial index (ABI) values <1.00 were identified from Chicago medical centers and followed annually. Magnetic resonance imaging was used to characterize SFA atherosclerotic plaque at baseline. Medical records for hospitalizations and procedures after baseline were adjudicated for lower extremity revascularization, amputation, and critical limb ischemia and also for new coronary events, ischemic stroke, and mortality.Of 254 participants with PAD, 62 (24%) had LRNC and 149 (59%) had calcium in the SFA at baseline. Cox regression analyses were adjusted for age, sex, race, comorbidities, baseline ABI, and other confounders. SFA LRNC was associated with an increased incidence of the combined outcome of lower extremity amputation, critical limb ischemia, ABI decline >0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval: 1.27 to 3.75; p = 0.005). The association of SFA LRNC with PAD events was maintained even when this combined outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p = 0.01). LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke.Among patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA LRNC prevent PAD events.

  View details for PubMedID 27838307

  View details for PubMedCentralID PMC5701810

• Baseline Assessment of 25-Hydroxyvitamin D Assay Performance: A Vitamin D Standardization Program (ASP) Interlaboratory Comparison Study JOURNAL OF AOAC INTERNATIONAL Wise, S. A., Phinney, K. W., Tai, S., Camara, J. E., Myers, G. L., Durazo-Arvizu, R., Tian, L., Hoofnagle, A. N., Bachmann, L. M., Young, I. S., Pettit, J., Caldwell, G., Liu, A., Brooks, S. J., Sarafin, K., Thamm, M., Mensink, G. M., Busch, M., Rabenberg, M., Cashman, K. D., Kiely, M., Kinsella, M., Galvin, K., Zhang, J. Y., Oh, K., Lee, S., Jung, C. L., Cox, L., Goldberg, G., Guberg, K., Prentice, A., Carter, G. D., Jones, J., Brannon, P. M., Lucas, R. M., Crump, P. M., Cavalier, E., Merkel, J., Betz, J. M., Sempos, C. T. 2017; 100 (5): 1244–52

  Abstract

  The Vitamin D Standardization Program (VDSP) coordinated an interlaboratory study to assess the comparability of measurements of total 25-hydroxyvitamin D [25(OH)D] in human serum, which is the primary marker of vitamin D status. A set of 50 individual donor samples were analyzed by 15 different laboratories representing national nutrition surveys, assay manufacturers, and clinical and/or research laboratories to provide results for total 25(OH)D using both immunoassays (IAs) and LC tandem MS (MS/MS). The results were evaluated relative to bias compared with the target values assigned based on a combination of measurements at Ghent University (Belgium) and the U.S. National Institute of Standards and Technology using reference measurement procedures for the determination of 25(OH)D2 and 25(OH)D3. CV and mean bias for each laboratory and assay platform were assessed and compared with previously established VDSP performance criteria, namely CV ≤ 10% and mean bias ≤ 5%. Nearly all LC-MS/MS results achieved VDSP criteria, whereas only 50% of IAs met the criterion for a ≤10% CV and only three of eight IAs achieved the ≤5% bias. These results establish a benchmark for the evaluation of 25(OH)D assay performance and standardization activities in the future.

  View details for PubMedID 28822355

• Racial differences in functional decline in peripheral artery disease and associations with socioeconomic status and education. Journal of vascular surgery McDermott, M. M., Polonsky, T. S., Kibbe, M. R., Tian, L., Zhao, L., Pearce, W. H., Gao, Y., Guralnik, J. M. 2017; 66 (3): 826-834

  Abstract

  The objective of this study was to determine whether blacks with lower extremity peripheral artery disease (PAD) have faster functional decline than whites with PAD.Participants with ankle-brachial index <0.90 were identified from Chicago medical centers and observed longitudinally. Mobility impairment and the 6-minute walk were assessed at baseline and every 6 to 12 months. Mobility loss was defined as becoming unable to walk up and down a flight of stairs or to walk ¼ mile without assistance.Of 1162 PAD participants, 305 (26%) were black. Median follow-up was 46.0 months. Among 711 PAD participants who walked 6 minutes continuously at baseline, black participants were more likely to become unable to walk 6 minutes continuously during follow-up (64/171 [37.4%] vs 156/540 [28.9%]; log-rank, P = .006). Black race was associated with becoming unable to walk 6 minutes continuously, adjusting for age, sex, ankle-brachial index, comorbidities, and other confounders (hazard ratio, 1.45; 95% confidence interval, 1.05-1.99; P = .022). This association was attenuated after adjustment for income and education (P = .229). Among 844 participants without baseline mobility impairment, black participants had a higher rate of mobility loss (64/209 [30.6%] vs 164/635 [25.8%]; log-rank, P = .009). Black race was associated with increased mobility loss, adjusting for potential confounders (hazard ratio, 1.42; 95% confidence interval, 1.04-1.94; P = .028). This association was attenuated after additional adjustment for income and education (P = .392) and physical activity (P = .113). There were no racial differences in average annual declines in 6-minute walk, usual-paced 4-meter walking velocity, or fast-paced 4-meter walking velocity.Black PAD patients have higher rates of mobility loss and becoming unable to walk for 6 minutes continuously. These differences appear related to racial differences in socioeconomic status and physical activity.

  View details for DOI 10.1016/j.jvs.2017.02.037

  View details for PubMedID 28502539

  View details for PubMedCentralID PMC5621652

• The Vitamin D Standardization Program (VDSP) Manual for Retrospective Laboratory Standardization of Serum 25-Hydroxyvitamin D Data. Journal of AOAC International Durazo-Arvizu, R. A., Tian, L., Brooks, S. P., Sarafin, K., Cashman, K. D., Kiely, M., Merkel, J., Myers, G. L., Coates, P. M., Sempos, C. T. 2017; 100 (5): 1234-1243

  Abstract

  Low concentrations of total 25-hydroxyvitamin D [25(OH)D], the principal biological measure of vitamin D status, have been associated with clinical and public health outcomes. The determination of levels under which there is an increase in the risk of disease, as well as comparisons across populations, have been difficult to establish due the large assay variability in measuring 25(OH)D. Accordingly, the Vitamin D Standardization Program (VDSP) includes the retrospective standardization of existing 25(OH)D values collected by epidemiological and clinical studies, as well as clinical trials, as one of its main objectives. We introduce methodology developed by the VDSP that can be used to standardize the measurement of time-stable analytes, including 25(OH)D, in samples that have been banked and maintained appropriately. Sample size estimation formulae are first applied to calculate the required number of banked blood samples to be reanalyzed using either of two approaches. In the first approach, existing samples are remeasured using the current measurement procedure, and an equation relating "old" to "current" measurements is obtained. A second set of sera, usually 40-50 single-donor serum samples, are measured with the current measurement procedure and an assay traceable to a reference measurement procedure and/or certified reference materials, which yields a second calibration equation. These two equations are combined to produce standardized levels from the original old values. This approach is necessary when study restrictions prevent serum samples from being shipped to an external laboratory and is illustrated with samples from the Canadian Health Measures Survey. When serum samples are permitted to be shared with other laboratories, or the study investigators can carry out the measurements with a traceable assay, a single calibration equation method is used. Existing samples are selected and remeasured using the available traceable assay. We outline the statistical theory supporting the VDSP protocol and provide implementation examples. The methods proposed are generalizable to any instance in which banked specimens have been properly prepared and stored and the analyte of interest is stable under those conditions.

  View details for DOI 10.5740/jaoacint.17-0196

  View details for PubMedID 28718397

• Surgical clipping or endovascular coiling for unruptured intracranial aneurysms: a pragmatic randomised trial. Journal of neurology, neurosurgery, and psychiatry Darsaut, T. E., Findlay, J. M., Magro, E., Kotowski, M., Roy, D., Weill, A., Bojanowski, M. W., Chaalala, C., Iancu, D., Lesiuk, H., Sinclair, J., Scholtes, F., Martin, D., Chow, M. M., O'Kelly, C. J., Wong, J. H., Butcher, K., Fox, A. J., Arthur, A. S., Guilbert, F., Tian, L., Chagnon, M., Nolet, S., Gevry, G., Raymond, J. 2017; 88 (8): 663-668

  Abstract

  Unruptured intracranial aneurysms (UIAs) are increasingly diagnosed and are commonly treated using endovascular treatment or microsurgical clipping. The safety and efficacy of treatments have not been compared in a randomised trial. How to treat patients with UIAs suitable for both options remains unknown.We randomly allocated clipping or coiling to patients with one or more 3-25 mm UIAs judged treatable both ways. The primary outcome was treatment failure, defined as: initial failure of aneurysm treatment, intracranial haemorrhage or residual aneurysm on 1-year imaging. Secondary outcomes included neurological deficits following treatment, hospitalisation >5 days, overall morbidity and mortality and angiographic results at 1 year.The trial was designed to include 260 patients. An analysis was performed for slow accrual: 136 patients were enrolled from 2010 through 2016 and 134 patients were treated. The 1-year primary outcome, available for 104 patients, was reached in 5/48 (10.4% (4.5%-22.2%)) patients allocated surgical clipping, and 10/56 (17.9% (10.0%-29.8%)) patients allocated endovascular coiling (OR: 0.54 (0.13-1.90), p=0.40). Morbidity and mortality (modified Rankin Scale>2) at 1 year occurred in 2/48 (4.2% (1.2%-14.0%)) and 2/56 (3.6% (1.0%-12.1%)) patients allocated clipping and coiling, respectively. New neurological deficits (15/65 vs 6/69; OR: 3.12 (1.05-10.57), p=0.031), and hospitalisations beyond 5 days (30/65 vs 6/69; OR: 8.85 (3.22-28.59), p=0.0001) were more frequent after clipping.Surgical clipping or endovascular coiling of UIAs did not show differences in morbidity at 1 year. Trial continuation and additional randomised evidence will be necessary to establish the supposed superior efficacy of clipping.

  View details for DOI 10.1136/jnnp-2016-315433

  View details for PubMedID 28634280

• Effect of Resveratrol on Walking Performance in Older People With Peripheral Artery Disease: The RESTORE Randomized Clinical Trial. JAMA cardiology McDermott, M. M., Leeuwenburgh, C., Guralnik, J. M., Tian, L., Sufit, R., Zhao, L., Criqui, M. H., Kibbe, M. R., Stein, J. H., Lloyd-Jones, D., Anton, S. D., Polonsky, T. S., Gao, Y., de Cabo, R., Ferrucci, L. 2017; 2 (8): 902-907

  Abstract

  Research shows that resveratrol, a sirtuin activator in red wine, improves exercise endurance and skeletal-muscle oxidative metabolism in animals and may enhance vascular function in humans. Resveratrol supplement sales exceed $30 million annually in the United States, but few data are available regarding its efficacy in humans.To determine whether resveratrol, 125 mg/d or 500 mg/d, improves the 6-minute walk performance in patients with peripheral artery disease (PAD).This parallel-design, double-blind, randomized clinical trial, called Resveratrol to Improve Outcomes in Older People With PAD (RESTORE), was conducted at Northwestern University. Sixty-six participants 65 years or older with PAD were randomized to receive a daily capsule of resveratrol, 125 mg or 500 mg, or placebo for 6 months. Participants were randomized using a randomly permuted block method stratified by baseline 6-minute walk test performance. This trial was conducted between January 1, 2015, and August 5, 2016, and data analyses were performed according to the intention-to-treat concept.Administration of resveratrol, 125 or 500 mg/d, or placebo once daily.The primary outcome measure was the change in 6-minute walk distance at the 6-month follow-up. One of the secondary outcomes was change in maximal treadmill walking time. Because of the preliminary nature of the trial, the a priori power calculation used a 1-sided test with a significance level of P < .10.The 66 participants were predominantly men (45 [68%]), had a mean (SD) age of 74.4 (6.6) years, and had a mean (SD) ankle brachial index of 0.67 (0.18). Sixty-four (97%) completed follow-up. Six-month mean (SE) changes in 6-minute walk distance were 4.6 (8.1) m for the 125-mg resveratrol group, -12.8 (7.5) m for the 500-mg resveratrol group, and -12.3 (7.9) m for the placebo group (P = .07 for the 125-mg resveratrol group vs placebo; P = .96 for the 500-mg resveratrol group vs placebo). Six-month mean (SE) changes in maximal treadmill walking time were 0.5 (2.3) minutes for the 125-mg resveratrol group, -0.6 (2.1) minutes for the 500-mg resveratrol group, and 0.4 (2.1) minutes for the placebo group (P = .18 for the 125-mg resveratrol group vs placebo; P = .12 for the 500-mg resveratrol group vs placebo).The RESTORE trial found no consistent evidence that resveratrol improves walking performance in patients 65 years or older with PAD.clinicaltrials.gov Identifier: NCT02246660.

  View details for DOI 10.1001/jamacardio.2017.0538

  View details for PubMedID 28403379

  View details for PubMedCentralID PMC5815080

• Pulmonary hospitalizations and ischemic heart disease events in patients with peripheral artery disease VASCULAR MEDICINE McDermott, M. M., Tian, L., Wunderink, R. G., Kalhan, R., Kibbe, M. R., Greenland, P., Tracy, R., Zhao, L., Liu, K., Huffman, M., Wilkins, J. T., Liao, Y., Shah, S., Jones, D. L., Green, D. 2017; 22 (3): 218-224

  Abstract

  The prognostic significance of acute pulmonary events in people with lower extremity peripheral artery disease (PAD) is unknown. We hypothesized that an acute pulmonary event (hospitalization for pneumonia and/or chronic lower respiratory disease (CLRD) exacerbation) would be associated with a higher rate of subsequent ischemic heart disease (IHD) events in PAD. A total of 569 PAD participants were systematically identified from among patients in Chicago medical practices and followed longitudinally. Hospitalizations after enrollment were evaluated and adjudicated for pulmonary events. The primary outcome was adjudicated myocardial infarctions, unstable angina, and IHD death. Of 569 PAD participants, 34 (6.0%) were hospitalized for a pulmonary event (11 CLRD exacerbation and 23 pneumonia) during a mean follow-up of 1.52 years±0.80. Participants hospitalized for a pulmonary event had a higher rate of subsequent IHD events than those not hospitalized for a pulmonary event (10/34 (29%) vs 38/535 (7.1%), p<0.001). After adjusting for age, sex, race, comorbidities, and other confounders, a pulmonary hospitalization was associated with an increased risk of a subsequent IHD event (hazard ratio (HR) = 12.42, 95% confidence interval (CI) = 5.35 to 28.86, p<0.001). Non-pulmonary hospitalizations were also associated with IHD events (HR = 3.39, 95% CI = 1.78 to 6.44, p<0.001), but this association was less strong compared to pulmonary hospitalizations and IHD events ( p = 0.011 for difference in the strength of association). In conclusion, hospitalization for an acute pulmonary event was associated with higher risk for subsequent IHD events in PAD. Future study should examine whether hospitalization for pulmonary events warrants increased surveillance or potential intervention to prevent IHD events in PAD.

  View details for DOI 10.1177/1358863X16680461

  View details for Web of Science ID 000401148700007

  View details for PubMedID 28466756

• Evaluating surrogate marker information using censored data. Statistics in medicine Parast, L., Cai, T., Tian, L. 2017; 36 (11): 1767-1782

  Abstract

  Given the long follow-up periods that are often required for treatment or intervention studies, the potential to use surrogate markers to decrease the required follow-up time is a very attractive goal. However, previous studies have shown that using inadequate markers or making inappropriate assumptions about the relationship between the primary outcome and surrogate marker can lead to inaccurate conclusions regarding the treatment effect. Currently available methods for identifying and validating surrogate markers tend to rely on restrictive model assumptions and/or focus on uncensored outcomes. The ability to use such methods in practice when the primary outcome of interest is a time-to-event outcome is difficult because of censoring and missing surrogate information among those who experience the primary outcome before surrogate marker measurement. In this paper, we propose a novel definition of the proportion of treatment effect explained by surrogate information collected up to a specified time in the setting of a time-to-event primary outcome. Our proposed approach accommodates a setting where individuals may experience the primary outcome before the surrogate marker is measured. We propose a robust non-parametric procedure to estimate the defined quantity using censored data and use a perturbation-resampling procedure for variance estimation. Simulation studies demonstrate that the proposed procedures perform well in finite samples. We illustrate the proposed procedures by investigating two potential surrogate markers for diabetes using data from the Diabetes Prevention Program. Copyright © 2017 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/sim.7220

  View details for PubMedID 28088843

  View details for PubMedCentralID PMC5413393

• Predicting complication risk in spine surgery: a prospective analysis of a novel risk assessment tool. Journal of neurosurgery. Spine Veeravagu, A., Li, A., Swinney, C., Tian, L., Moraff, A., Azad, T. D., Cheng, I., Alamin, T., Hu, S. S., Anderson, R. L., Shuer, L., Desai, A., Park, J., Olshen, R. A., Ratliff, J. K. 2017: 1-11

  Abstract

  OBJECTIVE The ability to assess the risk of adverse events based on known patient factors and comorbidities would provide more effective preoperative risk stratification. Present risk assessment in spine surgery is limited. An adverse event prediction tool was developed to predict the risk of complications after spine surgery and tested on a prospective patient cohort. METHODS The spinal Risk Assessment Tool (RAT), a novel instrument for the assessment of risk for patients undergoing spine surgery that was developed based on an administrative claims database, was prospectively applied to 246 patients undergoing 257 spinal procedures over a 3-month period. Prospectively collected data were used to compare the RAT to the Charlson Comorbidity Index (CCI) and the American College of Surgeons National Surgery Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator. Study end point was occurrence and type of complication after spine surgery. RESULTS The authors identified 69 patients (73 procedures) who experienced a complication over the prospective study period. Cardiac complications were most common (10.2%). Receiver operating characteristic (ROC) curves were calculated to compare complication outcomes using the different assessment tools. Area under the curve (AUC) analysis showed comparable predictive accuracy between the RAT and the ACS NSQIP calculator (0.670 [95% CI 0.60-0.74] in RAT, 0.669 [95% CI 0.60-0.74] in NSQIP). The CCI was not accurate in predicting complication occurrence (0.55 [95% CI 0.48-0.62]). The RAT produced mean probabilities of 34.6% for patients who had a complication and 24% for patients who did not (p = 0.0003). The generated predicted values were stratified into low, medium, and high rates. For the RAT, the predicted complication rate was 10.1% in the low-risk group (observed rate 12.8%), 21.9% in the medium-risk group (observed 31.8%), and 49.7% in the high-risk group (observed 41.2%). The ACS NSQIP calculator consistently produced complication predictions that underestimated complication occurrence: 3.4% in the low-risk group (observed 12.6%), 5.9% in the medium-risk group (observed 34.5%), and 12.5% in the high-risk group (observed 38.8%). The RAT was more accurate than the ACS NSQIP calculator (p = 0.0018). CONCLUSIONS While the RAT and ACS NSQIP calculator were both able to identify patients more likely to experience complications following spine surgery, both have substantial room for improvement. Risk stratification is feasible in spine surgery procedures; currently used measures have low accuracy.

  View details for DOI 10.3171/2016.12.SPINE16969

  View details for PubMedID 28430052

• Reduced dose CT with model-based iterative reconstruction compared to standard dose CT of the chest, abdomen, and pelvis in oncology patients: intra-individual comparison study on image quality and lesion conspicuity. Abdominal radiology Morimoto, L. N., Kamaya, A., Boulay-Coletta, I., Fleischmann, D., Molvin, L., Tian, L., Fisher, G., Wang, J., Willmann, J. K. 2017

  Abstract

  To compare image quality and lesion conspicuity of reduced dose (RD) CT with model-based iterative reconstruction (MBIR) compared to standard dose (SD) CT in patients undergoing oncological follow-up imaging.Forty-four cancer patients who had a staging SD CT within 12 months were prospectively included to undergo a weight-based RD CT with MBIR. Radiation dose was recorded and tissue attenuation and image noise of four tissue types were measured. Reproducibility of target lesion size measurements of up to 5 target lesions per patient were analyzed. Subjective image quality was evaluated for three readers independently utilizing 4- or 5-point Likert scales.Median radiation dose reduction was 46% using RD CT (P < 0.01). Median image noise across all measured tissue types was lower (P < 0.01) in RD CT. Subjective image quality for RD CT was higher (P < 0.01) in regard to image noise and overall image quality; however, there was no statistically significant difference regarding image sharpness (P = 0.59). There were subjectively more artifacts on RD CT (P < 0.01). Lesion conspicuity was subjectively better in RD CT (P < 0.01). Repeated target lesion size measurements were highly reproducible both on SD CT (ICC = 0.987) and RD CT (ICC = 0.97).RD CT imaging with MBIR provides diagnostic imaging quality and comparable lesion conspicuity on follow-up exams while allowing dose reduction by a median of 46% compared to SD CT imaging.

  View details for DOI 10.1007/s00261-017-1140-5

  View details for PubMedID 28417170

• Innovative methods for the identification of predictive biomarker signatures in oncology: Application to bevacizumab. Contemporary clinical trials communications Delmar, P., Irl, C., Tian, L. 2017; 5: 107-115

  Abstract

  Current methods for subgroup analyses of data collected from randomized clinical trials (RCTs) may lead to false-positives from multiple testing, lack power to detect moderate but clinically meaningful differences, or be too simplistic in characterizing patients who may benefit from treatment. Herein, we present a general procedure based on a set of newly developed statistical methods for the identification and evaluation of complex multivariate predictors of treatment effect. Furthermore, we implemented this procedure to identify a subgroup of patients who may receive the largest benefit from bevacizumab treatment using a panel of 10 biomarkers measured at baseline in patients enrolled on two RCTs investigating bevacizumab in metastatic breast cancer. Data were collected from patients with human epidermal growth factor receptor 2 (HER2)-negative (AVADO) and HER2-positive (AVEREL) metastatic breast cancer. We first developed a classification rule based on an estimated individual scoring system, using data from the AVADO study only. The classification rule takes into consideration a panel of biomarkers, including vascular endothelial growth factor (VEGF)-A. We then classified the patients in the independent AVEREL study into patient groups according to "promising" or "not-promising" treatment benefit based on this rule and conducted a statistical analysis within these subgroups to compute point estimates, confidence intervals, and p-values for treatment effect and its interaction. In the group with promising treatment benefit in the AVEREL study, the estimated hazard ratio of bevacizumab versus placebo for progression-free survival was 0.687 (95% confidence interval [CI]: 0.462-1.024, p = 0.065), while in the not-promising group the hazard ratio (HR) was 1.152 (95% CI: 0.526-2.524, p = 0.723). Using the median level of VEGF-A from the AVEREL study to divide the study population, then the HR becomes 0.711 (95% CI: 0.435-1.163, p = 0.174) in the promising group and 0.828 (95% CI: 0.496-1.380, p = 0.468) in the not-promising group. Similar results were obtained with the median VEGF-A levels from the AVADO study ("promising" group: HR = 0.709, 95%CI: 0.444-1.133, p = 0.151; "not-promising" group: HR = 0.851, 95% CI: 0.497-1.458, p = 0.556). Our analysis shows it is feasible to employ statistical methods for empirically constructing and validating a scoring system based on a panel of biomarkers. This scoring system can be used to estimate the treatment effect for individual patients and identify a subgroup of patients who may benefit from treatment. The proposed procedure can provide a general framework to organize many statistical methods (existing or to be developed) into a coherent set of analyses for the development of personalized medicines and has the potential of broad applications.

  View details for DOI 10.1016/j.conctc.2017.01.007

  View details for PubMedID 29740627

  View details for PubMedCentralID PMC5936698

• Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study (vol 14, 284, 2016) JOURNAL OF TRANSLATIONAL MEDICINE White, S. H., McDermott, M. M., Sufit, R. L., Kosmac, K., Bugg, A. W., Gonzalez-Freire, M., Ferrucci, L., Tian, L., Zhao, L., Gao, Y., Kibbe, M. R., Criqui, M. H., Leeuwenburgh, C., Peterson, C. A. 2017; 15: 45

  View details for PubMedID 28241774

• Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer. Radiology Wang, H., Lutz, A. M., Hristov, D., Tian, L., Willmann, J. K. 2017; 282 (2): 443-452

  Abstract

  Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction-replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016160032

  View details for PubMedID 27490690

• Patient subgroup identification for clinical drug development. Statistics in medicine Huang, X., Sun, Y., Trow, P., Chatterjee, S., Chakravartty, A., Tian, L., Devanarayan, V. 2017

  Abstract

  Causal mechanism of relationship between the clinical outcome (efficacy or safety endpoints) and putative biomarkers, clinical baseline, and related predictors is usually unknown and must be deduced empirically from experimental data. Such relationships enable the development of tailored therapeutics and implementation of a precision medicine strategy in clinical trials to help stratify patients in terms of disease progression, clinical response, treatment differentiation, and so on. These relationships often require complex modeling to develop the prognostic and predictive signatures. For the purpose of easier interpretation and implementation in clinical practice, defining a multivariate biomarker signature in terms of thresholds (cutoffs/cut points) on individual biomarkers is preferable. In this paper, we propose some methods for developing such signatures in the context of continuous, binary and time-to-event endpoints. Results from simulations and case study illustration are also provided. Copyright © 2017 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/sim.7236

  View details for PubMedID 28147447

• Spectroscopic Photoacoustic Molecular Imaging of Breast Cancer using a B7-H3-targeted ICG Contrast Agent THERANOSTICS Wilson, K. E., Bachawal, S. V., Abou-Elkacem, L., Jensen, K., Machtaler, S., Tian, L., Willmann, J. K. 2017; 7 (6): 1463-1476

  Abstract

  Purpose: Breast cancer imaging methods lack diagnostic accuracy, in particular for patients with dense breast tissue, and improved techniques are critically needed. The purpose of this study was to evaluate antibody-indocyanine green (ICG) conjugates, which undergo dynamic absorption spectrum shifts after cellular endocytosis and degradation, and spectroscopic photoacoustic (sPA) imaging to differentiate normal breast tissue from breast cancer by imaging B7-H3, a novel breast cancer associated molecular target. Methods: Quantitative immunohistochemical staining of endothelial and epithelial B7-H3 expression was assessed in 279 human breast tissue samples, including normal (n=53), benign lesions (11 subtypes, n=129), and breast cancers (4 subtypes, n=97). After absorption spectra of intracellular and degraded B7-H3-ICG and Isotype control-ICG (Iso-ICG) were characterized, sPA imaging in a transgenic murine breast cancer model (FVB/N-Tg(MMTVPyMT)634Mul) was performed and compared to imaging of control conditions [B7-H3-ICG in tumor negative animals (n=60), Iso-ICG (n=30), blocking B7-H3+B7-H3-ICG (n=20), and free ICG (n=20)] and validated with ex vivo histological analysis. Results: Immunostaining showed differential B7-H3 expression on both the endothelium and tumor epithelium in human breast cancer with an area under the ROC curve of 0.93 to differentiate breast cancer vs non-cancer. Combined in vitro/in vivo imaging showed that sPA allowed specific B7-H3-ICG detection down to the 13 nM concentration and differentiation from Iso-ICG. sPA molecular imaging of B7-H3-ICG showed a 3.01-fold (P<0.01) increase in molecular B7-H3-ICG signal in tumors compared to control conditions. Conclusions: B7-H3 is a promising target for both vascular and epithelial sPA imaging of breast cancer. Leveraging antibody-ICG contrast agents and their dynamic optical absorption spectra allows for highly specific sPA imaging of breast cancer.

  View details for DOI 10.7150/thno.18217

  View details for Web of Science ID 000398783200005

  View details for PubMedID 28529630

• Baseline Assessment of 25-Hydroxyvitamin D Reference Material and Proficiency Testing/External Quality Assurance Material Commutability: A Vitamin D Standardization Program Study. Journal of AOAC International Phinney, K. W., Sempos, C. T., Tai, S. S., Camara, J. E., Wise, S. A., Eckfeldt, J. H., Hoofnagle, A. N., Carter, G. D., Jones, J. n., Myers, G. L., Durazo-Arvizu, R. n., Miller, W. G., Bachmann, L. M., Young, I. S., Pettit, J. n., Caldwell, G. n., Liu, A. n., Brooks, S. P., Sarafin, K. n., Thamm, M. n., Mensink, G. B., Busch, M. n., Rabenberg, M. n., Cashman, K. D., Kiely, M. n., Galvin, K. n., Zhang, J. Y., Kinsella, M. n., Oh, K. n., Lee, S. W., Jung, C. L., Cox, L. n., Goldberg, G. n., Guberg, K. n., Meadows, S. n., Prentice, A. n., Tian, L. n., Brannon, P. M., Lucas, R. M., Crump, P. M., Cavalier, E. n., Merkel, J. n., Betz, J. M. 2017; 100 (5): 1288–93

  Abstract

  The Vitamin D Standardization Program (VDSP) coordinated a study in 2012 to assess the commutability of reference materials and proficiency testing/external quality assurance materials for total 25-hydroxyvitamin D [25(OH)D] in human serum, the primary indicator of vitamin D status. A set of 50 single-donor serum samples as well as 17 reference and proficiency testing/external quality assessment materials were analyzed by participating laboratories that used either immunoassay or LC-MS methods for total 25(OH)D. The commutability test materials included National Institute of Standards and Technology Standard Reference Material 972a Vitamin D Metabolites in Human Serum as well as materials from the College of American Pathologists and the Vitamin D External Quality Assessment Scheme. Study protocols and data analysis procedures were in accordance with Clinical and Laboratory Standards Institute guidelines. The majority of the test materials were found to be commutable with the methods used in this commutability study. These results provide guidance for laboratories needing to choose appropriate reference materials and select proficiency or external quality assessment programs and will serve as a foundation for additional VDSP studies.

  View details for PubMedID 28797319

• A New Overall-Subgroup Simultaneous Test for Optimal Inference in Biomarker-Targeted Confirmatory Trials Statistics in Biosciences Belitskaya, I., Wang, H., Shih, M., Tian, L., Doros, G., Lew, R. A., Lu, Y. 2017

  View details for DOI 10.1007/s12561-016-9174-8

• The Equivalence between Mann-Whitney Wilcoxon Test and Score Test Based on the Proportional Odds Model for Ordinal Responses Wang, Y., Tian, L., Li, M., Zhao, L., Zhang, R., Hua, G. IEEE. 2017

  View details for Web of Science ID 000426596000041

• Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials. Annals of the rheumatic diseases Peterfy, C., Strand, V., Tian, L., Østergaard, M., Lu, Y., DiCarlo, J., Countryman, P., Deodhar, A., Landewé, R., Ranganath, V. K., Troum, O., Conaghan, P. G. 2016

  Abstract

  In rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray.Pooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses.Progression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively).Early changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.

  View details for DOI 10.1136/annrheumdis-2016-210311

  View details for PubMedID 27974302

• Optimal stratification in outcome prediction using baseline information BIOMETRIKA Yong, F. H., Tian, L., Yu, S., Cai, T., Wei, L. J. 2016; 103 (4): 817-828

  View details for DOI 10.1093/biomet/asw049

  View details for Web of Science ID 000392813200005

• Optimal stratification in outcome prediction using baseline information. Biometrika Yong, F. H., Tian, L., Yu, S., Cai, T., Wei, L. J. 2016; 103 (4): 817-828

  Abstract

  A common practice in predictive medicine is to use current study data to construct a stratification procedure, which groups subjects according to baseline information and forms stratum-specific prevention or intervention strategies. A desirable stratification scheme would not only have small intra-stratum variation but also have a clinically meaningful discriminatory capability. We show how to obtain optimal stratification rules with such desirable properties from fitting a set of regression models relating the outcome to baseline covariates and creating scoring systems for predicting potential outcomes. We propose that all available optimal stratifications be evaluated with an independent dataset to select a final stratification. Lastly, we obtain inferential results for this selected stratification scheme with a holdout dataset. When only one study of moderate size is available, we combine the first two steps via crossvalidation. Extensive simulation studies are used to compare the proposed stratification strategy with alternatives. We illustrate the new proposal using an AIDS clinical trial for binary outcomes and a cardiovascular clinical study for censored event time outcomes.

  View details for DOI 10.1093/biomet/asw049

  View details for PubMedID 29422691

  View details for PubMedCentralID PMC5793688

• Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals. PLoS pathogens Qi, Q., Cavanagh, M. M., Le Saux, S., Wagar, L. E., Mackey, S., Hu, J., Maecker, H., Swan, G. E., Davis, M. M., Dekker, C. L., Tian, L., Weyand, C. M., Goronzy, J. J. 2016; 12 (10)

  Abstract

  Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population.

  View details for DOI 10.1371/journal.ppat.1005892

  View details for PubMedID 27764254

  View details for PubMedCentralID PMC5072604

• Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study JOURNAL OF TRANSLATIONAL MEDICINE White, S. H., McDermott, M. M., Sufit, R. L., Kosmac, K., Bugg, A. W., Gonzalez-Freire, M., Ferrucci, L., Tian, L., Zhao, L., Gao, Y., Kibbe, M. R., Criqui, M. H., Leeuwenburgh, C., Peterson, C. A. 2016; 14

  Abstract

  Patients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Additionally, reports are conflicted regarding fiber type distribution patterns in PAD, but agree that skeletal muscle mitochondrial respiration is impaired.To test the hypothesis that reduced muscle fiber oxidative activity and type I distribution are negatively associated with walking performance in PAD, calf muscle biopsies from non-PAD (n = 7) and PAD participants (n = 26) were analyzed immunohistochemically for fiber type and size, oxidative activity, markers of autophagy, and capillary density. Data were analyzed using analysis of covariance.There was a wide range in fiber type distribution among subjects with PAD (9-81 % type I fibers) that did not correlate with walking performance. However, mean type I fiber size correlated with 4-min normal- and fastest-paced walk velocity (r = 0.4940, P = 0.010 and r = 0.4944, P = 0.010, respectively). Although intensity of succinate dehydrogenase activity staining was consistent with fiber type, up to 17 % of oxidative fibers were devoid of mitochondria in their cores, and the core showed accumulation of the autophagic marker, LC3, which did not completely co-localize with LAMP2, a lysosome marker.Calf muscle type I fiber size positively correlates with walking performance in PAD. Accumulation of LC3 and a lack of co-localization of LC3 with LAMP2 in the area depleted of mitochondria in PAD fibers suggests impaired clearance of damaged mitochondria, which may contribute to reduced muscle oxidative capacity. Further study is needed to determine whether defective mitophagy is associated with decline in function over time, and whether interventions aimed at preserving mitochondrial function and improving autophagy can improve walking performance in PAD.

  View details for DOI 10.1186/s12967-016-1030-6

  View details for Web of Science ID 000384600600004

  View details for PubMedID 27687713

  View details for PubMedCentralID PMC5043620

• Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs. Journal of controlled release Mullick Chowdhury, S., Wang, T., Bachawal, S., Devulapally, R., Choe, J. W., Abou Elkacem, L., Yakub, B. K., Wang, D. S., Tian, L., Paulmurugan, R., Willmann, J. K. 2016; 238: 272-280

  Abstract

  Treatment options for patients with hepatocellular carcinoma (HCC) are limited, in particular in advanced and drug resistant HCC. MicroRNAs (miRNA) are non-coding small RNAs that are emerging as novel drugs for the treatment of cancer. The aim of this study was to assess treatment effects of two complementary miRNAs (sense miRNA-122, and antisense antimiR-21) encapsulated in biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP), administered by an ultrasound-guided and microbubble-enhanced delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Proliferation and invasiveness of human HCC cells after miRNA-122/antimiR-21 and doxorubicin treatment were assessed in vitro. Confocal microscopy and qRT-PCR were used to visualize and quantitate successful intracellular miRNA-loaded PLGA-NP delivery. Up and down-regulation of miRNA downstream targets and multidrug resistance proteins and extent of apoptosis were assessed in vivo in treated human HCC xenografts in mice. Compared to single miRNA therapy, combination therapy with the two complementary miRNAs resulted in significantly (P<0.05) stronger decrease in cell proliferation, invasion, and migration of HCC cells as well as higher resensitization to doxorubicin. Ultrasound-guided delivery significantly increased in vivo miRNA-loaded PLGA-NP delivery in human HCC xenografts compared to control conditions by 5-9 fold (P<0.001). miRNA-loaded PLGA-NP were internalized in HCC cells and anti-apoptotic proteins were down regulated with apoptosis in ~27% of the tumor volume of doxorubicin-resistant human HCC after a single treatment with complementary miRNAs and doxorubicin. Thus, ultrasound-guided delivery of complementary miRNAs is highly efficient in the treatment of doxorubicin- resistant and non-resistant HCC. Further development of this new treatment approach could aid in better treatment of patients with HCC.

  View details for DOI 10.1016/j.jconrel.2016.08.005

  View details for PubMedID 27503707

  View details for PubMedCentralID PMC5185600

• A Predictive Enrichment Procedure to Identify Potential Responders to a New Therapy for Randomized, Comparative Controlled Clinical Studies BIOMETRICS Li, J., Zhao, L., Tian, L., Cai, T., Claggett, B., Callegaro, A., Dizier, B., Spiessens, B., Ulloa-Montoya, F., Wei, L. 2016; 72 (3): 877-887

  Abstract

  To evaluate a new therapy versus a control via a randomized, comparative clinical study or a series of trials, due to heterogeneity of the study patient population, a pre-specified, predictive enrichment procedure may be implemented to identify an "enrichable" subpopulation. For patients in this subpopulation, the therapy is expected to have a desirable overall risk-benefit profile. To develop and validate such a "therapy-diagnostic co-development" strategy, a three-step procedure may be conducted with three independent data sets from a series of similar studies or a single trial. At the first stage, we create various candidate scoring systems based on the baseline information of the patients via, for example, parametric models using the first data set. Each individual score reflects an anticipated average treatment difference for future patients who share similar baseline profiles. A large score indicates that these patients tend to benefit from the new therapy. At the second step, a potentially promising, enrichable subgroup is identified using the totality of evidence from these scoring systems. At the final stage, we validate such a selection via two-sample inference procedures for assessing the treatment effectiveness statistically and clinically with the third data set, the so-called holdout sample. When the study size is not large, one may combine the first two steps using a "cross-training-evaluation" process. Comprehensive numerical studies are conducted to investigate the operational characteristics of the proposed method. The entire enrichment procedure is illustrated with the data from a cardiovascular trial to evaluate a beta-blocker versus a placebo for treating chronic heart failure patients.

  View details for DOI 10.1111/biom.12461

  View details for Web of Science ID 000383369000021

  View details for PubMedID 26689167

  View details for PubMedCentralID PMC4916037

• VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer. Cancer research Zhou, J., Wang, H., Zhang, H., Lutz, A. M., Tian, L., Hristov, D., Willmann, J. K. 2016; 76 (14): 4081-4089

  Abstract

  Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081-9. ©2016 AACR.

  View details for DOI 10.1158/0008-5472.CAN-15-3271

  View details for PubMedID 27206846

• Predicting Occurrence of Spine Surgery Complications Using "Big Data" Modeling of an Administrative Claims Database JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Ratliff, J. K., Balise, R., Veeravagu, A., Cole, T. S., Cheng, I., Olshen, R. A., Tian, L. 2016; 98 (10): 824-834

  Abstract

  Postoperative metrics are increasingly important in determining standards of quality for physicians and hospitals. Although complications following spinal surgery have been described, procedural and patient variables have yet to be incorporated into a predictive model of adverse-event occurrence. We sought to develop a predictive model of complication occurrence after spine surgery.We used longitudinal prospective data from a national claims database and developed a predictive model incorporating complication type and frequency of occurrence following spine surgery procedures. We structured our model to assess the impact of features such as preoperative diagnosis, patient comorbidities, location in the spine, anterior versus posterior approach, whether fusion had been performed, whether instrumentation had been used, number of levels, and use of bone morphogenetic protein (BMP). We assessed a variety of adverse events. Prediction models were built using logistic regression with additive main effects and logistic regression with main effects as well as all 2 and 3-factor interactions. Least absolute shrinkage and selection operator (LASSO) regularization was used to select features. Competing approaches included boosted additive trees and the classification and regression trees (CART) algorithm. The final prediction performance was evaluated by estimating the area under a receiver operating characteristic curve (AUC) as predictions were applied to independent validation data and compared with the Charlson comorbidity score.The model was developed from 279,135 records of patients with a minimum duration of follow-up of 30 days. Preliminary assessment showed an adverse-event rate of 13.95%, well within norms reported in the literature. We used the first 80% of the records for training (to predict adverse events) and the remaining 20% of the records for validation. There was remarkable similarity among methods, with an AUC of 0.70 for predicting the occurrence of adverse events. The AUC using the Charlson comorbidity score was 0.61. The described model was more accurate than Charlson scoring (p < 0.01).We present a modeling effort based on administrative claims data that predicts the occurrence of complications after spine surgery.We believe that the development of a predictive modeling tool illustrating the risk of complication occurrence after spine surgery will aid in patient counseling and improve the accuracy of risk modeling strategies.

  View details for DOI 10.2106/JBJS.15.00301

  View details for Web of Science ID 000378644500009

  View details for PubMedID 27194492

• Robust estimation of the proportion of treatment effect explained by surrogate marker information STATISTICS IN MEDICINE Parast, L., McDermott, M. M., Tian, L. 2016; 35 (10): 1637-1653

  Abstract

  In randomized treatment studies where the primary outcome requires long follow-up of patients and/or expensive or invasive obtainment procedures, the availability of a surrogate marker that could be used to estimate the treatment effect and could potentially be observed earlier than the primary outcome would allow researchers to make conclusions regarding the treatment effect with less required follow-up time and resources. The Prentice criterion for a valid surrogate marker requires that a test for treatment effect on the surrogate marker also be a valid test for treatment effect on the primary outcome of interest. Based on this criterion, methods have been developed to define and estimate the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate marker. These methods aim to identify useful statistical surrogates that capture a large proportion of the treatment effect. However, current methods to estimate this proportion usually require restrictive model assumptions that may not hold in practice and thus may lead to biased estimates of this quantity. In this paper, we propose a nonparametric procedure to estimate the proportion of treatment effect on the primary outcome that is explained by the treatment effect on a potential surrogate marker and extend this procedure to a setting with multiple surrogate markers. We compare our approach with previously proposed model-based approaches and propose a variance estimation procedure based on a perturbation-resampling method. Simulation studies demonstrate that the procedure performs well in finite samples and outperforms model-based procedures when the specified models are not correct. We illustrate our proposed procedure using a data set from a randomized study investigating a group-mediated cognitive behavioral intervention for peripheral artery disease participants.

  View details for DOI 10.1002/sim.6820

  View details for Web of Science ID 000373935400005

  View details for PubMedID 26631934

  View details for PubMedCentralID PMC4826843

• NADPH oxidase deficiency underlies dysfunction of aged CD8(+) Tregs JOURNAL OF CLINICAL INVESTIGATION Wen, Z., Shimojima, Y., Shirai, T., Li, Y., Ju, J., Yang, Z., Tian, L., Goronzy, J. J., Weyand, C. M. 2016; 126 (5): 1953-1967

  Abstract

  Immune aging results in progressive loss of both protective immunity and T cell-mediated suppression, thereby conferring susceptibility to a combination of immunodeficiency and chronic inflammatory disease. Here, we determined that older individuals fail to generate immunosuppressive CD8+CCR7+ Tregs, a defect that is even more pronounced in the age-related vasculitic syndrome giant cell arteritis. In young, healthy individuals, CD8+CCR7+ Tregs are localized in T cell zones of secondary lymphoid organs, suppress activation and expansion of CD4 T cells by inhibiting the phosphorylation of membrane-proximal signaling molecules, and effectively inhibit proliferative expansion of CD4 T cells in vitro and in vivo. We identified deficiency of NADPH oxidase 2 (NOX2) as the molecular underpinning of CD8 Treg failure in the older individuals and in patients with giant cell arteritis. CD8 Tregs suppress by releasing exosomes that carry preassembled NOX2 membrane clusters and are taken up by CD4 T cells. Overexpression of NOX2 in aged CD8 Tregs promptly restored suppressive function. Together, our data support NOX2 as a critical component of the suppressive machinery of CD8 Tregs and suggest that repairing NOX2 deficiency in these cells may protect older individuals from tissue-destructive inflammatory disease, such as large-vessel vasculitis.

  View details for DOI 10.1172/JCI84181

  View details for Web of Science ID 000375182100029

  View details for PubMedID 27088800

  View details for PubMedCentralID PMC4855948

• Community walking speed, sedentary or lying down time, and mortality in peripheral artery disease VASCULAR MEDICINE McDermott, M. M., Guralnik, J. M., Ferrucci, L., Tian, L., Kibbe, M. R., Greenland, P., Green, D., Liu, K., Zhao, L., Wilkins, J. T., Huffman, M. D., Shah, S. J., Liao, Y., Gao, Y., Lloyd-Jones, D. M., Criqui, M. H. 2016; 21 (2): 120-129

  Abstract

  We studied whether slower community walking speed and whether greater time spent lying down or sleeping were associated with higher mortality in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 0.90 were identified from Chicago medical centers. At baseline, participants reported their usual walking speed outside their home and the number of hours they spent lying down or sleeping per day. Cause of death was adjudicated using death certificates and medical record review. Analyses were adjusted for age, sex, race, comorbidities, ABI, and other confounders. Of 1314 PAD participants, 189 (14.4%) died, including 63 cardiovascular disease (CVD) deaths. Mean follow-up was 34.9 months ± 18.1. Relative to average or normal pace (2-3 miles/hour), slower walking speed was associated with greater CVD mortality: no walking at all: hazard ratio (HR) = 4.17, 95% confidence interval (CI) = 1.46-11.89; casual strolling (0-2 miles/hour): HR = 2.24, 95% CI = 1.16-4.32; brisk or striding (>3 miles/hour): HR = 0.55, 95% CI = 0.07-4.30. These associations were not significant after additional adjustment for the six-minute walk. Relative to sleeping or lying down for 8-9 hours, fewer or greater hours sleeping or lying down were associated with higher CVD mortality: 4-7 hours: HR = 2.08, 95% CI = 1.06-4.05; 10-11 hours: HR = 4.07, 95% CI = 1.86-8.89; ⩾ 12 hours: HR = 3.75, 95% CI = 1.47-9.62. These associations were maintained after adjustment for the six-minute walk. In conclusion, slower walking speed outside the home and less than 8 hours or more than 9 hours lying down per day are potentially modifiable behaviors associated with increased CVD mortality in patients with PAD.

  View details for DOI 10.1177/1358863X15626521

  View details for Web of Science ID 000372901000005

  View details for PubMedCentralID PMC5656391

• Community walking speed, sedentary or lying down time, and mortality in peripheral artery disease. Vascular medicine (London, England) McDermott, M. M., Guralnik, J. M., Ferrucci, L., Tian, L., Kibbe, M. R., Greenland, P., Green, D., Liu, K., Zhao, L., Wilkins, J. T., Huffman, M. D., Shah, S. J., Liao, Y., Gao, Y., Lloyd-Jones, D. M., Criqui, M. H. 2016; 21 (2): 120-9

  Abstract

  We studied whether slower community walking speed and whether greater time spent lying down or sleeping were associated with higher mortality in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 0.90 were identified from Chicago medical centers. At baseline, participants reported their usual walking speed outside their home and the number of hours they spent lying down or sleeping per day. Cause of death was adjudicated using death certificates and medical record review. Analyses were adjusted for age, sex, race, comorbidities, ABI, and other confounders. Of 1314 PAD participants, 189 (14.4%) died, including 63 cardiovascular disease (CVD) deaths. Mean follow-up was 34.9 months ± 18.1. Relative to average or normal pace (2-3 miles/hour), slower walking speed was associated with greater CVD mortality: no walking at all: hazard ratio (HR) = 4.17, 95% confidence interval (CI) = 1.46-11.89; casual strolling (0-2 miles/hour): HR = 2.24, 95% CI = 1.16-4.32; brisk or striding (>3 miles/hour): HR = 0.55, 95% CI = 0.07-4.30. These associations were not significant after additional adjustment for the six-minute walk. Relative to sleeping or lying down for 8-9 hours, fewer or greater hours sleeping or lying down were associated with higher CVD mortality: 4-7 hours: HR = 2.08, 95% CI = 1.06-4.05; 10-11 hours: HR = 4.07, 95% CI = 1.86-8.89; ⩾ 12 hours: HR = 3.75, 95% CI = 1.47-9.62. These associations were maintained after adjustment for the six-minute walk. In conclusion, slower walking speed outside the home and less than 8 hours or more than 9 hours lying down per day are potentially modifiable behaviors associated with increased CVD mortality in patients with PAD.

  View details for DOI 10.1177/1358863X15626521

  View details for PubMedID 26873873

  View details for PubMedCentralID PMC5656391

• Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination. Science translational medicine Qi, Q., Cavanagh, M. M., Le Saux, S., Namkoong, H., Kim, C., Turgano, E., Liu, Y., Wang, C., Mackey, S., Swan, G. E., Dekker, C. L., Olshen, R. A., Boyd, S. D., Weyand, C. M., Tian, L., Goronzy, J. J. 2016; 8 (332): 332ra46-?

  Abstract

  Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

  View details for DOI 10.1126/scitranslmed.aaf1725

  View details for PubMedID 27030598

• Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Science translational medicine Yang, Z., Shen, Y., Oishi, H., Matteson, E. L., Tian, L., Goronzy, J. J., Weyand, C. M. 2016; 8 (331): 331ra38-?

  Abstract

  In patients with rheumatoid arthritis (RA), CD4(+)T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) accumulation and reactive oxygen species (ROS) consumption. With surplus reductive equivalents, RA T cells insufficiently activated the redox-sensitive kinase ataxia telangiectasia mutated (ATM), bypassed the G2/M cell cycle checkpoint, and hyperproliferated. Moreover, insufficient ATM activation biased T cell differentiation toward the T helper 1 (TH1) and TH17 lineages, imposing a hyperinflammatory phenotype. We have identified several interventions that replenish intracellular ROS, which corrected the abnormal proliferative behavior of RA T cells and successfully suppressed synovial inflammation. Thus, rebalancing glucose utilization and restoring oxidant signaling may provide a therapeutic strategy to prevent autoimmunity in RA.

  View details for DOI 10.1126/scitranslmed.aad7151

  View details for PubMedID 27009267

• The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease JOURNAL OF EXPERIMENTAL MEDICINE Shirai, T., Nazarewicz, R. R., Wallis, B. B., Yanes, R. E., Watanabe, R., Hilhorst, M., Tian, L., Harrison, D. G., Giacomini, J. C., Assimes, T. L., Goronzy, J. J., Weyand, C. M. 2016; 213 (3): 337-354

  Abstract

  Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.

  View details for DOI 10.1084/jem.20150900

  View details for PubMedID 26926996

• On the Restricted Mean Survival Time Curve in Survival Analysis BIOMETRICS Zhao, L., Claggett, B., Tian, L., Uno, H., Pfeffer, M. A., Solomon, S. D., Trippa, L., Wei, L. J. 2016; 72 (1): 215-221

  Abstract

  For a study with an event time as the endpoint, its survival function contains all the information regarding the temporal, stochastic profile of this outcome variable. The survival probability at a specific time point, say t, however, does not transparently capture the temporal profile of this endpoint up to t. An alternative is to use the restricted mean survival time (RMST) at time t to summarize the profile. The RMST is the mean survival time of all subjects in the study population followed up to t, and is simply the area under the survival curve up to t. The advantages of using such a quantification over the survival rate have been discussed in the setting of a fixed-time analysis. In this article, we generalize this approach by considering a curve based on the RMST over time as an alternative summary to the survival function. Inference, for instance, based on simultaneous confidence bands for a single RMST curve and also the difference between two RMST curves are proposed. The latter is informative for evaluating two groups under an equivalence or noninferiority setting, and quantifies the difference of two groups in a time scale. The proposal is illustrated with the data from two clinical trials, one from oncology and the other from cardiology.

  View details for DOI 10.1111/biom.12384

  View details for Web of Science ID 000373914700022

  View details for PubMedID 26302239

• Incidence and Prognostic Significance of Depressive Symptoms in Peripheral Artery Disease JOURNAL OF THE AMERICAN HEART ASSOCIATION McDermott, M. M., Guralnik, J. M., Tian, L., Kibbe, M. R., Ferrucci, L., Zhao, L., Liu, K., Liao, Y., Gao, Y., Criqui, M. H. 2016; 5 (3)

  Abstract

  We compared the incidence of depression, defined by a Geriatric Depression Score (GDS) ≥6, between people with versus without peripheral artery disease (PAD). We determined whether depressive symptoms were associated with increased mortality in people with and without PAD.Nine hundred and fifty-one PAD patients and 478 non-PAD patients were recruited from Chicago medical centers and followed prospectively. At baseline and annually, participants completed the GDS (0-15 scale, score ≥6=depression) and 6-minute walk. Cause of death was confirmed with death certificates. The prevalence of a GDS ≥6 at baseline was 186/951 (19.6%) among PAD versus 63/478 (13.2%) among non-PAD participants (P=0.003). During a mean follow-up of 2.7±1.2 years, 122/712 (17.1%) of participants with PAD versus 51/403 (12.7%) without PAD developed a GDS ≥6 (P=0.047). Adjusting for age, sex, race, comorbidities, and other confounders, PAD participants had an increased rate of developing a GDS ≥6 compared to non-PAD participants (hazard ratio=1.54 (95% CI=1.05-2.25, P=0.026). This association was not statistically significant after adjusting for 6-minute walk (P=0.258). Among PAD participants, a baseline GDS ≥6 was associated with increased all-cause mortality, adjusting for confounders (hazard ratio=1.57, 95% CI=1.12-2.21, P=0.009). This association was not significant after adjusting for 6-minute walk (P=0.224).People with PAD have a higher incidence of depressive symptoms than people without PAD. In PAD, depressive symptoms are associated with increased all-cause and cardiovascular mortality. These associations are explained in part by poorer 6-minute walk among people with PAD and among depressed people with PAD, respectively.

  View details for DOI 10.1161/JAHA.115.002959

  View details for Web of Science ID 000385312200042

  View details for PubMedID 26994131

  View details for PubMedCentralID PMC4943270

• Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals CELL REPORTS Fang, F., Yu, M., Cavanagh, M. M., Saunders, J. H., Qi, Q., Ye, Z., Le Saux, S., Sultan, W., Turgano, E., Dekker, C. L., Tian, L., Weyand, C. M., Goronzy, J. J. 2016; 14 (5): 1218-1231

  Abstract

  In an immune response, CD4(+) T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4(+) T cells and found an increased induction of the ATPase CD39 with age. CD39(+) CD4(+) T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.

  View details for DOI 10.1016/j.celrep.2016.01.002

  View details for Web of Science ID 000369616100022

• Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals. Cell reports Fang, F., Yu, M., Cavanagh, M. M., Hutter Saunders, J., Qi, Q., Ye, Z., Le Saux, S., Sultan, W., Turgano, E., Dekker, C. L., Tian, L., Weyand, C. M., Goronzy, J. J. 2016; 14 (5): 1218-1231

  Abstract

  In an immune response, CD4(+) T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4(+) T cells and found an increased induction of the ATPase CD39 with age. CD39(+) CD4(+) T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.

  View details for DOI 10.1016/j.celrep.2016.01.002

  View details for PubMedID 26832412

• Changes in D-dimer and inflammatory biomarkers before ischemic events in patients with peripheral artery disease: The BRAVO Study VASCULAR MEDICINE McDermott, M. M., Liu, K., Green, D., Greenland, P., Tian, L., Kibbe, M., Tracy, R., Shah, S., Wilkins, J. T., Huffman, M., Zhao, L., Huang, C., Auerbach, A., Liao, Y., Skelly, C. L., McCarthy, W., Jones, D. L. 2016; 21 (1): 12-20

  Abstract

  Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event.

  View details for DOI 10.1177/1358863X15617541

  View details for Web of Science ID 000369075500002

  View details for PubMedID 26647446

• strmst2 and strmst2pw: New commands to compare survival curves using the restricted mean survival time STATA JOURNAL Cronin, A., Tian, L., Uno, H. 2016; 16 (3): 702-716

  View details for Web of Science ID 000384961300010

• Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes HAEMATOLOGICA Nakasone, H., Sahaf, B., Tian, L., Wang, T., Haagenson, M. D., Schoenrock, K., Perloff, S., Ryan, C. E., Wu, F., Spellman, S. R., Lee, S. J., Ritz, J., Miklos, D. B., Ctr Int Blood Marrow 2016; 101 (1): E30–E33

  View details for PubMedID 26494841

• Ultrasound Molecular Imaging of the Breast Cancer Neovasculature using Engineered Fibronectin Scaffold Ligands: A Novel Class of Targeted Contrast Ultrasound Agent. Theranostics Abou-Elkacem, L., Wilson, K. E., Johnson, S. M., Chowdhury, S. M., Bachawal, S., Hackel, B. J., Tian, L., Willmann, J. K. 2016; 6 (11): 1740-1752

  Abstract

  Molecularly-targeted microbubbles (MBs) are increasingly being recognized as promising contrast agents for oncological molecular imaging with ultrasound. With the detection and validation of new molecular imaging targets, novel binding ligands are needed that bind to molecular imaging targets with high affinity and specificity. In this study we assessed a novel class of potentially clinically translatable MBs using an engineered 10(th) type III domain of human-fibronectin (MB-FN3VEGFR2) scaffold-ligand to image VEGFR2 on the neovasculature of cancer. The in vitro binding of MB-FN3VEGFR2 to a soluble VEGFR2 was assessed by flow-cytometry (FACS) and binding to VEGFR2-expressing cells was assessed by flow-chamber cell attachment studies under flow shear stress conditions. In vivo binding of MB-FN3VEGFR2 was tested in a transgenic mouse model (FVB/N Tg(MMTV/PyMT634Mul) of breast cancer and control litter mates with normal mammary glands. In vitro FACS and flow-chamber cell attachment studies showed significantly (P<0.01) higher binding to VEGFR2 using MB-FN3VEGFR2 than control agents. In vivo ultrasound molecular imaging (USMI) studies using MB-FN3VEGFR2 demonstrated specific binding to VEGFR2 and was significantly higher (P<0.01) in breast cancer compared to normal breast tissue. Ex vivo immunofluorescence-analysis showed significantly (P<0.01) increased VEGFR2-expression in breast cancer compared to normal mammary tissue. Our results suggest that MBs coupled to FN3-scaffolds can be designed and used for USMI of breast cancer neoangiogenesis. Due to their small size, stability, solubility, the lack of glycosylation and disulfide bonds, FN3-scaffolds can be recombinantly produced with the advantage of generating small, high affinity ligands in a cost efficient way for USMI.

  View details for DOI 10.7150/thno.15169

  View details for PubMedID 27570547

  View details for PubMedCentralID PMC4997233

• A versatile test for equality of two survival functions based on weighted differences of Kaplan-Meier curves STATISTICS IN MEDICINE Uno, H., Tian, L., Claggett, B., Wei, L. J. 2015; 34 (28): 3680-3695

  View details for DOI 10.1002/sim.6591

  View details for PubMedID 26194988

• Ischemia-related changes in circulating stem and progenitor cells and associated clinical characteristics in peripheral artery disease VASCULAR MEDICINE Saber, R., Liu, K., Ferrucci, L., Criqui, M. H., Zhao, L., Tian, L., Guralnik, J. M., Liao, Y., Domanchuk, K., Kibbe, M. R., Green, D., Perlman, H., McDermott, M. M. 2015; 20 (6): 534-543

  View details for DOI 10.1177/1358863X15600255

  View details for PubMedID 26324152

• Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model RADIOLOGY Wang, H., Hristov, D., Qin, J., Tian, L., Willmann, J. K. 2015; 277 (2): 424-434

  Abstract

  To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time-intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis.Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P ≤ .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images.Three-dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy.

  View details for DOI 10.1148/radiol.2015142824

  View details for Web of Science ID 000368435100018

  View details for PubMedCentralID PMC4627439

• Standardizing 25-hydroxyvitamin D values from the Canadian Health Measures Survey. The American journal of clinical nutrition Sarafin, K., Durazo-Arvizu, R., Tian, L., Phinney, K. W., Tai, S., Camara, J. E., Merkel, J., Green, E., Sempos, C. T., Brooks, S. P. 2015; 102 (5): 1044-50

  Abstract

  The Canadian Health Measures Survey (CHMS) is an ongoing cross-sectional national survey that includes a measure of 25-hydroxyvitamin D [25(OH)D] by immunoassay. For cycles 1 and 2, the collection period occurred approximately every 2 y, with a new sample of ∼5600 individuals.The goal was to standardize the original 25(OH)D CHMS values in cycles 1 and 2 to the internationally recognized reference measurement procedures (RMPs) developed by the US National Institute for Standards and Technology (NIST) and Ghent University, Belgium.Standardization was accomplished by using a 2-step procedure. First, serum samples corresponding to the original plasma samples were remeasured by using the currently available immunoassay method. Second, 50 serum samples with known 25(OH)D values assigned by the NIST and Ghent reference method laboratories were measured by using the currently available immunoassay method. The mathematical models for each step-i.e., 1) YCurrent = XOriginal and 2) YNIST-Ghent = XCurrent -were estimated by using Deming regression, and the 2 models were solved to obtain a single equation for converting the "original" values to NIST-Ghent RMP values.After standardization (cycles 1 and 2 combined), the percentage of Canadians with 25(OH)D values <40 nmol/L increased from 16.4% (original) to 19.4% (standardized), and values <50 nmol/L increased from 29.0% (original) to 36.8% (standardized). The 25(OH)D standardized distributions (cycles 1 and 2 analyzed separately) were similar across age and sex groups; slightly higher values were associated with cycle 2 in the young and old. This finding contrasts with the original data, which indicated that cycle 2 values were lower for all age groups.The shifts in 25(OH)D distribution brought about by standardization indicate its importance in drawing correct conclusions about potential population deficiencies and insufficiencies and in permitting the comparison of distributions between national surveys.

  View details for DOI 10.3945/ajcn.114.103689

  View details for PubMedID 26423385

  View details for PubMedCentralID PMC4625585

• Three-dimensional Dynamic Contrast-enhanced US Imaging for Early Antiangiogenic Treatment Assessment in a Mouse Colon Cancer Model. Radiology Wang, H., Hristov, D., Qin, J., Tian, L., Willmann, J. K. 2015; 277 (2): 424-34

  Abstract

  To evaluate feasibility and reproducibility of three-dimensional (3D) dynamic contrast material-enhanced (DCE) ultrasonographic (US) imaging by using a clinical matrix array transducer to assess early antiangiogenic treatment effects in human colon cancer xenografts in mice.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. Three-dimensional DCE US imaging with two techniques (bolus and destruction-replenishment) was performed in human colon cancer xenografts (n = 38) by using a clinical US system and transducer. Twenty-one mice were imaged twice to assess reproducibility. Seventeen mice were scanned before and 24 hours after either antiangiogenic (n = 9) or saline-only (n = 8) treatment. Data sets of 3D DCE US examinations were retrospectively segmented into consecutive 1-mm imaging planes to simulate two-dimensional (2D) DCE US imaging. Six perfusion parameters (peak enhancement [PE], area under the time-intensity curve [AUC], time to peak [TTP], relative blood volume [rBV], relative blood flow [rBF], and blood flow velocity) were measured on both 3D and 2D data sets. Percent area of blood vessels was quantified ex vivo with immunofluorescence. Statistical analyses were performed with the Wilcoxon rank test by calculating intraclass correlation coefficients and by using Pearson correlation analysis.Reproducibility of both 3D DCE US imaging techniques was good to excellent (intraclass correlation coefficient, 0.73-0.86). PE, AUC, rBV, and rBF significantly decreased (P ≤ .04) in antiangiogenic versus saline-treated tumors. rBV (r = 0.74; P = .06) and rBF (r = 0.85; P = .02) correlated with ex vivo percent area of blood vessels, although the statistical significance of rBV was not reached, likely because of small sample size. Overall, 2D DCE-US overestimated and underestimated treatment effects from up to 125-fold to170-fold compared with 3D DCE US imaging. If the central tumor plane was assessed, treatment response was underestimated up to threefold or overestimated up to 57-fold on 2D versus 3D DCE US images.Three-dimensional DCE US imaging with a clinical matrix array transducer is feasible and reproducible to assess tumor perfusion in human colon cancer xenografts in mice and allows for assessment of early treatment response after antiangiogenic therapy.

  View details for DOI 10.1148/radiol.2015142824

  View details for PubMedID 26020439

  View details for PubMedCentralID PMC4627439

• Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy. Haematologica Nakasone, H., Remberger, M., Tian, L., Brodin, P., Sahaf, B., Wu, F., Mattsson, J., Lowsky, R., Negrin, R., Miklos, D. B., Meyer, E. 2015; 100 (11): 1477-1485

  Abstract

  Sex-mismatched hematopoietic cell transplantation is linked to increased graft-versus-host disease and mortality in myeloablative conditioning. Here we evaluated outcomes of 1,041 adult transplant recipients at two centers between 2006 and 2013 and investigated how the effect of sex-mismatching differed in myeloablative, reduced-intensity, and non-myeloablative total lymphoid irradiation with anti-thymocyte globulin conditioning. Among patients who underwent myeloablative conditioning, male recipients with female donors had increased chronic graft-versus-host disease (hazard ratio 1.83, P<0.01), increased non-relapse mortality (hazard ratio 1.84, P=0.022) and inferior overall survival (hazard ratio 1.59, P=0.018). In contrast, among patients who received reduced-intensity conditioning, male recipients with female donors had increased acute graft-versus-host disease (hazard ratio 1.96, P<0.01) but no difference in non-relapse mortality or overall survival. Among the patients who underwent total lymphoid irradiation with anti-thymocyte globulin, male recipients with female donors showed no increase in graft-versus-host disease or non-relapse mortality. Notably, only in the cohort receiving total lymphoid irradiation with anti-thymocyte globulin were male recipients with female donors significantly associated with reduced relapse (hazard ratio 0.64, P<0.01), and allo-antibody responses against H-Y antigens were predictive of reduced relapse. In the cohort given total lymphoid irradiation with anti-thymocyte globulin, the graft-versus-leukemia effect resulted in superior overall survival in recipients of sex-mismatched grafts (HR 0.69, P=0.037). In addition, only in the cohort treated with total lymphoid irradiation with anti-thymocyte globulin were female recipients with male donors associated with reduced relapse (hazard ratio 0.59, P<0.01) and superior survival (hazard ratio 0.61, P=0.014) compared with sex-matched pairs. We conclude that the risks and benefits of sex-mismatched transplants appear to differ according to conditioning strategy and this could affect donor selection.

  View details for DOI 10.3324/haematol.2015.125294

  View details for PubMedID 26250581

• Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent RADIOLOGY Wang, H., Felt, S. A., Machtaler, S., Guracar, I., Luong, R., Bettinger, T., Tian, L., Lutz, A. M., Willmann, J. K. 2015; 276 (3): 809-817

  Abstract

  Purpose To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin-targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. Materials and Methods The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin-targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 10(8) MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. Results Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 10(8) MB/kg and plateaued between a dose of 10 and a dose of 20 × 10(8) MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). Conclusion Quantitative measurements of inflammation obtained by using dual-selectin-targeted US are reproducible and correlate well with the extent of inflammation at histologic examination in a porcine acute ileitis model as a next step toward clinical translation. (©) RSNA, 2015 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2015142478

  View details for PubMedID 25965901

• Association of 6-Minute Walk Performance and Physical Activity With Incident Ischemic Heart Disease Events and Stroke in Peripheral Artery Disease JOURNAL OF THE AMERICAN HEART ASSOCIATION McDermott, M. M., Greenland, P., Tian, L., Kibbe, M. R., Green, D., Zhao, L., Criqui, M. H., Guralnik, J. M., Ferrucci, L., Liu, K., Wilkins, J. T., Huffman, M. D., Shah, S. J., Liao, Y., Lloyd-Jones, D. M. 2015; 4 (7)

  View details for DOI 10.1161/JAHA.115.001846

  View details for PubMedID 26219563

• Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging. Cancer research Bachawal, S. V., Jensen, K. C., Wilson, K. E., Tian, L., Lutz, A. M., Willmann, J. K. 2015; 75 (12): 2501-2509

  Abstract

  Ultrasound complements mammography as an imaging modality for breast cancer detection, especially in patients with dense breast tissue, but its utility is limited by low diagnostic accuracy. One emerging molecular tool to address this limitation involves contrast-enhanced ultrasound using microbubbles targeted to molecular signatures on tumor neovasculature. In this study, we illustrate how tumor vascular expression of B7-H3 (CD276), a member of the B7 family of ligands for T-cell coregulatory receptors, can be incorporated into an ultrasound method that can distinguish normal, benign, precursor, and malignant breast pathologies for diagnostic purposes. Through an IHC analysis of 248 human breast specimens, we found that vascular expression of B7-H3 was selectively and significantly higher in breast cancer tissues. B7-H3 immunostaining on blood vessels distinguished benign/precursors from malignant lesions with high diagnostic accuracy in human specimens. In a transgenic mouse model of cancer, the B7-H3-targeted ultrasound imaging signal was increased significantly in breast cancer tissues and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence. Our findings offer a preclinical proof of concept for the use of B7-H3-targeted ultrasound molecular imaging as a tool to improve the diagnostic accuracy of breast cancer detection in patients. Cancer Res; 75(12); 2501-9. ©2015 AACR.

  View details for DOI 10.1158/0008-5472.CAN-14-3361

  View details for PubMedID 25899053

  View details for PubMedCentralID PMC4470725

• Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans BLOOD Nakasone, H., Tian, L., Sahaf, B., Kawase, T., Schoenrock, K., Perloff, S., Ryan, C. E., Paul, J., Popli, R., Wu, F., Otani, J. M., Coller, J., Warren, E. H., Miklos, D. B. 2015; 125 (20): 3193-3201

  Abstract

  Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant: 78 (57%) of F→M patients were seropositive for at least 1 of the 6 HY-Abs, and 3-month seropositivity for each HY-Ab was associated with a persistent seropositive response throughout the posttransplant follow-up period (P < .001 in each). There were no associations between pretransplant features and 3-month overall HY-Ab development. Detection of multiple HY-Abs at 3 months (represented by HY score) was significantly associated with an increased risk of cGVHD (P < .0001) and nonrelapse mortality (P < .01). Compared to clinical factors alone, the addition of HY score to clinical factors improved the predictive potential of cGVHD (P < .01). Monitoring HY-Ab development thus stratifies cGVHD risk in F→M HCT patients and may support preemptive prophylaxis therapy for cGVHD beginning at 3 months posttransplant.

  View details for DOI 10.1182/blood-2014-11-613323

  View details for PubMedID 25766725

• Unsupervised Exercise and Mobility Loss in Peripheral Artery Disease: A Randomized Controlled Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION McDermott, M. M., Guralnik, J. M., Criqui, M. H., Ferrucci, L., Liu, K., Spring, B., Tian, L., Domanchuk, K., Kibbe, M., Zhao, L., Jones, D. L., Liao, Y., Gao, Y., Rejeski, W. J. 2015; 4 (5)

  Abstract

  Few medical therapies improve lower extremity functioning in people with lower extremity peripheral artery disease (PAD). Among people with PAD, we studied whether a group-mediated cognitive behavioral intervention promoting home-based unsupervised exercise prevented mobility loss and improved functional performance compared to control.One hundred ninety-four PAD participants were randomized. During months 1 to 6, the intervention group met weekly with other PAD participants and a facilitator. Group support and self-regulatory skills were used to help participants adhere to walking exercise. Ninety-percent of exercise was conducted at or near home. The control group attended weekly lectures. During months 6 to 12, each group received telephone contact only. Primary outcomes have been reported. Here we compare changes in exploratory outcomes of mobility loss (the inability to climb a flight of stairs or walk one-quarter mile without assistance), walking velocity, and the Short Physical Performance Battery. Compared to controls, fewer participants randomized to the intervention experienced mobility loss at 6-month follow-up: 6.3% versus 26.5%, P=0.002, odds ratio=0.19 (95% CI=0.06 to 0.58) and at 12-month follow-up: 5.2% versus 18.5%, P=0.029, odds ratio=0.24 (95% CI=0.06 to 0.97). The intervention improved fast-paced 4-m walking velocity at 6-month follow-up (P=0.005) and the Short Physical Performance Battery at 12-month follow-up (P=0.027), compared to controls.In exploratory analyses, a group-mediated cognitive behavioral intervention promoting unsupervised walking exercise prevented mobility loss and improved functioning at 6- and 12-month follow-up in PAD patients.URL: http://clinicaltrials.gov. Unique identifier: NCT00693940.

  View details for DOI 10.1161/JAHA.114.001659

  View details for Web of Science ID 000356347600005

  View details for PubMedID 25994445

• Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer. Investigative radiology Wang, H., Kaneko, O. F., Tian, L., Hristov, D., Willmann, J. K. 2015; 50 (5): 322-329

  Abstract

  We sought to assess the feasibility and reproducibility of 3-dimensional ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression in tumor angiogenesis using a clinical matrix array transducer and a clinical grade VEGFR2-targeted contrast agent in a murine model of human colon cancer.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice with human colon cancer xenografts (n = 33) were imaged with a clinical ultrasound system and transducer (Philips iU22; X6-1) after intravenous injection of either clinical grade VEGFR2-targeted microbubbles or nontargeted control microbubbles. Nineteen mice were scanned twice to assess imaging reproducibility. Fourteen mice were scanned both before and 24 hours after treatment with either bevacizumab (n = 7) or saline only (n = 7). Three-dimensional USMI data sets were retrospectively reconstructed into multiple consecutive 1-mm-thick USMI data sets to simulate 2-dimensional imaging. Vascular VEGFR2 expression was assessed ex vivo using immunofluorescence.Three-dimensional USMI was highly reproducible using both VEGFR2-targeted microbubbles and nontargeted control microbubbles (intraclass correlation coefficient, 0.83). The VEGFR2-targeted USMI signal significantly (P = 0.02) decreased by 57% after antiangiogenic treatment compared with the control group, which correlated well with ex vivo VEGFR2 expression on immunofluorescence (ρ = 0.93, P = 0.003). If only central 1-mm tumor planes were analyzed to assess antiangiogenic treatment response, the USMI signal change was significantly (P = 0.006) overestimated by an average of 27% (range, 2%-73%) compared with 3-dimensional USMI.Three-dimensional USMI is feasible and highly reproducible and allows accurate assessment and monitoring of VEGFR2 expression in tumor angiogenesis in a murine model of human colon cancer.

  View details for DOI 10.1097/RLI.0000000000000128

  View details for PubMedID 25575176

• Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer JOURNAL OF CONTROLLED RELEASE Wang, T., Choe, J. W., Pu, K., Devulapally, R., Bachawal, S., Machtaler, S., Chowdhury, S. M., Luong, R., Tian, L., Khuri-Yakub, B., Rao, J., Paulmurugan, R., Willmann, J. K. 2015; 203: 99-108

  Abstract

  Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.

  View details for DOI 10.1016/j.jconrel.2015.02.018

  View details for Web of Science ID 000351696600011

  View details for PubMedID 25687306

• Noninvasive pulmonary nodule elastometry by CT and deformable image registration RADIOTHERAPY AND ONCOLOGY Negandar, M., Fasola, C. E., Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Fleischmann, D., Tian, L., Loo, B. W., Maxim, P. G. 2015; 115 (1): 35-40

  View details for DOI 10.1016/j.radonc.2015.03.015

  View details for Web of Science ID 000356736300007

• Noninvasive pulmonary nodule elastometry by CT and deformable image registration. Radiotherapy and oncology Negahdar, M., Fasola, C. E., Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Fleischmann, D., Tian, L., Loo, B. W., Maxim, P. G. 2015; 115 (1): 35-40

  Abstract

  To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring.We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring.For all 30 tumors the Dice coefficient was 0.79±0.07 and 0.79±0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81±0.1. The elasticity of MPNs was 1.24±0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung.We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules.

  View details for DOI 10.1016/j.radonc.2015.03.015

  View details for PubMedID 25824979

• Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors. Journal of thoracic oncology Padda, S. K., Riess, J. W., Schwartz, E. J., Tian, L., Kohrt, H. E., Neal, J. W., West, R. B., Wakelee, H. A. 2015; 10 (3): 500-508

  Abstract

  Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 and the remaining as PD-L1.PD-L1 scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.

  View details for DOI 10.1097/JTO.0000000000000429

  View details for PubMedID 25402569

• Treatment selections using risk-benefit profiles based on data from comparative randomized clinical trials with multiple endpoints BIOSTATISTICS Claggett, B., Tian, L., Castagno, D., Wei, L. 2015; 16 (1): 60-72

  Abstract

  In a typical randomized clinical study to compare a new treatment with a control, oftentimes each study subject may experience any of several distinct outcomes during the study period, which collectively define the "risk-benefit" profile. To assess the effect of treatment, it is desirable to utilize the entirety of such outcome information. The times to these events, however, may not be observed completely due to, for example, competing risks or administrative censoring. The standard analyses based on the time to the first event, or individual component analyses with respect to each event time, are not ideal. In this paper, we classify each patient's risk-benefit profile, by considering all event times during follow-up, into several clinically meaningful ordinal categories. We first show how to make inferences for the treatment difference in a two-sample setting where categorical data are incomplete due to censoring. We then present a systematic procedure to identify patients who would benefit from a specific treatment using baseline covariate information. To obtain a valid and efficient system for personalized medicine, we utilize a cross-validation method for model building and evaluation and then make inferences using the final selected prediction procedure with an independent data set. The proposal is illustrated with the data from a clinical trial to evaluate a beta-blocker for treating chronic heart failure patients.

  View details for DOI 10.1093/biostatistics/kxu037

  View details for Web of Science ID 000347417500007

  View details for PubMedID 25122189

  View details for PubMedCentralID PMC4263228

• Allogeneic hematopoietic cell transplant for normal karyotype AML: indirect evidence of selection for adverse molecular profile. Bone marrow transplantation Percival, M. M., Medeiros, B. C., Tian, L. n., Robeson, S. n., Laport, G. G., Johnston, L. J., Shizuru, J. A., Miklos, D. B., Arai, S. n., Weng, W. K., Negrin, R. S., Lowsky, R. n. 2015

  View details for PubMedID 25893457

• Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging. Theranostics Machtaler, S., Knieling, F., Luong, R., Tian, L., Willmann, J. K. 2015; 5 (11): 1175-1186

  Abstract

  Ultrasound (US) molecular imaging has shown promise in assessing inflammation in preclinical, murine models of inflammatory bowel disease. These models, however, initiated acute inflammation on previously normal colons, in contrast to patients where acute exacerbations are often in chronically inflamed regions. In this study, we explored the potential of dual P- and E-selectin targeted US imaging for assessing acute inflammation on a murine quiescent chronic inflammatory background.Chronic colitis was induced using three cycles of 4% DSS in male FVB mice. Acute inflammation was initiated 2 weeks after the final DSS cycle through rectal administration of 1% TNBS. Mice at different stages of inflammation were imaged using a small animal ultrasound system following i.v. injection of microbubbles targeted to P- and E-selectin. In vivo imaging results were correlated with ex vivo immunofluorescence and histology.Induction of acute inflammation resulted in an increase in the targeted US signal from 5.5 ± 5.1 arbitrary units (a.u.) at day 0 to 61.0 ± 45.2 a.u. (P < 0.0001) at day 1, 36.3 ± 33.1 a.u. at day 3, returning to levels similar to control at day 5. Immunofluorescence showed significant increase in the percentage of P- and E-selectin positive vessels at day 1 (P-selectin: 21.0 ± 7.1% of vessels; P < 0.05; E-selectin: 16.4 ±3.7%; P < 0.05) compared to day 0 (P-selectin: 10.3 ± 5.7%; E-selectin: 7.3 ± 7.0%).Acute inflammation can be accurately measured in a clinically relevant murine model of chronic IBD using ultrasound molecular imaging with a dual P- and E- selectin-targeted contrast agent.

  View details for DOI 10.7150/thno.13048

  View details for PubMedID 26379784

  View details for PubMedCentralID PMC4568446

• Assessment of Inflammation in an Acute on Chronic Model of Inflammatory Bowel Disease with Ultrasound Molecular Imaging THERANOSTICS Machtaler, S., Knieling, F., Luong, R., Tian, L., Willmann, J. K. 2015; 5 (11): 1175-1186

  View details for DOI 10.7150/thno.13048

  View details for Web of Science ID 000360297600001

• A Simple Method for Estimating Interactions Between a Treatment and a Large Number of Covariates JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Tian, L., Alizadeh, A. A., Gentles, A. J., Tibshirani, R. 2014; 109 (508): 1517-1532

  Abstract

  We consider a setting in which we have a treatment and a potentially large number of covariates for a set of observations, and wish to model their relationship with an outcome of interest. We propose a simple method for modeling interactions between the treatment and covariates. The idea is to modify the covariate in a simple way, and then fit a standard model using the modified covariates and no main effects. We show that coupled with an efficiency augmentation procedure, this method produces clinically meaningful estimators in a variety of settings. It can be useful for practicing personalized medicine: determining from a large set of biomarkers the subset of patients that can potentially benefit from a treatment. We apply the method to both simulated datasets and real trial data. The modified covariates idea can be used for other purposes, for example, large scale hypothesis testing for determining which of a set of covariates interact with a treatment variable.

  View details for DOI 10.1080/01621459.2014.951443

  View details for Web of Science ID 000346797000016

  View details for PubMedCentralID PMC4338439

• Associations of diabetes mellitus and other cardiovascular disease risk factors with decline in the ankle-brachial index VASCULAR MEDICINE Forbang, N. I., McDermott, M. M., Liao, Y., Ix, J. H., Allison, M. A., Liu, K., Tian, L., Evans, N., Criqui, M. H. 2014; 19 (6): 465-472

  Abstract

  We compared the associations of diabetes mellitus (DM) and other cardiovascular disease (CVD) risk factors with decline in the ankle-brachial index (ABI) over 4 years in participants with and without peripheral artery disease (PAD). A total of 566 participants, 300 with PAD, were followed prospectively for 4 years. Mean (SD) baseline ABI values were 0.70 (0.13) for participants with both PAD and DM, 0.67 (0.14) for participants with only PAD, 1.10 (0.13) for participants with only DM, and 1.10 (0.10) for participants with neither PAD nor DM. After adjusting for age, sex, and baseline ABI, the corresponding ABI change from baseline to 4-year follow-up were -0.02, -0.04, +0.05, and +0.05, respectively. Compared to participants with neither PAD nor DM, participants with only PAD showed significantly more ABI decline (p <0.01), while the decline in participants with both PAD and DM was borderline non-significant (p = 0.06). After adjustments for baseline ABI, age, sex, African American ethnicity, and other CVD risk factors, independent factors associated with ABI decline in participants with PAD in the lower ABI leg were older age and elevated D-dimer. DM was not related to ABI decline. Despite being an important risk factor for PAD, DM was not independently associated with ABI decline. This could reflect the effect of DM promoting both PAD and lower-extremity arterial stiffness, resulting in a small decline in the ABI over time. In conclusion, ABI change over time in persons with diabetes may not accurately reflect underlying atherosclerosis.

  View details for DOI 10.1177/1358863X14554033

  View details for Web of Science ID 000345859100005

  View details for PubMedID 25358555

• Meta-Analysis With Fixed, Unknown, Study-Specific Parameters JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Claggett, B., Xie, M., Tian, L. 2014; 109 (508): 1660-1671

  View details for DOI 10.1080/01621459.2014.957288

  View details for Web of Science ID 000346797000027

• The estimation of calibration equations for variables with heteroscedastic measurement errors STATISTICS IN MEDICINE Tian, L., Durazo-Arvizu, R. A., Myers, G., Brooks, S., Sarafin, K., Sempos, C. T. 2014; 33 (25): 4420-4436

  Abstract

  In clinical chemistry and medical research, there is often a need to calibrate the values obtained from an old or discontinued laboratory procedure to the values obtained from a new or currently used laboratory method. The objective of the calibration study is to identify a transformation that can be used to convert the test values of one laboratory measurement procedure into the values that would be obtained using another measurement procedure. However, in the presence of heteroscedastic measurement error, there is no good statistical method available for estimating the transformation. In this paper, we propose a set of statistical methods for a calibration study when the magnitude of the measurement error is proportional to the underlying true level. The corresponding sample size estimation method for conducting a calibration study is discussed as well. The proposed new method is theoretically justified and evaluated for its finite sample properties via an extensive numerical study. Two examples based on real data are used to illustrate the procedure.

  View details for DOI 10.1002/sim.6235

  View details for Web of Science ID 000342898500007

  View details for PubMedID 24935784

• High-risk plaque in the superficial femoral artery of people with peripheral artery disease: Prevalence and associated clinical characteristics ATHEROSCLEROSIS Polonsky, T. S., Liu, K., Tian, L., Carr, J., Carroll, T. J., Berry, J., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Kibbe, M. R., Kramer, C. M., Li, F., Xu, D., Zhao, X., Yuan, C., McDermott, M. M. 2014; 237 (1): 169-176

  Abstract

  We used magnetic resonance imaging (MRI) to study the prevalence and associated clinical characteristics of high-risk plaque (defined as presence of lipid-rich necrotic core [LRNC] and intraplaque hemorrhage) in the superficial femoral arteries (SFA) among people with peripheral artery disease (PAD).The prevalence and clinical characteristics associated with high-risk plaque in the SFA are unknown.Three-hundred-three participants with PAD underwent MRI of the proximal SFA using a 1.5 T S platform. Twelve contiguous 2.5 mm cross-sectional images were obtained.LRNC was present in 68 (22.4%) participants. Only one had intra-plaque hemorrhage. After adjusting for age and sex, smoking prevalence was higher among adults with LRNC than among those without LRNC (35.9% vs. 21.4%, p = 0.02). Among participants with vs. without LRNC there were no differences in mean percent lumen area (31% vs. 33%, p = 0.42), normalized mean wall area (0.71 vs. 0.70, p = 0.67) or maximum wall area (0.96 vs. 0.92, p = 0.54) in the SFA. Among participants with LRNC, cross-sectional images containing LRNC had a smaller percent lumen area (33% ± 1% vs. 39% ± 1%, p < 0.001), greater normalized mean wall thickness (0.25 ± 0.01 vs. 0.22 ± 0.01, p < 0.001), and greater normalized maximum wall thickness (0.41 ± 0.01 vs. 0.31 ± 0.01, p < 0.001), compared to cross-sectional images without LRNC.Fewer than 25% of adults with PAD had high-risk plaque in the proximal SFA using MRI. Smoking was the only clinical characteristic associated with presence of LRNC. Further study is needed to determine the prognostic significance of LRNC in the SFA.http://www.clinicaltrials.gov. Unique identifier: NCT00520312.

  View details for DOI 10.1016/j.atherosclerosis.2014.08.034

  View details for Web of Science ID 000345011300028

  View details for PubMedID 25240112

• A Simple Method for Estimating Interactions between a Treatment and a Large Number of Covariates. Journal of the American Statistical Association Tian, L., Alizadeh, A. A., Gentles, A. J., Tibshirani, R. 2014; 109 (508): 1517-1532

  Abstract

  We consider a setting in which we have a treatment and a potentially large number of covariates for a set of observations, and wish to model their relationship with an outcome of interest. We propose a simple method for modeling interactions between the treatment and covariates. The idea is to modify the covariate in a simple way, and then fit a standard model using the modified covariates and no main effects. We show that coupled with an efficiency augmentation procedure, this method produces clinically meaningful estimators in a variety of settings. It can be useful for practicing personalized medicine: determining from a large set of biomarkers the subset of patients that can potentially benefit from a treatment. We apply the method to both simulated datasets and real trial data. The modified covariates idea can be used for other purposes, for example, large scale hypothesis testing for determining which of a set of covariates interact with a treatment variable.

  View details for DOI 10.1080/01621459.2014.951443

  View details for PubMedID 25729117

  View details for PubMedCentralID PMC4338439

• Discussion. Biometrics Tian, L. 2014; 70 (3): 710-713

  View details for DOI 10.1111/biom.12188

  View details for PubMedID 24889101

• Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. Journal of clinical oncology Uno, H., Claggett, B., Tian, L., Inoue, E., Gallo, P., Miyata, T., Schrag, D., Takeuchi, M., Uyama, Y., Zhao, L., Skali, H., Solomon, S., Jacobus, S., Hughes, M., Packer, M., Wei, L. 2014; 32 (22): 2380-2385

  Abstract

  In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.

  View details for DOI 10.1200/JCO.2014.55.2208

  View details for PubMedID 24982461

  View details for PubMedCentralID PMC4105489

• Collateral vessel number, plaque burden, and functional decline in peripheral artery disease. Vascular medicine (London, England) McDermott, M. M., Carr, J., Liu, K., Kramer, C. M., Yuan, C., Tian, L., Criqui, M. H., Guralnik, J. M., Ferrucci, L., Zhao, L., Xu, D., Kibbe, M., Berry, J., Carroll, T. J. 2014; 19 (4): 281-288

  Abstract

  Associations of collateral vessels and lower extremity plaque with functional decline are unknown. Among people with peripheral artery disease (PAD), we determined whether greater superficial femoral artery (SFA) plaque burden combined with fewer lower extremity collateral vessels was associated with faster functional decline, compared to less plaque and/or more numerous collateral vessels. A total of 226 participants with ankle-brachial index (ABI) <1.00 underwent magnetic resonance imaging of lower extremity collateral vessels and cross-sectional imaging of the proximal SFA. Participants were categorized as follows: Group 1 (best), maximum plaque area < median and collateral vessel number ≥6 (median); Group 2, maximum plaque area < median and collateral vessel number <6; Group 3, maximum plaque area > median and collateral vessel number ≥6; Group 4 (worst), maximum plaque area > median and collateral vessel number <6. Functional measures were performed at baseline and annually for 2 years. Analyses adjust for age, sex, race, comorbidities, and other confounders. Annual changes in usual-paced walking velocity were: Group 1, +0.01 m/s; Group 2, -0.02 m/s; Group 3, -0.01 m/s; Group 4, -0.05 m/s (p-trend=0.008). Group 4 had greater decline than Group 1 (p<0.001), Group 2 (p=0.029), and Group 3 (p=0.010). Similar trends were observed for fastest-paced 4-meter walking velocity (p-trend=0.018). Results were not substantially changed when analyses were repeated with additional adjustment for ABI. However, there were no associations of SFA plaque burden and collateral vessel number with decline in 6-minute walk. In summary, a larger SFA plaque burden combined with fewer collateral vessels is associated with a faster decline in usual and fastest-paced walking velocity in PAD.

  View details for DOI 10.1177/1358863X14540362

  View details for PubMedID 25047855

  View details for PubMedCentralID PMC4317389

• Collateral vessel number, plaque burden, and functional decline in peripheral artery disease VASCULAR MEDICINE McDermott, M. M., Carr, J., Liu, K., Kramer, C. M., Yuan, C., Tian, L., Criqui, M. H., Guralnik, J. M., Ferrucci, L., Zhao, L., Xu, D., Kibbe, M., Berry, J., Carroll, T. J. 2014; 19 (4): 281-288

  View details for DOI 10.1177/1358863X14540362

  View details for Web of Science ID 000340161000005

• European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation BLOOD CANCER JOURNAL Medeiros, B. C., Tian, L., Robenson, S., Laport, G. G., JOHNSTON, L. J., Shizuru, J. A., Miklos, D. B., Arai, S., Benjamin, J. E., Weng, W., Negrin, R. S., Lowsky, R. 2014; 4

  View details for DOI 10.1038/bcj.2014.35

  View details for PubMedID 24879117

• Vulnerable blood in high risk vascular patients: Study design and methods CONTEMPORARY CLINICAL TRIALS McDermott, M. M., Greenland, P., Liu, K., Tian, L., Green, D., Shah, S. J., Huffman, M., Wilkins, J., Kibbe, M., Liao, Y., Huang, C., Skelly, C., Jacobs, C., McCarthy, W., Auerbach, A., Lloyd-Jones, D. 2014; 38 (1): 121-129

  Abstract

  Basic research suggests that rapid increases in circulating inflammatory and hemostatic blood markers may trigger or indicate impending plaque rupture and coronary thrombosis, resulting in acute ischemic heart disease (IHD) events. However, these associations are not established in humans.The Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study will determine whether levels of inflammatory and hemostatic biomarkers rapidly increase during the weeks prior to an acute IHD event in people with lower extremity peripheral artery disease (PAD). The BRAVO Study will determine whether biomarker levels measured immediately prior to an IHD event are higher than levels not preceding an IHD event; whether participants who experience an IHD event (cases) have higher biomarker levels immediately prior to the event and higher biomarker levels at each time point leading up to the IHD event than participants without an IHD event (controls); and whether case participants have greater increases in biomarkers during the months leading up to the event than controls. BRAVO enrolled 595 patients with PAD, a population at high risk for acute IHD events. After a baseline visit, participants returned every two months for blood collection, underwent an electrocardiogram to identify new silent myocardial infarctions, and were queried about new hospitalizations since their prior study visit. Mortality data were also collected. Participants were followed prospectively for up to three years.BRAVO results will provide important information about the pathophysiology of IHD events and may lead to improved therapies for preventing IHD events in high-risk patients.

  View details for DOI 10.1016/j.cct.2014.03.009

  View details for Web of Science ID 000337203900013

  View details for PubMedID 24721480

  View details for PubMedCentralID PMC4082976

• Sex modifies the APOE-related risk of developing Alzheimer disease. Annals of neurology Altmann, A., Tian, L., Henderson, V. W., Greicius, M. D. 2014; 75 (4): 563-573

  Abstract

  The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative.Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women).APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.

  View details for DOI 10.1002/ana.24135

  View details for PubMedID 24623176

• Predicting the restricted mean event time with the subject's baseline covariates in survival analysis BIOSTATISTICS Tian, L., Zhao, L., Wei, L. J. 2014; 15 (2): 222-233

  Abstract

  For designing, monitoring, and analyzing a longitudinal study with an event time as the outcome variable, the restricted mean event time (RMET) is an easily interpretable, clinically meaningful summary of the survival function in the presence of censoring. The RMET is the average of all potential event times measured up to a time point τ and can be estimated consistently by the area under the Kaplan-Meier curve over $[0, \tau ]$. In this paper, we study a class of regression models, which directly relates the RMET to its "baseline" covariates for predicting the future subjects' RMETs. Since the standard Cox and the accelerated failure time models can also be used for estimating such RMETs, we utilize a cross-validation procedure to select the "best" among all the working models considered in the model building and evaluation process. Lastly, we draw inferences for the predicted RMETs to assess the performance of the final selected model using an independent data set or a "hold-out" sample from the original data set. All the proposals are illustrated with the data from the an HIV clinical trial conducted by the AIDS Clinical Trials Group and the primary biliary cirrhosis study conducted by the Mayo Clinic.

  View details for DOI 10.1093/biostatistics/kxt050

  View details for Web of Science ID 000338110100002

  View details for PubMedID 24292992

  View details for PubMedCentralID PMC3944973

• Landmark Estimation of Survival and Treatment Effect in a Randomized Clinical Trial JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Parast, L., Tian, L., Cai, T. 2014; 109 (505): 384-394

  View details for DOI 10.1080/01621459.2013.842488

  View details for Web of Science ID 000333787300030

• Vitamin D status, functional decline, and mortality in peripheral artery disease VASCULAR MEDICINE McDermott, M. M., Liu, K., Ferrucci, L., Tian, L., Guralnik, J., Kopp, P., Van Horn, L., Liao, Y., Green, D., Kibbe, M., Sufit, R., Zhao, L., Criqui, M. H. 2014; 19 (1): 18-26

  Abstract

  Associations of vitamin D levels with prospectively measured functional decline and mortality in people with lower extremity peripheral artery disease (PAD) are unknown. We determined whether lower baseline vitamin D levels are associated with a faster decline in functional performance and higher mortality among people with and without PAD. A total of 658 participants (395 with PAD) underwent baseline measurement of 25-hydroxyvitamin D (DiaSorin radioimmunoassay), a 6-minute walk test, 4-meter walking velocity and the Short Physical Performance Battery (SPPB), and were followed annually for up to 4 years. Analyses were adjusted for age, sex, race, body mass index, comorbidities, the ankle-brachial index, and other confounders. Among participants with PAD, lower baseline vitamin D levels were associated with a faster decline in the 6-minute walk (vitamin D < 30 nmol/L: -70.0 feet/year; vitamin D 30 to < 50 nmol/L: -72.3 feet/year; vitamin D 50 to < 75 nmol/L: -35.5 feet/year; vitamin D 75 to < 120 nmol/L: -35.9 feet/year; p trend=0.012). PAD participants with vitamin D < 30 nmol/L had a faster decline in the SPPB and 6-minute walk compared to those with levels of 50 to < 75 (p=0.034 and p=0.04, respectively). Among participants without PAD, lower vitamin D was associated with a faster decline in the fast 4-meter walking velocity (p trend=0.003). There were no significant associations of baseline vitamin D levels with all-cause or cardiovascular disease mortality in PAD or non-PAD participants. In conclusion, among individuals with and without PAD, low vitamin D status was associated with a faster decline in some measures of functional performance but was not related to mortality.

  View details for DOI 10.1177/1358863X13518364

  View details for Web of Science ID 000337579400003

  View details for PubMedID 24442622

• A group-mediated, home-based physical activity intervention for patients with peripheral artery disease: effects on social and psychological function. Journal of translational medicine Rejeski, W. J., Spring, B., Domanchuk, K., Tao, H., Tian, L., Zhao, L., McDermott, M. M. 2014; 12 (1): 29-?

  Abstract

  PAD is a disabling, chronic condition of the lower extremities that affects approximately 8 million people in the United States. The purpose of this study was to determine whether an innovative home-based walking exercise program for patients with peripheral artery disease (PAD) improves self-efficacy for walking, desire for physical competence, satisfaction for physical functioning, social functioning, and acceptance of PAD related pain and discomfort.The design was a 6-month randomized controlled clinical trial of 194 patients with PAD. Participants were randomized to 1 of 2 parallel groups: a home-based group-mediated cognitive behavioral walking intervention or an attention control condition.Of the 194 participants randomized, 178 completed the baseline and 6-month follow-up visit. The mean age was 70.66 (±9.44) and was equally represented by men and women. Close to half of the cohort was African American. Following 6-months of treatment, the intervention group experienced greater improvement on self-efficacy (p = .0008), satisfaction with functioning (p = .0003), pain acceptance (p = .0002), and social functioning (p = .0008) than the control group; the effects were consistent across a number of potential moderating variables. Change in these outcomes was essentially independent of change in 6-minute walk performance.[ClinicalTrials.gov Identifier: NCT00693940].

  View details for DOI 10.1186/1479-5876-12-29

  View details for PubMedID 24467875

  View details for PubMedCentralID PMC3910685

• Multiparametric spectroscopic photoacoustic imaging of breast cancer development in a transgenic mouse model. Theranostics Wilson, K. E., Bachawal, S. V., Tian, L., Willmann, J. K. 2014; 4 (11): 1062-1071

  Abstract

  To evaluate the potential of multiparametric spectroscopic photoacoustic imaging using oxygen saturation, total hemoglobin, and lipid content to differentiate among four different breast histologies (normal, hyperplasia, ductal carcinoma in situ (DCIS), and invasive breast carcinoma) in a transgenic mouse model of breast cancer development.Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mammary glands (n=251) of a transgenic mouse model of breast cancer development (FVB/N-Tg(MMTV-PyMT)634Mul) were imaged using B-mode ultrasound and spectroscopic photoacoustic imaging, analyzed for oxygen saturation, total hemoglobin, and lipid content, and processed for histological analysis. Statistical analysis was performed using one-way ANOVA, two-sample t-tests, logistic regression, and ROC analysis.Eighty-two normal, 12 hyperplastic, 96 DCIS, and 61 invasive breast carcinoma mammary glands were analyzed. Based on spectroscopic photoacoustic imaging, the oxygen saturation of hyperplasia (50.6%), DCIS (43.0%), and invasive carcinoma (46.2%) significantly increased compared to normal glands (35.5%, P <0.0001), while both total hemoglobin (P<0.01), and lipid content (P<0.0008) significantly decreased with advancing histology. In differentiating normal and hyperplasia from DCIS and invasive breast carcinoma, multiparametric imaging of oxygen saturation, lipid content, and raw photoacoustic signal at 750 nm provided an AUC value of 0.770.Multiparametric spectroscopic photoacoustic imaging is feasible and allows detection of differences in concentration of tissue chromophores among different histologies in a transgenic mouse model of breast cancer development.

  View details for DOI 10.7150/thno.9922

  View details for PubMedID 25285161

  View details for PubMedCentralID PMC4173758

• Landmark Estimation of Survival and Treatment Effect in a Randomized Clinical Trial. Journal of the American Statistical Association Parast, L., Tian, L., Cai, T. 2014; 109 (505): 384-394

  Abstract

  In many studies with a survival outcome, it is often not feasible to fully observe the primary event of interest. This often leads to heavy censoring and thus, difficulty in efficiently estimating survival or comparing survival rates between two groups. In certain diseases, baseline covariates and the event time of non-fatal intermediate events may be associated with overall survival. In these settings, incorporating such additional information may lead to gains in efficiency in estimation of survival and testing for a difference in survival between two treatment groups. If gains in efficiency can be achieved, it may then be possible to decrease the sample size of patients required for a study to achieve a particular power level or decrease the duration of the study. Most existing methods for incorporating intermediate events and covariates to predict survival focus on estimation of relative risk parameters and/or the joint distribution of events under semiparametric models. However, in practice, these model assumptions may not hold and hence may lead to biased estimates of the marginal survival. In this paper, we propose a semi-nonparametric two-stage procedure to estimate and compare t-year survival rates by incorporating intermediate event information observed before some landmark time, which serves as a useful approach to overcome semi-competing risks issues. In a randomized clinical trial setting, we further improve efficiency through an additional calibration step. Simulation studies demonstrate substantial potential gains in efficiency in terms of estimation and power. We illustrate our proposed procedures using an AIDS Clinical Trial Protocol 175 dataset by estimating survival and examining the difference in survival between two treatment groups: zidovudine and zidovudine plus zalcitabine.

  View details for DOI 10.1080/01621459.2013.842488

  View details for PubMedID 24659838

  View details for PubMedCentralID PMC3960087

• Multiparametric Spectroscopic Photoacoustic Imaging of Breast Cancer Development in a Transgenic Mouse Model THERANOSTICS Wilson, K. E., Bachawal, S. V., Tian, L., Willmann, J. K. 2014; 4 (11): 1062-1071

  View details for DOI 10.7150/thno.9922

  View details for Web of Science ID 000345212900001

• A Prosthesis Control System Based on the Combination of Speech and sEMG Signals and Its Performance Assessment 3rd International Conference on Health Information Science (HIS) Wei, Z., Fang, P., Tian, L., Zhuo, Q., Li, G. SPRINGER-VERLAG BERLIN. 2014: 72–82

  View details for Web of Science ID 000341117700009

• Density estimation on multivariate censored data with optional Polya tree BIOSTATISTICS Seok, J., Tian, L., Wong, W. H. 2014; 15 (1): 182-195

  Abstract

  Analyzing the failure times of multiple events is of interest in many fields. Estimating the joint distribution of the failure times in a non-parametric way is not straightforward because some failure times are often right-censored and only known to be greater than observed follow-up times. Although it has been studied, there is no universally optimal solution for this problem. It is still challenging and important to provide alternatives that may be more suitable than existing ones in specific settings. Related problems of the existing methods are not only limited to infeasible computations, but also include the lack of optimality and possible non-monotonicity of the estimated survival function. In this paper, we proposed a non-parametric Bayesian approach for directly estimating the density function of multivariate survival times, where the prior is constructed based on the optional Pólya tree. We investigated several theoretical aspects of the procedure and derived an efficient iterative algorithm for implementing the Bayesian procedure. The empirical performance of the method was examined via extensive simulation studies. Finally, we presented a detailed analysis using the proposed method on the relationship among organ recovery times in severely injured patients. From the analysis, we suggested interesting medical information that can be further pursued in clinics.

  View details for DOI 10.1093/biostatistics/kxt025

  View details for Web of Science ID 000328286700019

  View details for PubMedID 23902636

  View details for PubMedCentralID PMC3862208

• Home-Based Walking Exercise in Peripheral Artery Disease: 12-Month Follow-up of the Goals Randomized Trial. Journal of the American Heart Association McDermott, M. M., Guralnik, J. M., Criqui, M. H., Ferrucci, L., Zhao, L., Liu, K., Domanchuk, K., Spring, B., Tian, L., Kibbe, M., Liao, Y., Lloyd Jones, D., Rejeski, W. J. 2014; 3 (3)

  Abstract

  We studied whether a 6-month group-mediated cognitive behavioral (GMCB) intervention for peripheral artery disease (PAD) participants, which promoted home-based walking exercise, improved 6-minute walk and other outcomes at 12-month follow-up, 6 months after completing the intervention, compared to a control group.We randomized PAD participants to a GMCB intervention or a control group. During phase I (months 1 to 6), the intervention used group support and self-regulatory skills during weekly on-site meetings to help participants adhere to home-based exercise. The control group received weekly on-site lectures on topics unrelated to exercise. Primary outcomes were measured at the end of phase I. During phase II (months 7 to 12), each group received telephone contact. Compared to controls, participants randomized to the intervention increased their 6-minute walk distance from baseline to 12-month follow-up, (from 355.4 to 381.9 m in the intervention versus 353.1 to 345.6 m in the control group; mean difference=+34.1 m; 95% confidence interval [CI]=+14.6, +53.5; P<0.001) and their Walking Impairment Questionnaire (WIQ) speed score (from 36.1 to 46.5 in the intervention group versus 34.9 to 36.5 in the control group; mean difference =+8.8; 95% CI=+1.6, +16.1; P=0.018). Change in the WIQ distance score was not different between the 2 groups at 12-month follow-up (P=0.139).A weekly on-site GMCB intervention that promoted home-based walking exercise intervention for people with PAD demonstrated continued benefit at 12-month follow-up, 6 months after the GMCB intervention was completed.ClinicalTrials.gov. Unique identifier: NCT00693940.

  View details for DOI 10.1161/JAHA.113.000711

  View details for PubMedID 24850615

• Nocturnal Intermittent Hypoxia Is Independently Associated with Pain in Subjects Suffering from Sleep-disordered Breathing. Anesthesiology Doufas, A. G., Tian, L., Davies, M. F., Warby, S. C. 2013; 119 (5): 1149-1162

  Abstract

  On the basis of experimental and clinical evidence, the authors hypothesized that nocturnal hypoxemia would be associated with pain reports in subjects suffering from sleep-disordered breathing, independently of sleep fragmentation and inflammation.After obtaining institutional approval and access to the Cleveland Family Study phenotype and genotype data, the authors used proportional odds regression to examine the association between arterial desaturation and four different types of pain, as well as their composite measure, sequentially adjusted for: (1) clinical characteristics and (2) sleep fragmentation and inflammation. The authors also examined the association of selected candidate single-nucleotide polymorphisms with pain reports.Decreased minimum nocturnal arterial saturation increased the odds for morning headache (adjusted odds ratio per SD=1.36; 95% CI [1.08-1.71]; P=0.009), headache disrupting sleep (1.29 [1.10-1.51]; P=0.002), and chest pain while in bed (1.37 [1.10-1.70]; P=0.004). A decrease in the minimum nocturnal saturation from 92 to 75% approximately doubled the odds for pain. One single-nucleotide polymorphism for the α 1 chain of collagen type XI (COL11A1-rs1676486) gene was significantly associated with headache disrupting sleep (odds ratio=1.72 [1.01-2.94]; P=0.038), pain disrupting sleep (odds ratio=1.85 [1.04-3.28]; P=0.018), and pain composite (odds ratio=1.89 [1.14-3.14]; P=0.001).Nocturnal arterial desaturation may be associated with an increased pain in subjects with sleep-disordered breathing, independently of sleep fragmentation and inflammation.

  View details for DOI 10.1097/ALN.0b013e3182a951fc

  View details for PubMedID 24025612

• Progenitor cell release plus exercise to improve functional performance in peripheral artery disease: The PROPEL Study CONTEMPORARY CLINICAL TRIALS Domanchuk, K., Ferrucci, L., Guralnik, J. M., Criqui, M. H., Tian, L., Liu, K., Losordo, D., Stein, J., Green, D., Kibbe, M., Zhao, L., Annex, B., Perlman, H., Lloyd-Jones, D., Pearce, W., Taylor, D., McDermott, M. M. 2013; 36 (2): 502-509

  Abstract

  Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.

  View details for DOI 10.1016/j.cct.2013.09.011

  View details for Web of Science ID 000329265300019

  View details for PubMedID 24080099

  View details for PubMedCentralID PMC3939047

• Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology Foygel, K., Wang, H., Machtaler, S., Lutz, A. M., Chen, R., Pysz, M., Lowe, A. W., Tian, L., Carrigan, T., Brentnall, T. A., Willmann, J. K. 2013; 145 (4): 885-894 e3

  Abstract

  Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.

  View details for DOI 10.1053/j.gastro.2013.06.011

  View details for PubMedID 23791701

• Evaluating subject-level incremental values of new markers for risk classification rule LIFETIME DATA ANALYSIS Cai, T., Tian, L., Lloyd-Jones, D., Wei, L. J. 2013; 19 (4): 547-567

  Abstract

  Suppose that we need to classify a population of subjects into several well-defined ordered risk categories for disease prevention or management with their "baseline" risk factors/markers. In this article, we present a systematic approach to identify subjects using their conventional risk factors/markers who would benefit from a new set of risk markers for more accurate classification. Specifically for each subgroup of individuals with the same conventional risk estimate, we present inference procedures for the reclassification and the corresponding correct re-categorization rates with the new markers. We then apply these new tools to analyze the data from the Cardiovascular Health Study sponsored by the US National Heart, Lung, and Blood Institute. We used Framingham risk factors plus the information of baseline anti-hypertensive drug usage to identify adult American women who may benefit from the measurement of a new blood biomarker, CRP, for better risk classification in order to intensify prevention of coronary heart disease for the subsequent 10 years.

  View details for DOI 10.1007/s10985-013-9272-6

  View details for Web of Science ID 000326295000006

  View details for PubMedID 23807696

• Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology Foygel, K., Wang, H., Machtaler, S., Lutz, A. M., Chen, R., Pysz, M., Lowe, A. W., Tian, L., Carrigan, T., Brentnall, T. A., Willmann, J. K. 2013; 145 (4): 885-894 e3

  Abstract

  Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging.Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC.Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC.We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients.

  View details for DOI 10.1053/j.gastro.2013.06.011

  View details for PubMedID 23791701

• AKI in Hospitalized Children: Epidemiology and Clinical Associations in a National Cohort. Clinical journal of the American Society of Nephrology Sutherland, S. M., Ji, J., Sheikhi, F. H., Widen, E., Tian, L., Alexander, S. R., Ling, X. B. 2013; 8 (10): 1661-1669

  Abstract

  Although AKI is common among hospitalized children, comprehensive epidemiologic data are lacking. This study characterizes pediatric AKI across the United States and identifies AKI risk factors using high-content/high-throughput analytic techniques.For the cross-sectional analysis of the 2009 Kids Inpatient Database, AKI events were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Demographics, incident rates, and outcome data were analyzed and reported for the entire AKI cohort as well as AKI subsets. Statistical learning methods were applied to the highly imbalanced dataset to derive AKI-related risk factors.Of 2,644,263 children, 10,322 children developed AKI (3.9/1000 admissions). Although 19% of the AKI cohort was ≤1 month old, the highest incidence was seen in children 15-18 years old (6.6/1000 admissions); 49% of the AKI cohort was white, but AKI incidence was higher among African Americans (4.5 versus 3.8/1000 admissions). In-hospital mortality among patients with AKI was 15.3% but higher among children ≤1 month old (31.3% versus 10.1%, P<0.001) and children requiring critical care (32.8% versus 9.4%, P<0.001) or dialysis (27.1% versus 14.2%, P<0.001). Shock (odds ratio, 2.15; 95% confidence interval, 1.95 to 2.36), septicemia (odds ratio, 1.37; 95% confidence interval, 1.32 to 1.43), intubation/mechanical ventilation (odds ratio, 1.2; 95% confidence interval, 1.16 to 1.25), circulatory disease (odds ratio, 1.47; 95% confidence interval, 1.32 to 1.65), cardiac congenital anomalies (odds ratio, 1.2; 95% confidence interval, 1.13 to 1.23), and extracorporeal support (odds ratio, 2.58; 95% confidence interval, 2.04 to 3.26) were associated with AKI.AKI occurs in 3.9/1000 at-risk US pediatric hospitalizations. Mortality is highest among neonates and children requiring critical care or dialysis. Identified risk factors suggest that AKI occurs in association with systemic/multiorgan disease more commonly than primary renal disease.

  View details for DOI 10.2215/CJN.00270113

  View details for PubMedID 23833312

• Home-Based Walking Exercise Intervention in Peripheral Artery Disease A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION McDermott, M. M., Liu, K., Guralnik, J. M., Criqui, M. H., Spring, B., Tian, L., Domanchuk, K., Ferrucci, L., Lloyd-Jones, D., Kibbe, M., Tao, H., Zhao, L., Liao, Y., Rejeski, W. J. 2013; 310 (1): 57-65

  Abstract

  Clinical practice guidelines state there is insufficient evidence to support advising patients with peripheral artery disease (PAD) to participate in a home-based walking exercise program.To determine whether a home-based walking exercise program that uses a group-mediated cognitive behavioral intervention, incorporating both group support and self-regulatory skills, can improve functional performance compared with a health education control group in patients with PAD with and without intermittent claudication.Randomized controlled clinical trial of 194 patients with PAD, including 72.2% without classic symptoms of intermittent claudication, performed in Chicago, Illinois between July 22, 2008, and December 14, 2012.Participants were randomized to 1 of 2 parallel groups: a home-based group-mediated cognitive behavioral walking intervention or an attention control condition.The primary outcome was 6-month change in 6-minute walk performance. Secondary outcomes included 6-month change in treadmill walking, physical activity, the Walking Impairment Questionnaire (WIQ), and Physical and Mental Health Composite Scores from the 12-item Short-Form Health Survey.Participants randomized to the intervention group significantly increased their 6-minute walk distance ([reported in meters] 357.4 to 399.8 vs 353.3 to 342.2 for those in the control group; mean difference, 53.5 [95% CI, 33.2 to 73.8]; P < .001), maximal treadmill walking time (intervention, 7.91 to 9.44 minutes vs control, 7.56 to 8.09; mean difference, 1.01 minutes [95% CI, 0.07 to 1.95]; P = .04), accelerometer-measured physical activity over 7 days (intervention, 778.0 to 866.1 vs control, 671.6 to 645.0; mean difference, 114.7 activity units [95% CI, 12.82 to 216.5]; P = .03), WIQ distance score (intervention, 35.3 to 47.4 vs control, 33.3 to 34.4; mean difference, 11.1 [95% CI, 3.9 to 18.1]; P = .003), and WIQ speed score (intervention, 36.1 to 47.7 vs control, 35.3-36.6; mean difference, 10.4 [95% CI, 3.4 to 17.4]; P = .004).A home-based walking exercise program significantly improved walking endurance, physical activity, and patient-perceived walking endurance and speed in PAD participants with and without classic claudication symptoms. These findings have implications for the large number of patients with PAD who are unable or unwilling to participate in supervised exercise programs.clinicaltrials.gov Identifier: NCT00693940.

  View details for Web of Science ID 000321253000023

  View details for PubMedID 23821089

• Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. Clinical immunology Kohrt, H. E., Tian, L., Li, L., Alizadeh, A. A., Hsieh, S., Tibshirani, R. J., Strober, S., Sarwal, M., Lowsky, R. 2013; 148 (1): 124-135

  Abstract

  Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications.

  View details for DOI 10.1016/j.clim.2013.04.013

  View details for PubMedID 23685278

• A unified inference procedure for a class of measures to assess improvement in risk prediction systems with survival data STATISTICS IN MEDICINE Uno, H., Tian, L., Cai, T., Kohane, I. S., Wei, L. J. 2013; 32 (14): 2430-2442

  Abstract

  Risk prediction procedures can be quite useful for the patient's treatment selection, prevention strategy, or disease management in evidence-based medicine. Often, potentially important new predictors are available in addition to the conventional markers. The question is how to quantify the improvement from the new markers for prediction of the patient's risk in order to aid cost-benefit decisions. The standard method, using the area under the receiver operating characteristic curve, to measure the added value may not be sensitive enough to capture incremental improvements from the new markers. Recently, some novel alternatives to area under the receiver operating characteristic curve, such as integrated discrimination improvement and net reclassification improvement, were proposed. In this paper, we consider a class of measures for evaluating the incremental values of new markers, which includes the preceding two as special cases. We present a unified procedure for making inferences about measures in the class with censored event time data. The large sample properties of our procedures are theoretically justified. We illustrate the new proposal with data from a cancer study to evaluate a new gene score for prediction of the patient's survival.

  View details for DOI 10.1002/sim.5647

  View details for Web of Science ID 000319880100008

  View details for PubMedID 23037800

• Molecular Imaging of Inflammation in Inflammatory Bowel Disease with a Clinically Translatable Dual-Selectin-targeted US Contrast Agent: Comparison with FDG PET/CT in a Mouse Model. Radiology Wang, H., Machtaler, S., Bettinger, T., Lutz, A. M., Luong, R., Bussat, P., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 267 (3): 818-829

  Abstract

  Purpose: To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model. Materials and Methods: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis. Results: MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ≤ .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (ρ = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014). Conclusion: US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122509/-/DC1.

  View details for DOI 10.1148/radiol.13122509

  View details for PubMedID 23371306

• Effectively Selecting a Target Population for a Future Comparative Study JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Zhao, L., Tian, L., Cai, T., Claggett, B., Wei, L. J. 2013; 108 (502): 527-539

  View details for DOI 10.1080/01621459.2013.770705

  View details for Web of Science ID 000321727700014

• Proximal Superficial Femoral Artery Occlusion, Collateral Vessels, and Walking Performance in Peripheral Artery Disease JACC-CARDIOVASCULAR IMAGING McDermott, M. M., Carroll, T. J., Kibbe, M., Kramer, C. M., Liu, K., Guralnik, J. M., Keeling, A. N., Criqui, M. H., Ferrucci, L., Yuan, C., Tian, L., Liao, Y., Berry, J., Zhao, L., Carr, J. 2013; 6 (6): 687-694

  Abstract

  We studied associations of magnetic resonance imaging (MRI)-measured superficial femoral artery (SFA) occlusions with functional performance, leg symptoms, and collateral vessel number in peripheral artery disease (PAD). We studied associations of collateral vessel number with functional performance in PAD.Associations of MRI-detected SFA occlusion and collateral vessel number with functional performance among individuals with PAD have not been reported.A total of 457 participants with an ankle brachial index (ABI) <1.00 had MRI measurement of the proximal SFA with 12 consecutive 2.5-μm cross-sectional images. An occluded SFA was defined as an SFA in which at least 1 segment was occluded. A nonoccluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography. Lower extremity functional performance was measured with the 6-min walk, 4-m walking velocity at usual and fastest pace, and the Short Physical Performance Battery (SPPB) (0 to 12 scale, 12 = best).Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer 6-min walk performance (1,031 vs. 1,169 feet, p = 0.006), slower fast-paced walking velocity (1.15 vs. 1.22 m/s, p = 0.042), and lower SPPB score (9.07 vs. 9.75, p = 0.038) compared with the absence of an SFA occlusion. More numerous collateral vessels were associated with better 6-min walk performance (0 to 3 collaterals-1,064 feet, 4 to 7 collaterals-1,165 feet, ≥8 collaterals-1,246 feet, p trend = 0.007), faster usual-paced walking speed (0 to 3 collaterals-0.84 m/s, 4 to 7 collaterals-0.88 m/s, ≥8 collaterals-0.91 m/s, p trend = 0.029), and faster rapid-paced walking speed (0 to 3 collaterals-1.17 m/s, 4 to 7 collaterals-1.22 m/s, ≥8 collaterals-1.29 m/s, p trend = 0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders.Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, whereas more numerous collaterals are associated with better functional performance. (Magnetic Resonance Imaging to Identify Characteristics of Plaque Build-Up in People With Peripheral Arterial Disease; NCT00520312).

  View details for DOI 10.1016/j.jcmg.2012.10.024

  View details for Web of Science ID 000320977200008

  View details for PubMedID 23647796

• Evaluation of Vitamin D Standardization Program protocols for standardizing serum 25-hydroxyvitamin D data: a case study of the program's potential for national nutrition and health surveys AMERICAN JOURNAL OF CLINICAL NUTRITION Cashman, K. D., Kiely, M., Kinsella, M., Durazo-Arvizu, R. A., Tian, L., Zhang, Y., Lucey, A., Flynn, A., Gibney, M. J., Vesper, H. W., Phinney, K. W., Coates, P. M., Picciano, M. F., Sempos, C. T. 2013; 97 (6): 1235-1242

  Abstract

  The Vitamin D Standardization Program (VDSP) has developed protocols for standardizing procedures of 25-hydroxyvitamin D [25(OH)D] measurement in National Health/Nutrition Surveys to promote 25(OH)D measurements that are accurate and comparable over time, location, and laboratory procedure to improve public health practice.We applied VDSP protocols to existing ELISA-derived serum 25(OH)D data from the Irish National Adult Nutrition Survey (NANS) as a case-study survey and evaluated their effectiveness by comparison of the protocol-projected estimates with those from a reanalysis of survey serums by using liquid chromatography-tandem mass spectrometry (LC-tandem MS).The VDSP reference system and protocols were applied to ELISA-based serum 25(OH)D data from the representative NANS sample (n = 1118). A reanalysis of 99 stored serums by using standardized LC-tandem MS and resulting regression equations yielded predicted standardized serum 25(OH)D values, which were then compared with LC-tandem MS reanalyzed values for all serums.Year-round prevalence rates for serum 25(OH)D concentrations <30, <40, and <50 nmol/L were 6.5%, 21.9%, and 40.0%, respectively, via original ELISA measurements and 11.4%, 25.3%, and 43.7%, respectively, when VDSP protocols were applied. Differences in estimates at <30- and <40-nmol/L thresholds, but not at the <50-nmol/L threshold, were significant (P < 0.05). A reanalysis of all serums by using LC-tandem MS confirmed prevalence estimates as 11.2%, 27.2%, and 45.0%, respectively. Prevalences of serum 25(OH)D concentrations >125 nmol/L were 1.2%, 0.3%, and 0.6% by means of ELISA, VDSP protocols, and LC-tandem MS, respectively.VDSP protocols hold a major potential for national nutrition and health surveys in terms of the standardization of serum 25(OH)D data.

  View details for DOI 10.3945/ajcn.112.057182

  View details for Web of Science ID 000319371500012

  View details for PubMedID 23615829

  View details for PubMedCentralID PMC3652922

• Declining Walking Impairment Questionnaire Scores Are Associated With Subsequent Increased Mortality in Peripheral Artery Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Jain, A., Liu, K., Ferrucci, L., Criqui, M. H., Tian, L., Guralnik, J. M., Tao, H., McDermott, M. M. 2013; 61 (17): 1820-1829

  Abstract

  This study determined whether greater 2-year declines in Walking Impairment Questionnaire (WIQ) stair climbing, distance, or speed scores were associated with higher all-cause and cardiovascular disease (CVD) mortality among men and women with lower extremity peripheral artery disease (PAD).Associations of decline in the WIQ with mortality among people with PAD are unknown.Participants were 442 men and women with PAD identified from Chicago area medical centers. The WIQ was completed at baseline and at 2-year follow-up. Cox proportional hazard models were used to assess associations across categories of 2-year changes in WIQ stair climbing, WIQ distance, and WIQ speed scores with subsequent all-cause and CVD mortality, adjusting for age, sex, race, ankle-brachial index, body mass index, smoking, comorbidities, and other covariates.One hundred twenty-three participants (27.8%) died during a median follow-up of 4.7 years after the 2-year change in WIQ score measurements. Forty-five participants died from CVD. Adjusting for covariates, participants with WIQ score declines ≥20.0 points had higher all-cause mortality (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.01 to 3.68 for WIQ stair climbing; HR: 2.34, 95% CI: 1.15 to 4.75 for WIQ distance; and HR: 3.55, 95% CI: 1.57 to 8.04 for WIQ speed, respectively) compared with participants with ≥20.0 point improvement in each of the corresponding WIQ categories. Participants with ≥20.0 point declines in the WIQ distance score had higher CVD mortality (HR: 4.56, 95% CI: 1.30 to 16.01) compared with those with ≥20.0 point improvement in the WIQ distance score.Patients with PAD who experienced ≥20.0 point declines in the WIQ stair climbing, distance, and speed scores had a higher rate of all-cause mortality compared with those with less declines in each WIQ score.

  View details for DOI 10.1016/j.jacc.2013.01.060

  View details for Web of Science ID 000317842200011

  View details for PubMedID 23500321

• Comparative effectiveness study of self-directed walking exercise, lower extremity revascularization, and functional decline in peripheral artery disease JOURNAL OF VASCULAR SURGERY McDermott, M. M., Kibbe, M., Guralnik, J. M., Pearce, W. H., Tian, L., Liao, Y., Zhao, L., Criqui, M. H. 2013; 57 (4): 990-?

  Abstract

  Among individuals with peripheral artery disease (PAD), we compared annual change in 6-minute walk performance between participants who neither underwent lower extremity revascularization nor walked for exercise (group 1, reference), those who walked regularly for exercise (group 2), and those who underwent lower extremity revascularization (group 3).Participants were recruited from Chicago-area vascular laboratories and followed annually. Change in 6-minute walk was calculated beginning at the study visit preceding lower extremity revascularization or exercise behavior and continuing for 1 additional year after the therapy was reported. Results are adjusted for age, sex, race, comorbidities, and other confounders.Of 348 PAD participants, 43 underwent revascularization during median follow-up of 84 months. Adjusted annual declines in 6-minute walk were -96.6 feet/year for group 1, -49.9 feet/year for group 2, and -32.6 feet/year for group 3 (P < .001). Forty-one percent of revascularizations were not associated with ankle-brachial index (ABI) improvement. When group 3 was limited to participants with ABI improvement ≥0.15 after revascularization, annual adjusted changes in 6-minute walk were -97.7 feet/year for group 1, -46.5 feet/year for group 2, and +68.1 feet/year for group 3 (P < .001). When group 3 was limited to participants without ABI improvement ≥0.15 after revascularization, annual adjusted changes in 6-minute walk were -99.2 feet/year for group 1, -48.0 feet/year for group 2, and -61.7 feet/year for group 3 (P < .001).A large proportion of PAD participants did not have ABI improvement of at least 0.15 at follow-up study visit after revascularization. The benefits of lower extremity revascularization in patients with PAD appear closely tied to improvements in the ABI after revascularization.

  View details for DOI 10.1016/j.jvs.2012.09.068

  View details for Web of Science ID 000317187900013

  View details for PubMedID 23352363

• Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model CANCER RESEARCH Bachawal, S. V., Jensen, K. C., Lutz, A. M., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 73 (6): 1689-1698

  Abstract

  While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MB(VEGFR2)) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MB(VEGFR2) than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R(2) = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women.

  View details for DOI 10.1158/0008-5472.CAN-12-3391

  View details for Web of Science ID 000316187500006

  View details for PubMedID 23328585

  View details for PubMedCentralID PMC3602408

• Experimental Pain and Opioid Analgesia in Volunteers at High Risk for Obstructive Sleep Apnea PLOS ONE Doufas, A. G., Tian, L., Padrez, K. A., Suwanprathes, P., Cardell, J. A., Maecker, H. T., Panousis, P. 2013; 8 (1)

  Abstract

  Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.Clinicaltrials.gov NCT00672737.

  View details for DOI 10.1371/journal.pone.0054807

  View details for Web of Science ID 000315483200027

  View details for PubMedID 23382975

  View details for PubMedCentralID PMC3558510

• Experimental pain and opioid analgesia in volunteers at high risk for obstructive sleep apnea. PloS one Doufas, A. G., Tian, L., Padrez, K. A., Suwanprathes, P., Cardell, J. A., Maecker, H. T., Panousis, P. 2013; 8 (1)

  Abstract

  Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.Clinicaltrials.gov NCT00672737.

  View details for DOI 10.1371/journal.pone.0054807

  View details for PubMedID 23382975

  View details for PubMedCentralID PMC3558510

• Estimating Subject-Specific Treatment Differences for Risk-Benefit Assessment with Applications to Beta-Blocker Effectiveness Trials 21st International-Chinese-Statistical-Association (ICSA) Applied Statistics Symposium Claggett, B., Tian, L., Zhao, L., Castagno, D., Wei, L. SPRINGER. 2013: 75–86

  View details for DOI 10.1007/978-1-4614-7846-1_7

  View details for Web of Science ID 000347151000007

• Cloud-based solution to identify statistically significant MS peaks differentiating sample categories. BMC research notes Ji, J., Ling, J., Jiang, H., Wen, Q., Whitin, J. C., Tian, L., Cohen, H. J., Ling, X. B. 2013; 6: 109-?

  Abstract

  Mass spectrometry (MS) has evolved to become the primary high throughput tool for proteomics based biomarker discovery. Until now, multiple challenges in protein MS data analysis remain: large-scale and complex data set management; MS peak identification, indexing; and high dimensional peak differential analysis with the concurrent statistical tests based false discovery rate (FDR). "Turnkey" solutions are needed for biomarker investigations to rapidly process MS data sets to identify statistically significant peaks for subsequent validation.Here we present an efficient and effective solution, which provides experimental biologists easy access to "cloud" computing capabilities to analyze MS data. The web portal can be accessed at http://transmed.stanford.edu/ssa/.Presented web application supplies large scale MS data online uploading and analysis with a simple user interface. This bioinformatic tool will facilitate the discovery of the potential protein biomarkers using MS.

  View details for DOI 10.1186/1756-0500-6-109

  View details for PubMedID 23522030

  View details for PubMedCentralID PMC3621609

• Identification of Candidate Transcriptional Biomarkers Associated with Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kohrt, H. E., Tian, L., Li, L., Alizadeh, A. A., Hsieh, S., Strober, S., Sarwal, M., Lowsky, R. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838905099

• The Group Oriented Arterial Leg Study (GOALS) to improve walking performance in patients with peripheral arterial disease CONTEMPORARY CLINICAL TRIALS McDermott, M. M., Domanchuk, K., Liu, K., Guralnik, J. M., Tian, L., Criqui, M. H., Ferrucci, L., Kibbe, M., Jones, D., Pearce, W. H., Zhao, L., Spring, B., Rejeski, W. J. 2012; 33 (6): 1311-1320

  Abstract

  People with lower extremity peripheral artery disease (PAD) have greater functional impairment and faster functional decline than those without PAD. We describe methods for the Group Oriented Arterial Leg Study (GOALS), an ongoing randomized controlled clinical trial designed to determine whether a Group-Mediated Cognitive Behavioral (GMCB) intervention improves functional performance in PAD participants, compared to a health education control condition. In GOALS, PAD participants were randomized to either an intervention or a health education control condition in a parallel design. Both conditions consist of weekly group sessions with other PAD participants. In the intervention, cognitive behavioral techniques are used to assist participants in setting and adhering to home-based walking exercise goals. Participants are encouraged to walk for exercise at home at least 5 days/week. In the control condition, participants receive lectures on health-related topics. After 6 months of on-site weekly sessions, participants are transitioned to telephone follow-up for another 6 months. Participants in the intervention are asked to continue home walking exercise. The primary outcome is change in six-minute walk performance between baseline and six-month follow-up. Secondary outcomes include change in six-minute walk performance at 12-month follow-up, and change in treadmill walking performance, the Walking Impairment Questionnaire, quality of life, and physical activity at six and 12-month follow-up. In conclusion, if our group-mediated cognitive behavioral intervention is associated with improved walking performance in individuals with PAD, results will have major public health implications for the large and growing number of people with PAD.

  View details for DOI 10.1016/j.cct.2012.08.001

  View details for Web of Science ID 000310825400025

  View details for PubMedID 23158112

• Vitamin D status and functional performance in peripheral artery disease VASCULAR MEDICINE McDermott, M. M., Liu, K., Ferrucci, L., Tian, L., Guralnik, J., Kopp, P., Tao, H., Van Horn, L., Liao, Y., Green, D., Kibbe, M., Criqui, M. H. 2012; 17 (5): 294-302

  Abstract

  The clinical implications of low vitamin D in peripheral artery disease (PAD) are unknown. We hypothesized that among individuals with PAD, lower levels of 25-hydroxyvitamin D would be associated with poorer functional performance, more adverse calf muscle characteristics, and poorer peripheral nerve function. Participants were 402 men and women with PAD who underwent measurement of 25-hydroxyvitamin D (DiaSorin radioimmunoassay) along with 6-minute walk testing, measurement of walking velocity at usual and fastest pace, computed tomography-measured calf muscle density, and peripheral nerve conduction velocity (NCV). Among PAD participants, 20.4% had 25-hydroxyvitamin D levels < 30 nmol/L, consistent with deficient vitamin D status. Adjusting for age, sex, and race, lower 25-hydroxyvitamin D levels were associated with poorer 6-minute walk performance (p trend = 0.002), slower usual-paced 4-meter walking velocity (p trend = 0.031), slower fast-paced 4-meter walking velocity (p trend = 0.043), and lower calf muscle density (p trend = 0.031). After additional adjustment for body mass index (BMI) and diabetes, none of these associations remained statistically significant. However, lower levels of 25-hydroxyvitamin D were associated with poorer peroneal NCV (p trend = 0.013) and poorer sural NCV (p trend = 0.039), even after adjusting for age, sex, race, BMI, comorbidities, smoking, physical activity, and other confounders. In conclusion, vitamin D deficiency is common among people with PAD encountered in clinical settings. After adjusting for BMI and diabetes mellitus, we found no significant associations of lower levels of 25-hydroxyvitamin D with poorer functional performance or calf muscle characteristics. Associations of low vitamin D levels with poorer peripheral nerve function require further study.

  View details for DOI 10.1177/1358863X12448457

  View details for Web of Science ID 000309358900002

  View details for PubMedID 22814997

• Utilizing the integrated difference of two survival functions to quantify the treatment contrast for designing, monitoring, and analyzing a comparative clinical study CLINICAL TRIALS Zhao, L., Tian, L., Uno, H., Solomon, S. D., Pfeffer, M. A., Schindler, J. S., Wei, L. J. 2012; 9 (5): 570-577

  Abstract

  Consider a comparative, randomized clinical study with a specific event time as the primary end point. In the presence of censoring, standard methods of summarizing the treatment difference are based on Kaplan-Meier curves, the logrank test, and the point and interval estimates via Cox's procedure. Moreover, for designing and monitoring the study, one usually utilizes an event-driven scheme to determine the sample sizes and interim analysis time points.When the proportional hazards (PHs) assumption is violated, the logrank test may not have sufficient power to detect the difference between two event time distributions. The resulting hazard ratio estimate is difficult, if not impossible, to interpret as a treatment contrast. When the event rates are low, the corresponding interval estimate for the 'hazard ratio' can be quite large due to the fact that the interval length depends on the observed numbers of events. This may indicate that there is not enough information for making inferences about the treatment comparison even when there is no difference between two groups. This situation is quite common for a postmarketing safety study. We need an alternative way to quantify the group difference.Instead of quantifying the treatment group difference using the hazard ratio, we consider an easily interpretable and model-free parameter, the integrated survival rate difference over a prespecified time interval, as an alternative. We present the inference procedures for such a treatment contrast. This approach is purely nonparametric and does not need any model assumption such as the PHs. Moreover, when we deal with equivalence or noninferiority studies and the event rates are low, our procedure would provide more information about the treatment difference. We used a cardiovascular trial data set to illustrate our approach.The results using the integrated event rate differences have a heuristic interpretation for the treatment difference even when the PHs assumption is not valid. When the event rates are low, for example, for the cardiovascular study discussed in this article, the procedure for the integrated event rate difference provides tight interval estimates in contrast to those based on the event-driven inference method.The design of a trial with the integrated event rate difference may be more complicated than that using the event-driven procedure. One may use simulation to determine the sample size and the estimated duration of the study.The procedure discussed in this article can be a useful alternative to the standard PHs method in the survival analysis.

  View details for DOI 10.1177/1740774512455464

  View details for Web of Science ID 000309730200002

  View details for PubMedID 22914867

• Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging ANGIOGENESIS Pysz, M. A., Guracar, I., Foygel, K., Tian, L., Willmann, J. K. 2012; 15 (3): 433-442

  Abstract

  To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system.The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis.MIP percent contrast area was significantly different (P < 0.001) with and without motion compensation. Differences in percent contrast area correlated significantly (P < 0.001) with x- and y-displacements. MIP percent contrast area measurements were more reproducible with motion compensation (ICC = 0.69) than without (ICC = 0.51) on two consecutive ultrasound scans. Following anti-vascular therapy, motion-compensated MIP percent contrast area significantly (P = 0.03) decreased by 39.4 ± 14.6 % compared to non-treated mice and correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05).Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts.

  View details for DOI 10.1007/s10456-012-9271-3

  View details for Web of Science ID 000307272200009

  View details for PubMedID 22535383

• Plaque Characteristics in the Superficial Femoral Artery Correlate with Walking Impairment Questionnaire Scores in Peripheral Arterial Disease: The Walking and Leg Circulation Study (WALCS) III. Journal of surgical radiology McDermott, M. M., Liu, K., Carroll, T. J., Kibbe, M., Ferrucci, L., Guralnik, J. M., Morasch, M., Pearce, W., Carr, J., Yuan, C., Kramer, C. M., Tian, L., Liao, Y., Li, D., Criqui, M. H. 2012; 3 (3): 148-157

  Abstract

  We studied associations of magnetic resonance imaging (MRI)-measured plaque area and relative percent lumen reduction in the proximal superficial femoral artery with Walking Impairment Questionnaire (WIQ) scores and quality of life in people with lower extremity peripheral arterial disease (PAD).Four-hundred forty-two participants with PAD underwent cross-sectional imaging of the proximal superficial femoral artery with MRI, and completed the WIQ and the Short-Form-12 mental and physical functioning questionnaires. Questionnaires were scored on a 0-100 scale (100=best). Results adjust for age, sex, race, the ankle brachial index (ABI), comorbidities, and other covariates.Adjusting for age, sex, race, ABI, comorbidities, and other covariates, higher mean plaque area was associated with poorer WIQ distance scores (1st quintile (least plaque)-44.8, 2nd quintile-43.3, 3rd quintile-38.9, 4th quintile-34.6, 5th quintile (greatest plaque)-30.6, p trend <0.001) and poorer WIQ speed scores (1st quintile-40.6, 2nd quintile-39.6, 3rd quintile-39.5, 4th quintile-32.8, 5th quintile-33.0, p trend =0.019). Similar associations of higher maximum plaque area, mean lumen reduction, and maximum lumen reduction with poorer WIQ distance and speed scores were observed. Plaque measures were not associated with WIQ stair climbing scores or SF-12 scores.Among participants with PAD, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated with poorer walking endurance and slower walking speed as measured by the WIQ, even after adjusting for the ABI.

  View details for PubMedID 29188081

  View details for PubMedCentralID PMC5703222

• Fast microbubble dwell-time based ultrasonic molecular imaging approach for quantification and monitoring of angiogenesis in cancer. Quantitative imaging in medicine and surgery Pysz, M. A., Guracar, I., Tian, L., Willmann, J. K. 2012; 2 (2): 68-80

  Abstract

  PURPOSE: To develop and test a fast ultrasonic molecular imaging technique for quantification and monitoring of angiogenesis in cancer. MATERIALS AND METHODS: A new software algorithm measuring the dwell time of contrast microbubbles in near real-time (henceforth, fast method) was developed and integrated in a clinical ultrasound system. In vivo quantification and monitoring of tumor angiogenesis during anti-VEGF antibody therapy was performed in human colon cancer xenografts in mice (n=20) using the new fast method following administration of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast microbubbles. Imaging results were compared with a traditional destruction/replenishment approach (henceforth, traditional method) in an intra-animal comparison. RESULTS: There was excellent correlation (R(2)=0.93; P<0.001) between the fast method and the traditional method in terms of VEGFR2-targeted in vivo ultrasonic molecular imaging with significantly higher (P=0.002) imaging signal in colon cancer xenografts using VEGFR2-targeted compared to control non-targeted contrast microbubbles. The new fast method was highly reproducible (ICC=0.87). Following anti-angiogenic therapy, ultrasonic molecular imaging signal decreased by an average of 41±10%, whereas imaging signal increased by an average of 54±8% in non-treated tumors over a 72-hour period. Decreased VEGFR2 expression levels following anti-VEGF therapy were confirmed on ex vivo immunofluorescent staining. CONCLUSIONS: Fast ultrasonic molecular imaging based on dwell time microbubble signal measurements correlates well with the traditional measurement method, and allows reliable in vivo monitoring of anti-angiogenic therapy in human colon cancer xenografts. The improved work-flow afforded by the new quantification approach may facilitate clinical translation of ultrasonic molecular imaging.

  View details for PubMedID 22943043

• The Walking Impairment Questionnaire stair-climbing score predicts mortality in men and women with peripheral arterial disease JOURNAL OF VASCULAR SURGERY Jain, A., Liu, K., Ferrucci, L., Criqui, M. H., Tian, L., Guralnik, J. M., Tao, H., McDermott, M. M. 2012; 55 (6): 1662-U440

  Abstract

  The Walking Impairment Questionnaire (WIQ) measures self-reported walking distance, walking speed, and stair-climbing ability in men and women with lower extremity peripheral arterial disease (PAD). We determined whether poorer WIQ scores are associated with higher all-cause and cardiovascular disease (CVD) mortality in individuals with and without PAD.We identified 1048 men and women with and without PAD from Chicago-area medical centers. Participants completed the WIQ at baseline and were monitored for a median of 4.5 years. Cox proportional hazards models were used to relate baseline WIQ scores with death, adjusting for age, sex, race, the ankle-brachial index (ABI), comorbidities, and other covariates.During follow-up, 461 participants (44.0%) died, including 158 deaths from CVD. PAD participants in the lowest baseline quartile of the WIQ stair-climbing scores had higher all-cause mortality (hazard ratio, 1.70; 95% confidence interval, 1.08-2.66, P = .02) and higher CVD mortality (hazard ratio, 3.11; 95% confidence interval, 1.30-7.47, P = .01) compared with those with the highest baseline WIQ stair-climbing score. Among PAD participants, there were no significant associations of lower baseline WIQ distance or speed scores with rates of all-cause mortality (P = .20 and P = .07 for trend, respectively) or CVD mortality (P = .51 and P = .33 for trend, respectively). Among non-PAD participants there were no significant associations of lower baseline WIQ stair-climbing, distance, or speed score with rates of all-cause mortality (P = .94, P = .69, and P = .26, for trend, respectively) or CVD mortality (P = .28, P = .68, and P = .78, for trend, respectively).Among participants with PAD, lower WIQ stair-climbing scores are associated with higher all-cause and CVD mortality, independently of the ABI and other covariates.

  View details for DOI 10.1016/j.jvs.2011.12.010

  View details for Web of Science ID 000304206000017

  View details for PubMedID 22608041

• On the covariate-adjusted estimation for an overall treatment difference with data from a randomized comparative clinical trial BIOSTATISTICS Tian, L., Cai, T., Zhao, L., Wei, L. 2012; 13 (2): 256-273

  Abstract

  To estimate an overall treatment difference with data from a randomized comparative clinical study, baseline covariates are often utilized to increase the estimation precision. Using the standard analysis of covariance technique for making inferences about such an average treatment difference may not be appropriate, especially when the fitted model is nonlinear. On the other hand, the novel augmentation procedure recently studied, for example, by Zhang and others (2008. Improving efficiency of inferences in randomized clinical trials using auxiliary covariates. Biometrics 64, 707-715) is quite flexible. However, in general, it is not clear how to select covariates for augmentation effectively. An overly adjusted estimator may inflate the variance and in some cases be biased. Furthermore, the results from the standard inference procedure by ignoring the sampling variation from the variable selection process may not be valid. In this paper, we first propose an estimation procedure, which augments the simple treatment contrast estimator directly with covariates. The new proposal is asymptotically equivalent to the aforementioned augmentation method. To select covariates, we utilize the standard lasso procedure. Furthermore, to make valid inference from the resulting lasso-type estimator, a cross validation method is used. The validity of the new proposal is justified theoretically and empirically. We illustrate the procedure extensively with a well-known primary biliary cirrhosis clinical trial data set.

  View details for DOI 10.1093/biostatistics/kxr050

  View details for Web of Science ID 000301293800006

  View details for PubMedID 22294672

  View details for PubMedCentralID PMC3297822

• Higher body mass index is associated with more adverse changes in calf muscle characteristics in peripheral arterial disease 59th Annual Scientific Session of the American-College-of-Cardiology Raval, Z., Liu, K., Tian, L., Ferrucci, L., Guralnik, J. M., Liao, Y., Criqui, M. H., McDermott, M. M. MOSBY-ELSEVIER. 2012: 1015–24

  Abstract

  This study investigated whether higher body mass index (BMI) is associated with more adverse lower extremity muscle characteristics at baseline and more adverse changes in muscle over time among participants with lower extremity peripheral arterial disease (PAD).This was a longitudinal, observational study of 425 men and women with PAD and 261 without PAD. Computed tomography was used to measure calf muscle characteristics at baseline and every 2 years. Knee extension isometric strength, power, and 6-minute walk distance were measured at baseline and annually. Baseline BMI (kg/m(2)) categories were ideal (20-25), overweight (>25-30), and obese (>30). Analyses adjust for age, race, sex, ankle brachial index, comorbidities, and other covariates.At baseline, higher BMI among participants with PAD was associated with greater calf muscle area (ideal BMI: 5181 mm(2); overweight: 5513 mm(2); obese: 5695 mm(2); P = .0009 for trend), higher calf muscle percentage of fat (6.38%, 10.28%, 17.44%, respectively, P < .0001 for trend), lower calf muscle density (P < .0001 for trend), and higher isometric knee extension strength (P = .015 for trend). Among participants with PAD, higher BMI was associated with greater declines in calf muscle area (P = .030 for trend) and greater increases in calf muscle percentage of fat (P = .023 for trend). Among participants without PAD, there were no significant associations of baseline BMI with changes in lower extremity muscle outcomes over time.Among PAD participants, higher BMI is associated with greater calf muscle area at baseline. However, higher BMI is associated with more adverse calf muscle density and calf muscle percentage of fat at baseline and greater declines in calf muscle area over time.

  View details for DOI 10.1016/j.jvs.2011.10.105

  View details for Web of Science ID 000302145700016

  View details for PubMedID 22365177

• Calf Muscle Characteristics, Strength Measures, and Mortality in Peripheral Arterial Disease A Longitudinal Study JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McDermott, M. M., Liu, K., Tian, L., Guralnik, J. M., Criqui, M. H., Liao, Y., Ferrucci, L. 2012; 59 (13): 1159-1167

  Abstract

  This study analyzed whether lower calf muscle density and poorer upper and lower extremity strength are associated with higher mortality rates in men and women with peripheral arterial disease (PAD).Men and women with lower extremity PAD have lower calf muscle density and reduced lower extremity strength compared with individuals without PAD.At baseline, participants underwent measurement of calf muscle density with computed tomography in addition to knee extension power and isometric knee extension, plantar flexion, and hand grip strength measures. Participants were followed up annually for up to 4 years. Results were adjusted for age, sex, race, body mass index, ankle-brachial index, smoking, physical activity, and comorbidities.Among 434 PAD participants, 103 (24%) died during a mean follow-up of 47.6 months. Lower calf muscle density was associated with higher all-cause mortality (lowest density tertile hazard ratio [HR]: 1.80 [95% confidence interval (CI): 1.07 to 3.03], second tertile HR: 0.91 (95% CI: 0.51 to 1.62); highest density tertile HR: 1.00; p trend = 0.020) and higher cardiovascular disease mortality (lowest density tertile HR: 2.39 [95% CI: 0.90 to 6.30], second tertile HR: 0.85 [95% CI: 0.27 to 2.71]; highest density tertile HR: 1.00; p trend = 0.047). Poorer plantar flexion strength (p trend = 0.004), lower baseline leg power (p trend = 0.046), and poorer handgrip (p trend = 0.005) were associated with higher all-cause mortality.These data demonstrate that lower calf muscle density and weaker plantar flexion strength, knee extension power, and hand grip were associated with increased mortality in these participants with PAD, independently of the ankle-brachial index and other confounders.

  View details for DOI 10.1016/j.jacc.2011.12.019

  View details for Web of Science ID 000301950300006

  View details for PubMedID 22440216

• A signal processing approach for enriched region detection in RNA polymerase II ChIP-seq data 1st Annual Meeting of the Great Lakes Bioinformatics (GLBIO) Han, Z., Tian, L., Pecot, T., Huang, T., Machiraju, R., Huang, K. BIOMED CENTRAL LTD. 2012

  Abstract

  RNA polymerase II (PolII) is essential in gene transcription and ChIP-seq experiments have been used to study PolII binding patterns over the entire genome. However, since PolII enriched regions in the genome can be very long, existing peak finding algorithms for ChIP-seq data are not adequate for identifying such long regions.Here we propose an enriched region detection method for ChIP-seq data to identify long enriched regions by combining a signal denoising algorithm with a false discovery rate (FDR) approach. The binned ChIP-seq data for PolII are first processed using a non-local means (NL-means) algorithm for purposes of denoising. Then, a FDR approach is developed to determine the threshold for marking enriched regions in the binned histogram.We first test our method using a public PolII ChIP-seq dataset and compare our results with published results obtained using the published algorithm HPeak. Our results show a high consistency with the published results (80-100%). Then, we apply our proposed method on PolII ChIP-seq data generated in our own study on the effects of hormone on the breast cancer cell line MCF7. The results demonstrate that our method can effectively identify long enriched regions in ChIP-seq datasets. Specifically, pertaining to MCF7 control samples we identified 5,911 segments with length of at least 4 Kbp (maximum 233,000 bp); and in MCF7 treated with E2 samples, we identified 6,200 such segments (maximum 325,000 bp).We demonstrated the effectiveness of this method in studying binding patterns of PolII in cancer cells which enables further deep analysis in transcription regulation and epigenetics. Our method complements existing peak detection algorithms for ChIP-seq experiments.

  View details for DOI 10.1186/1471-2105-13-S2-S2

  View details for Web of Science ID 000303936000003

  View details for PubMedID 22536865

  View details for PubMedCentralID PMC3375632

• Dietary Patterns Are Associated with Disease Risk among Participants in the Women's Health Initiative Observational Study JOURNAL OF NUTRITION Van Horn, L., Tian, L., Neuhouser, M. L., Howard, B. V., Eaton, C. B., Snetselaar, L., Matthan, N. R., Lichtenstein, A. H. 2012; 142 (2): 284-291

  View details for DOI 10.3945/jn.111.145375

  View details for Web of Science ID 000299408700013

• Dietary patterns are associated with disease risk among participants in the Women's Health Initiative Observational Study. journal of nutrition Horn, L. V., Tian, L., Neuhouser, M. L., Howard, B. V., Eaton, C. B., Snetselaar, L., Matthan, N. R., Lichtenstein, A. H. 2012; 142 (2): 284-291

  Abstract

  Coronary heart disease (CHD) is the leading cause of death in women. A nested case-control study tested whether dietary patterns predicted CHD events among 1224 participants in the Women's Health Initiative-Observational Study (WHI-OS) with centrally confirmed CHD, fatal or nonfatal myocardial infarct compared to 1224 WHI-OS controls matched for age, enrollment date, race/ethnicity, and absence of CHD at baseline or follow-up. The first six principal components explained >75% of variation in dietary intakes and K-mean analysis based on these six components produced three clusters. Diet cluster 1 was rich in carbohydrate, vegetable protein, fiber, dietary vitamin K, folate, carotenoids, α-linolenic acid [18:3(n-3)], linoleic acid [18:2(n-6)], and supplemental calcium and vitamin D. Diet cluster 2 was rich in total and animal protein, arachidonic acid [20:4(n-6)], DHA [22:6(n-3)], vitamin D, and calcium. Diet cluster 3 was rich in energy, total fat, and trans fatty acids (all P < 0.01). Conditional logistic regression analysis demonstrated diet cluster 1 was associated with lower CHD risk than diet cluster 2 (reference group) adjusted for smoking, education, and physical activity [OR = 0.79 (95% CI = 0.64, 0.99); P = 0.038]. This difference was not significant after adjustment for BMI and systolic blood pressure. Diet cluster 3 was associated with higher CHD risk than diet cluster 2 [OR = 1.28 (95% CI = 1.04, 1.57); P = 0.019], but this difference did not remain significant after adjustment for smoking, education, and physical activity. Within this WHI-OS cohort, distinct dietary patterns may be associated with subsequent CHD outcomes.

  View details for DOI 10.3945/jn.111.145375

  View details for PubMedID 22190026

  View details for PubMedCentralID PMC3260060

• A Pharmacoepidemiological Network Model for Drug Safety Surveillance Statins and Rhabdomyolysis DRUG SAFETY Reis, B. Y., Olson, K. L., Tian, L., Bohn, R. L., Brownstein, J. S., Park, P. J., Cziraky, M. J., Wilson, M. D., Mandl, K. D. 2012; 35 (5): 395-406

  Abstract

  Recent withdrawals of major drugs have highlighted the critical importance of drug safety surveillance in the postmarketing phase. Limitations of spontaneous report data have led drug safety professionals to pursue alternative postmarketing surveillance approaches based on healthcare administrative claims data. These data are typically analysed by comparing the adverse event rates associated with a drug of interest to those of a single comparable reference drug.The aim of this study was to determine whether adverse event detection can be improved by incorporating information from multiple reference drugs. We developed a pharmacological network model that implemented this approach and evaluated its performance.We studied whether adverse event detection can be improved by incorporating information from multiple reference drugs, and describe two approaches for doing so. The first, reported previously, combines a set of related drugs into a single reference cohort. The second is a novel pharmacoepidemiological network model, which integrates multiple pair-wise comparisons across an entire set of related drugs into a unified consensus safety score for each drug. We also implemented a single reference drug approach for comparison with both multi-drug approaches. All approaches were applied within a sequential analysis framework, incorporating new information as it became available and addressing the issue of multiple testing over time. We evaluated all these approaches using statin (HMG-CoA reductase inhibitors) safety data from a large healthcare insurer in the US covering April 2000 through March 2005.We found that both multiple reference drug approaches offer earlier detection (6-13 months) than the single reference drug approach, without triggering additional false positives.Such combined approaches have the potential to be used with existing healthcare databases to improve the surveillance of therapeutics in the postmarketing phase over single-comparator methods. The proposed network approach also provides an integrated visualization framework enabling decision makers to understand the key high-level safety relationships amongst a group of related drugs.

  View details for Web of Science ID 000303692300005

  View details for PubMedID 22506565

• Ultrasound-Mediated Gene Delivery with Cationic Versus Neutral Microbubbles: Effect of DNA and Microbubble Dose on In Vivo Transfection Efficiency THERANOSTICS Panje, C. M., Wang, D. S., Pysz, M. A., Paulmurugan, R., Ren, Y., Tranquart, F., Tian, L., Willmann, J. K. 2012; 2 (11): 1078-1091

  Abstract

  To assess the effect of varying microbubble (MB) and DNA doses on the overall and comparative efficiencies of ultrasound (US)-mediated gene delivery (UMGD) to murine hindlimb skeletal muscle using cationic versus neutral MBs.Cationic and control neutral MBs were characterized for size, charge, plasmid DNA binding, and ability to protect DNA against endonuclease degradation. UMGD of a codon optimized firefly luciferase (Fluc) reporter plasmid to endothelial cells (1 MHz, 1 W/cm², 20% duty cycle, 1 min) was performed in cell culture using cationic, neutral, or no MBs. In vivo UMGD to mouse hindlimb muscle was performed by insonation (1 MHz, 2 W/cm², 50% duty cycle, 5 min) after intravenous administration of Fluc combined with cationic, neutral, or no MBs. Gene delivery efficiency was assessed by serial in vivo bioluminescence imaging. Efficiency of in vivo UMGD with cationic versus neutral MBs was systematically evaluated by varying plasmid DNA dose (10, 17.5, 25, 37.5, and 50 µg) while maintaining a constant MB dose of 1x10(8) MBs and by changing MB dose (1x10(7), 5x10(7), 1x10(8), or 5x10(8) MBs) while keeping a constant DNA dose of 50 µg.Cationic and size-matched control neutral MBs differed significantly in zeta potential with cationic MBs being able to bind plasmid DNA (binding capacity of 0.03 pg/MB) and partially protect DNA from nuclease degradation while neutral MBs could not. Cationic MBs enhanced UMGD compared to neutral MBs as well as no MB and no US controls both in cell culture (P < 0.001) and in vivo (P < 0.05). Regardless of MB type, in vivo UMGD efficiency increased dose-dependently with DNA dose and showed overall maximum transfection with 50 µg DNA. However, there was an inverse correlation (ρ = -0.90; P = 0.02) between DNA dose and the degree of enhanced UMGD efficiency observed with using cationic MBs instead of neutral MBs. The delivery efficiency advantage associated with cationic MBs was most prominent at the lowest investigated DNA dose (7.5-fold increase with cationic versus neutral MBs at a DNA dose of 10 µg; P = 0.02) compared to only a 1.4-fold increase at a DNA dose of 50 µg (P < 0.01). With increasing MB dose, overall in vivo UMGD efficiency increased dose-dependently with a maximum reached at a dose of 1x10(8) MBs with no further significant increase with 5x10(8) MBs (P = 0.97). However, compared to neutral MBs, cationic MBs enhanced UMGD efficiency the most at low MB doses. Relative enhancement of UMGD efficiency using cationic over neutral MBs decreased from a factor of 27 for 1x10(7) MBs (P = 0.02) to a factor of 1.4 for 1x10(8) MBs (P < 0.01) and no significant difference for 5x10(8) MBs.Cationic MBs enhance UMGD to mouse skeletal muscle relative to neutral MBs but this is dependent on MB and DNA dose. The enhancement effect of cationic MBs on UMGD efficiency is more evident when lower doses of MBs or DNA are used, whereas the advantage of cationic MBs over neutral MBs is substantially reduced in the presence of excess MBs or DNA.

  View details for DOI 10.7150/thno.4240

  View details for Web of Science ID 000312955800005

  View details for PubMedID 23227124

  View details for PubMedCentralID PMC3516840

• Antiangiogenic and Radiation Therapy Early Effects on In Vivo Computed Tomography Perfusion Parameters in Human Colon Cancer Xenografts in Mice INVESTIGATIVE RADIOLOGY Ren, Y., Fleischmann, D., Foygel, K., Molvin, L., Lutz, A. M., Koong, A. C., Jeffrey, R. B., Tian, L., Willmann, J. K. 2012; 47 (1): 25-32

  Abstract

  To assess early treatment effects on computed tomography (CT) perfusion parameters after antiangiogenic and radiation therapy in subcutaneously implanted, human colon cancer xenografts in mice and to correlate in vivo CT perfusion parameters with ex vivo assays of tumor vascularity and hypoxia.Dynamic contrast-enhanced CT (perfusion CT, 129 mAs, 80 kV, 12 slices × 2.4 mm; 150 μL iodinated contrast agent injected at a rate of 1 mL/min intravenously) was performed in 100 subcutaneous human colon cancer xenografts on baseline day 0. Mice in group 1 (n=32) received a single dose of the antiangiogenic agent bevacizumab (10 mg/kg body weight), mice in group 2 (n=32) underwent a single radiation treatment (12 Gy), and mice in group 3 (n=32) remained untreated. On days 1, 3, 5, and 7 after treatment, 8 mice from each group underwent a second CT perfusion scan, respectively, after which tumors were excised for ex vivo analysis. Four mice were killed after baseline scanning on day 0 for ex vivo analysis. Blood flow (BF), blood volume (BV), and flow extraction product were calculated using the left ventricle as an arterial input function. Correlation of in vivo CT perfusion parameters with ex vivo microvessel density and extent of tumor hypoxia were assessed by immunofluorescence. Reproducibility of CT perfusion parameter measurements was calculated in an additional 8 tumor-bearing mice scanned twice within 5 hours with the same CT perfusion imaging protocol.The intraclass correlation coefficients for BF, BV, and flow extraction product from repeated CT perfusion scans were 0.93 (95% confidence interval: 0.78, 0.97), 0.88 (0.66, 0.95), and 0.88 (0.56, 0.95), respectively. Changes in perfusion parameters and tumor volumes over time were different between treatments. After bevacizumab treatment, all 3 perfusion parameters significantly decreased from day 1 (P ≤ 0.006) and remained significantly decreased until day 7 (P ≤ 0.008); tumor volume increased significantly only on day 7 (P=0.04). After radiation treatment, all 3 perfusion parameters decreased significantly on day 1 (P < 0.001); BF and flow extraction product increased again on day 3 and 5, although without reaching statistically significant difference; and tumor volumes did not change significantly at all time points (P ≥ 0.3). In the control group, all 3 perfusion parameters did not change significantly, whereas tumor volume increased significantly at all the time points, compared with baseline (P ≤ 0.04). Ex vivo immunofluorescent staining showed good correlation between all 3 perfusion parameters and microvessel density (ρ=0.71, 0.66, and 0.69 for BF, BV, and flow extraction product, respectively; P < 0.001). There was a trend toward negative correlation between extent of hypoxia and all 3 perfusion parameters (ρ=-0.53, -0.47, and -0.40 for BF, BV, and flow extraction product, respectively; P ≥ 0.05).CT perfusion allows a reproducible, noninvasive assessment of tumor vascularity in human colon cancer xenografts in mice. After antiangiogenic and radiation therapy, BF, BV, and flow extraction product significantly decrease and change faster than the tumor volume.

  View details for DOI 10.1097/RLI.0b013e31823a82f6

  View details for Web of Science ID 000298400100006

  View details for PubMedID 22178893

• Quantification and Monitoring of Inflammation in Murine Inflammatory Bowel Disease with Targeted Contrast-enhanced US RADIOLOGY Deshpande, N., Lutz, A. M., Ren, Y., Foygel, K., Tian, L., Schneider, M., Pai, R., Pasricha, P. J., Willmann, J. K. 2012; 262 (1): 172-180

  Abstract

  To evaluate ultrasonography (US) by using contrast agent microbubbles (MBs) targeted to P-selectin (MB(P-selectin)) to quantify P-selectin expression levels in inflamed tissue and to monitor response to therapy in a murine model of chemically induced inflammatory bowel disease (IBD).All procedures in which laboratory animals were used were approved by the institutional administrative panel on laboratory animal care. Binding affinity and specificity of MB(P-selectin) were tested in cell culture experiments under flow shear stress conditions and compared with control MBs (MB(Control)). In vivo binding specificity of MB(P-selectin) to P-selectin was tested in mice with trinitrobenzenesulfonic acid-induced colitis (n = 22) and control mice (n = 10). Monitoring of anti-tumor necrosis factor α antibody therapy was performed over 5 days in an additional 30 mice with colitis by using P-selectin-targeted US imaging, by measuring bowel wall thickness and perfusion, and by using a clinical disease activity index score. In vivo targeted contrast material-enhanced US signal was quantitatively correlated with ex vivo expression levels of P-selectin as assessed by quantitative immunofluorescence.Attachment of MB(P-selectin) to endothelial cells was significantly (P = .0001) higher than attachment of MB(Control) and significantly (ρ = 0.83, P = .04) correlated with expression levels of P-selectin on endothelial cells. In vivo US signal in mice with colitis was significantly higher (P = .0001) with MB(P-selectin) than with MB(Control). In treated mice, in vivo US signal decreased significantly (P = .0001) compared with that in nontreated mice and correlated well with ex vivo P-selectin expression levels (ρ = 0.69; P = .04). Colonic wall thickness (P ≥ .06), bowel wall perfusion (P ≥ .85), and clinical disease activity scoring (P ≥ .06) were not significantly different between treated and nontreated mice at any time.Targeted contrast-enhanced US imaging enables noninvasive in vivo quantification and monitoring of P-selectin expression in inflammation in murine IBD.

  View details for DOI 10.1148/radiol.11110323

  View details for Web of Science ID 000298611500021

  View details for PubMedID 22056689

  View details for PubMedCentralID PMC3244669

• Graphical Procedures for Evaluating Overall and Subject-Specific Incremental Values from New Predictors with Censored Event Time Data BIOMETRICS Uno, H., Cai, T., Tian, L., Wei, L. J. 2011; 67 (4): 1389-1396

  Abstract

  Quantitative procedures for evaluating added values from new markers over a conventional risk scoring system for predicting event rates at specific time points have been extensively studied. However, a single summary statistic, for example, the area under the receiver operating characteristic curve or its derivatives, may not provide a clear picture about the relationship between the conventional and the new risk scoring systems. When there are no censored event time observations in the data, two simple scatterplots with individual conventional and new scores for "cases" and "controls" provide valuable information regarding the overall and the subject-specific level incremental values from the new markers. Unfortunately, in the presence of censoring, it is not clear how to construct such plots. In this article, we propose a nonparametric estimation procedure for the distributions of the differences between two risk scores conditional on the conventional score. The resulting quantile curves of these differences over the subject-specific conventional score provide extra information about the overall added value from the new marker. They also help us to identify a subgroup of future subjects who need the new predictors, especially when there is no unified utility function available for cost-risk-benefit decision making. The procedure is illustrated with two data sets. The first is from a well-known Mayo Clinic primary biliary cirrhosis liver study. The second is from a recent breast cancer study on evaluating the added value from a gene score, which is relatively expensive to measure compared with the routinely used clinical biomarkers for predicting the patient's survival after surgery.

  View details for DOI 10.1111/j.1541-0420.2011.01600.x

  View details for Web of Science ID 000298095900022

  View details for PubMedID 21504421

• A Perturbation Method for Inference on Regularized Regression Estimates JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Minnier, J., Tian, L., Cai, T. 2011; 106 (496): 1371-1382

  View details for DOI 10.1198/jasa.2011.tm10382

  View details for Web of Science ID 000299662900012

• Associations of the Ankle Brachial Index With Functional Performance Varies Between Participants With Vs. Without Diabetes Mellitus Scientific Sessions of the American-Heart-Association/Resuscitation Science Symposium Jain, A., Liu, K., Ferrucci, L., Criqui, M. H., Tian, L., Guralnik, J. M., Tao, H., McDermott, M. M. LIPPINCOTT WILLIAMS & WILKINS. 2011

  View details for Web of Science ID 000299738705081

• AUC-based biomarker ensemble with an application on gene scores predicting low bone mineral density BIOINFORMATICS Zhao, X. G., Dai, W., Li, Y., Tian, L. 2011; 27 (21): 3050-3055

  Abstract

  The area under the receiver operating characteristic (ROC) curve (AUC), long regarded as a 'golden' measure for the predictiveness of a continuous score, has propelled the need to develop AUC-based predictors. However, the AUC-based ensemble methods are rather scant, largely due to the fact that the associated objective function is neither continuous nor concave. Indeed, there is no reliable numerical algorithm identifying optimal combination of a set of biomarkers to maximize the AUC, especially when the number of biomarkers is large.We have proposed a novel AUC-based statistical ensemble methods for combining multiple biomarkers to differentiate a binary response of interest. Specifically, we propose to replace the non-continuous and non-convex AUC objective function by a convex surrogate loss function, whose minimizer can be efficiently identified. With the established framework, the lasso and other regularization techniques enable feature selections. Extensive simulations have demonstrated the superiority of the new methods to the existing methods. The proposal has been applied to a gene expression dataset to construct gene expression scores to differentiate elderly women with low bone mineral density (BMD) and those with normal BMD. The AUCs of the resulting scores in the independent test dataset has been satisfactory.Aiming for directly maximizing AUC, the proposed AUC-based ensemble method provides an efficient means of generating a stable combination of multiple biomarkers, which is especially useful under the high-dimensional settings.lutian@stanford.edu.Supplementary data are available at Bioinformatics online.

  View details for DOI 10.1093/bioinformatics/btr516

  View details for Web of Science ID 000296099300018

  View details for PubMedID 21908541

  View details for PubMedCentralID PMC3198577

• Comparing costs associated with risk stratification rules for t-year survival BIOSTATISTICS Cai, T., Tian, L., Lloyd-Jones, D. M. 2011; 12 (4): 597-609

  Abstract

  Accurate risk prediction is an important step in developing optimal strategies for disease prevention and treatment. Based on the predicted risks, patients can be stratified to different risk categories where each category corresponds to a particular clinical intervention. Incorrect or suboptimal interventions are likely to result in unnecessary financial and medical consequences. It is thus essential to account for the costs associated with the clinical interventions when developing and evaluating risk stratification (RS) rules for clinical use. In this article, we propose to quantify the value of an RS rule based on the total expected cost attributed to incorrect assignment of risk groups due to the rule. We have established the relationship between cost parameters and optimal threshold values used in the stratification rule that minimizes the total expected cost over the entire population of interest. Statistical inference procedures are developed for evaluating and comparing given RS rules and examined through simulation studies. The proposed procedures are illustrated with an example from the Cardiovascular Health Study.

  View details for DOI 10.1093/biostatistics/kxr001

  View details for Web of Science ID 000294806800001

  View details for PubMedID 21415016

• Lower Extremity Nerve Function, Calf Skeletal Muscle Characteristics, and Functional Performance in Peripheral Arterial Disease JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Garg, P. K., Liu, K., Ferrucci, L., Guralnik, J. M., Criqui, M. H., Tian, L., Sufit, R., Nishida, T., Tao, H., Liao, Y., McDermott, M. M. 2011; 59 (10): 1855-1863

  Abstract

  To determine whether poor lower extremity nerve function is associated with less-favorable calf muscle characteristics and greater functional impairment in people with and without peripheral arterial disease (PAD).Cross-sectional.Three Chicago-area medical centers.Four hundred thirteen participants with PAD (ankle-brachial index (ABI) < 0.90) and 255 without.Electrodiagnostic testing of the peroneal nerve was performed. Calf muscle cross-sectional area and percentage fat were measured using computed tomography at 66.7% of the distance between the distal and proximal tibia. Six-minute walk performance was measured.Adjusting for age, sex, race, ABI, leg symptoms, smoking, physical activity, comorbidities, and other covariates, lower peroneal nerve conduction velocity (NCV) was associated with lower calf muscle area (first quartile 4,770.3 mm(2) , fourth quartile 5,571 mm(2) , P < .001) and poorer 6-minute walk distance (first quartile 989.2 feet, fourth quartile 1,210.8 feet, P < .001) in participants without diabetes mellitus with PAD. Lower peroneal NCV was associated with lower calf muscle area (first quartile 5,166.0 mm(2) , fourth quartile 6,003.8 mm(2) , P = .01) and poorer 6-minute walk distance (first quartile 866.4 feet, fourth quartile 1,082.5 feet, P = .01) in participants with diabetes mellitus and PAD as well. In participants without PAD, lower peroneal NCV was not associated with lower calf muscle area but was associated with poorer 6-minute walk distance only in participants without diabetes mellitus (first quartile 1,317.0 feet, fourth quartile 1,570.4 feet, P-trend < .001).Lower peroneal nerve function is associated with smaller calf muscle area and greater functional impairment in individuals with PAD. Future study is needed to determine whether improving peroneal NCV prevents loss of calf muscle and functional decline in people with PAD.

  View details for DOI 10.1111/j.1532-5415.2011.03600.x

  View details for Web of Science ID 000296449300010

  View details for PubMedID 22091499

• Management of Pediatric Intracranial Arteriovenous Malformations: Experience With Multimodality Therapy NEUROSURGERY Darsaut, T. E., Guzman, R., Marcellus, M. L., Edwards, M. S., Tian, L., Do, H. M., Chang, S. D., Levy, R. P., Adler, J. R., Marks, M. P., Steinberg, G. K. 2011; 69 (3): 540-556

  Abstract

  Successful management of pediatric arteriovenous malformations (AVMs) often requires a balanced application of embolization, surgery, and radiosurgery.To describe our experience treating pediatric AVMs.We analyzed 120 pediatric patients (< 18 years of age) with AVMs treated with various combinations of radiosurgery, surgery, and endovascular techniques.Between 1985 and 2009, 76 children with low Spetzler-Martin grade (1-3) and 44 with high-grade (4-5) AVMs were treated. Annual risk of hemorrhage from presentation to initial treatment was 4.0%, decreasing to 3.2% after treatment initiation until confirmed obliteration. Results for AVM obliteration were available in 101 patients. Initial single-modality therapy led to AVM obliteration in 51 of 67 low-grade (76%) and 3 of 34 high-grade (9%) AVMs, improving to 58 of 67 (87%) and 9 of 34 (26%), respectively, with further treatment. Mean time to obliteration was 1.8 years for low-grade and 6.4 years for high-grade AVMs. Disabling neurological complications occurred in 4 of 77 low-grade (5%) and 12 of 43 high-grade (28%) AVMs. At the final clinical follow-up (mean, 9.2 years), 48 of 67 patients (72%) with low-grade lesions had a modified Rankin Scale score (mRS) of 0 to 1 compared with 12 of 34 patients (35%) with high-grade AVMs. On multivariate analysis, significant risk factors for poor final clinical outcome (mRS ≥ 2) included baseline mRS ≥ 2 (odds ratio, 9.51; 95% confidence interval, 3.31-27.37; P < .01), left-sided location (odds ratio, 3.03; 95% confidence interval, 1.11-8.33; P = .03), and high AVM grade (odds ratio, 4.35; 95% confidence interval, 1.28-14.28; P = .02).Treatment of pediatric AVMs with multimodality therapy can substantially improve obliteration rates and may decrease AVM hemorrhage rates. The poor natural history and risks of intervention must be carefully considered when deciding to treat high-grade pediatric AVMs.

  View details for DOI 10.1227/NEU.0b013e3182181c00

  View details for PubMedID 21430584

• Cystic Fibrosis Carrier Screening in Obstetric Clinical Practice: Knowledge, Practices, and Barriers, a Decade After Publication of Screening Guidelines GENETIC TESTING AND MOLECULAR BIOMARKERS Darcy, D., Tian, L., Taylor, J., Schrijver, I. 2011; 15 (7-8): 517-523

  Abstract

  Cystic fibrosis (CF) carrier screening guidelines have been in place for almost a decade. The purpose of this study was to determine the current awareness by obstetricians of the existence and content of practice guidelines, the variety in practice regarding CF carrier screening, and the level of knowledge regarding CF genetics and screening result interpretation. We also explored potential barriers to offering screening and whether academic affiliation or type of practice influenced outcome.An online survey program was used to deliver a questionnaire to obstetricians throughout the United States. One hundred fifty-six respondents participated, with 143 answering all questions in the survey.Although most obstetricians are aware of screening guidelines and have accurate knowledge about CF carrier screening, 12.3% were not aware of carrier screening guidelines, 17.7% were unable to interpret basic results, 16.5% experienced barriers to offering screening, and 43% lacked information regarding carrier rates, screening sensitivity, and residual risk.Most obstetricians offer CF carrier screening and will refer to genetic counseling services at times. However, we identified a deficiency of information in a concerning percentage of practitioners. This deficiency could be improved by targeted and readily accessible educational efforts, especially for obstetricians not affiliated with academia.

  View details for DOI 10.1089/gtmb.2010.0228

  View details for Web of Science ID 000292773700011

  View details for PubMedID 21453058

• GLYCEMIC CONTROL BY A GLUCOSE MANAGEMENT SERVICE AND INFECTION RATES AFTER LIVER TRANSPLANTATION ENDOCRINE PRACTICE Wallia, A., Parikh, N. D., O'Shea-Mahler, E., Schmidt, K., Desantis, A. J., Tian, L., Levitsky, J., Molitch, M. E. 2011; 17 (4): 546-551

  Abstract

  To present an analysis of glycemic control before and after introduction of a dedicated glucose management service (GMS) and outcomes within 1 year after liver transplantation (LT).We conducted a retrospective review of patients undergoing LT, who were treated with insulin infusions after LT, before and after introduction of a GMS. Outcome measures within 1 year after LT included graft rejection, infection, prolonged ventilation (>48 hours on a ventilator), and graft survival. A multiple logistic regression was used to examine the relationship between GMS use and outcomes.This study consisted of 73 (35 GMS and 38 non-GMS) organ transplant recipients. The mean perioperative blood glucose level in the GMS group was lower than in the non-GMS group: unadjusted, by 31.1 mg/dL (P = .001); adjusted for pre-insulin drip glucose, age, sex, Model for End-Stage Liver Disease (MELD) score, and type of transplant, by 23.4 mg/dL (P = .020). There were 27 rejection episodes, 48 infections, 26 episodes of prolonged ventilation, and 64 patients with graft survival at 1 year. The infection rate was lower in the GMS group than in the non-GMS group: the unadjusted odds ratio was 0.28 (P = .015); when adjustments were made for pre-insulin drip glucose, pretransplant glucose, age, sex, MELD score, type of transplant, and diabetes status before transplantation, the odds ratio was 0.24 (95% confidence interval, 0.06 to 0.97; P = .045). No significant associations were noted between GMS group and rejection rates, prolonged ventilation, or graft survival.In this study of LT patients, a GMS was associated with improved glycemic control and reduced postoperative infections. Further studies investigating effects of strict glycemic control after LT are warranted.

  View details for DOI 10.4158/EP10343.OR

  View details for Web of Science ID 000294276000002

  View details for PubMedID 21324822

  View details for PubMedCentralID PMC3158277

• Superficial Femoral Artery Plaque and Functional Performance in Peripheral Arterial Disease Walking and Leg Circulation Study (WALCS III) JACC-CARDIOVASCULAR IMAGING McDermott, M. M., Liu, K., Carroll, T. J., Tian, L., Ferrucci, L., Li, D., Carr, J., Guralnik, J. M., Kibbe, M., Pearce, W. H., Yuan, C., McCarthy, W., Kramer, C. M., Tao, H., Liao, Y., Clark, E. T., Xu, D., Berry, J., Orozco, J., Sharma, L., Criqui, M. H. 2011; 4 (7): 730-739

  Abstract

  We studied associations of magnetic resonance imaging measurements of plaque area and relative percent lumen reduction in the proximal superficial femoral artery with functional performance among participants with peripheral arterial disease.The clinical significance of directly imaged plaque characteristics in lower extremity arteries is not well established.A total of 454 participants with an ankle brachial index <1.00 underwent magnetic resonance cross-sectional imaging of the proximal superficial femoral artery and completed a 6-min walk test, measurement of 4-m walking velocity at usual and fastest pace, and measurement of physical activity with a vertical accelerometer.Adjusting for age, sex, race, body mass index, smoking, statin use, comorbidities, and other covariates, higher mean plaque area (1st quintile [least plaque]: 394 m, 2nd quintile: 360 m, 3rd quintile: 359 m, 4th quintile: 329 m, 5th quintile [greatest plaque]: 311 m; p trend <0.001) and smaller mean percent lumen area (1st quintile [greatest plaque]: 319 m, 2nd quintile: 330 m, 3rd quintile: 364 m, 4th quintile: 350 m, 5th quintile: 390 m; p trend <0.001) were associated with shorter distance achieved in the 6-min walk test. Greater mean plaque area was also associated with slower usual-paced walking velocity (p trend = 0.006) and slower fastest-paced 4-m walking velocity (p trend = 0.003). Associations of mean plaque area and mean lumen area with 6-min walk distance remained statistically significant even after additional adjustment for the ankle brachial index and leg symptoms.Among participants with peripheral arterial disease, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated independently with poorer functional performance, even after adjusting for the ankle brachial index and leg symptoms.

  View details for DOI 10.1016/j.jcmg.2011.04.009

  View details for Web of Science ID 000293180100007

  View details for PubMedID 21757163

• Sex-Specific Cognitive Deficits and Regional Brain Volume Loss in Mice Exposed to Chronic, Sublethal Hypoxia PEDIATRIC RESEARCH Lan, W. J., Priestley, M., Mayoral, S. R., Tian, L., Shamloo, M., Penn, A. A. 2011; 70 (1): 15-20

  Abstract

  Male sex is an independent risk factor for long-term neurologic deficits in human preterm infants. Using a chronic, sublethal hypoxia (CSH) mouse model of preterm brain injury, we recently demonstrated acute brain volume loss with an increased male susceptibility to hippocampal volume loss and hypomyelination. We now characterize the long-term, sex-specific effects of CSH on cognition and brain growth. Neonatal mice were treated with CSH for 8 d, raised in normoxia thereafter and underwent behavioral testing at 6 wk of age. Behavioral assays sensitive to hippocampal function were chosen. CSH-treated males had impairments in associative learning, spatial memory, and long-term social memory compared with control males. In contrast, CSH-treated females were less impaired. Persistent reductions in hippocampal and cerebellar volumes were found in adult CSH-treated males, whereas regional brain volumes in adult CSH-treated females were indistinguishable from controls. Similar to human preterm infants, males exposed to hypoxia are especially vulnerable to short-term and long-term deficits in cognition and brain growth.

  View details for Web of Science ID 000292015100004

  View details for PubMedID 21436761

• Greater Sedentary Hours and Slower Walking Speed Outside the Home Predict Faster Declines in Functioning and Adverse Calf Muscle Changes in Peripheral Arterial Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McDermott, M. M., Liu, K., Ferrucci, L., Tian, L., Guralnik, J. M., Liao, Y., Criqui, M. H. 2011; 57 (23): 2356-2364

  Abstract

  In participants with peripheral arterial disease (PAD), we determined whether more sedentary behavior and slower outdoor walking speed were associated with faster functional decline and more adverse changes in calf muscle characteristics over time.Modifiable behaviors associated with faster functional decline in lower-extremity PAD are understudied.Participants were 384 men and women with an ankle brachial index <0.90 followed for a median of 47 months. At baseline, participants reported the number of hours they spent sitting per day and their walking speeds outside their homes. Participants underwent baseline and annual measures of objective functional performance. Calf muscle characteristics were measured with computed tomography at baseline and every 2 years subsequently. Analyses were adjusted for age, sex, race, comorbidities, ankle brachial index, and other confounders.Slower walking speed outside the home was associated with faster annual decline in calf muscle density (brisk/striding pace -0.32 g/cm(3), average pace -0.46 g/cm(3), casual strolling -1.03 g/cm(3), no walking at all -1.43 g/cm(3), p trend <0.001). Greater hours sitting per day were associated with faster decline in 6-min walk (<4 h: -35.8 feet/year; 4 to <7 h: -41.1 feet/year; 8 to <11 h: -68.7 feet; ≥12 h: -78.0 feet; p trend = 0.008). Similar associations were observed for greater hours sitting per day and faster declines in fast-paced (p trend = 0.018) and usual-paced (p trend < 0.001) 4-m walking velocity.Greater sedentary hours per day and slower outdoor walking speed are modifiable behaviors that are associated with faster functional decline and greater decline in calf muscle density, respectively, in patients with PAD.

  View details for DOI 10.1016/j.jacc.2010.12.038

  View details for Web of Science ID 000291147200009

  View details for PubMedID 21636037

• The Highest Confidence Density Region and Its Usage for Joint Inferences about Constrained Parameters BIOMETRICS Tian, L., Wang, R., Cai, T., Wei, L. 2011; 67 (2): 604-610

  Abstract

  Suppose that we are interested in making joint inferences about a set of constrained parameters. Confidence regions for these parameters are often constructed via a normal approximation of the distribution of a consistent estimator for a transformation of the parameters. In this article, we utilize the confidence distribution, a frequentist counterpart to the posterior distribution in Bayesian statistics, to obtain optimal confidence regions for the parameters. Members of such a region can be generated efficiently via a standard Markov chain Monte Carlo algorithm. We then apply this technique to draw inferences about the temporal profile of the survival function with censored observations. We illustrate the new proposal with the survival data from the well-known Mayo primary biliary cirrhosis study and show that the volume of the new 0.95 confidence region is only one thirty-fourth of that of the conventional confidence band.

  View details for DOI 10.1111/j.1541-0420.2010.01486.x

  View details for Web of Science ID 000292504000028

  View details for PubMedID 20825392

• Lower calf muscle density is associated with mobility loss and mortality in peripheral arterial disease McDermott, M. M., Liu, K., Guralnik, J. M., Tian, L., Ferrucci, L., Pearce, W. H., Liao, Y., Criqui, M. H. SAGE PUBLICATIONS LTD. 2011: 232–33

  View details for Web of Science ID 000291218600038

• Poorer clock draw test scores are associated with greater functional impairment in peripheral artery disease: The Walking and Leg Circulation Study II VASCULAR MEDICINE Zimmermann, L. J., Ferrucci, L., Liu, K., Tian, L., Guralnik, J. M., Criqui, M. H., Liao, Y., McDermott, M. M. 2011; 16 (3): 173-181

  Abstract

  We hypothesized that, in the absence of clinically recognized dementia, cognitive dysfunction measured by the clock draw test (CDT) is associated with greater functional impairment in men and women with peripheral artery disease (PAD). Participants were men and women aged 60 years and older with Mini-Mental Status Examination scores ≥ 24 with PAD (n = 335) and without PAD (n = 234). We evaluated the 6-minute walk test, 4-meter walking velocity at usual and fastest pace, the Short Physical Performance Battery (SPPB), and accelerometer-measured physical activity. CDTs were scored using the Shulman system as follows: Category 1 (worst): CDT score 0-2; Category 2: CDT score 3; Category 3 (best): CDT score 4-5. Results were adjusted for age, sex, race, education, ankle-brachial index (ABI), and comorbidities. In individuals with PAD, lower CDT scores were associated with slower 4-meter usual-paced walking velocity (Category 1: 0.78 meters/second; Category 2: 0.83 meters/second; Category 3: 0.86 meters/second; p-trend = 0.025) and lower physical activity (Category 1: 420 activity units; Category 2: 677 activity units; Category 3: 701 activity units; p-trend = 0.045). Poorer CDT scores were also associated with worse functional performance in individuals without PAD (usual and fast-paced walking velocity and SPPB, p-trend = 0.022, 0.043, and 0.031, respectively). In conclusion, cognitive impairment identified with CDT is independently associated with greater functional impairment in older, dementia-free individuals with and without PAD. Longitudinal studies are necessary to explore whether baseline CDT scores and changes in CDT scores over time can predict long-term decline in functional performance in individuals with and without PAD.

  View details for DOI 10.1177/1358863X11407109

  View details for Web of Science ID 000291218600002

  View details for PubMedID 21636676

• Estimating Subject-Specific Dependent Competing Risk Profile with Censored Event Time Observations BIOMETRICS Li, Y., Tian, L., Wei, L. 2011; 67 (2): 427-435

  Abstract

  In a longitudinal study, suppose that the primary endpoint is the time to a specific event. This response variable, however, may be censored by an independent censoring variable or by the occurrence of one of several dependent competing events. For each study subject, a set of baseline covariates is collected. The question is how to construct a reliable prediction rule for the future subject's profile of all competing risks of interest at a specific time point for risk-benefit decision making. In this article, we propose a two-stage procedure to make inferences about such subject-specific profiles. For the first step, we use a parametric model to obtain a univariate risk index score system. We then estimate consistently the average competing risks for subjects who have the same parametric index score via a nonparametric function estimation procedure. We illustrate this new proposal with the data from a randomized clinical trial for evaluating the efficacy of a treatment for prostate cancer. The primary endpoint for this study was the time to prostate cancer death, but had two types of dependent competing events, one from cardiovascular death and the other from death of other causes.

  View details for DOI 10.1111/j.1541-0420.2010.01456.x

  View details for Web of Science ID 000292504000010

  View details for PubMedID 20618311

  View details for PubMedCentralID PMC2970653

• Relation of Interleukin-6 and Vascular Cellular Adhesion Molecule-1 Levels to Functional Decline in Patients With Lower Extremity Peripheral Arterial Disease AMERICAN JOURNAL OF CARDIOLOGY McDermott, M. M., Liu, K., Ferrucci, L., Tian, L., Guralnik, J. M., Tao, H., Ridker, P. M., Criqui, M. H. 2011; 107 (9): 1392-1398

  Abstract

  The aim of this study was to determine whether persistently high levels of interleukin-6 (IL-6) or soluble vascular adhesion molecule-1 (sVCAM-1) are associated with faster functional decline compared to fluctuating or persistently low biomarker levels in 255 participants with peripheral arterial disease. Participants underwent baseline and ≥2 annual follow-up measures of IL-6 and sVCAM-1. Participants were categorized as follows: category 1, annual levels of IL-6 (or sVCAM-1) were in the lowest tertile for ≥3 study visits; category 3, annual levels of IL-6 (or sVCAM-1) were in the highest tertile for ≥3 visits. Category 2 levels of IL-6 (or sVCAM-1) did not meet criteria for group 1 or 3. Six-minute walking distance, fastest paced 4-m walking velocity, and the Short Physical Performance Battery were measured annually. Results were adjusted for age, gender, race, co-morbidities, statin use, physical activity, the ankle-brachial index, and other confounders. Across IL-6 categories, average annual decreases in 6-minute walking distance were -21.4 feet in category 1, -49.2 feet in category 2, and -76.8 feet in category 3 (p for trend = 0.013), and average annual decreases in Short Physical Performance Battery score were -0.18, -0.45, and -0.62, respectively (p for trend = 0.022). Similar associations of IL-6 categories with decrease in fastest paced walking velocity were observed (p for trend = 0.034). There were no significant associations of sVCAM-1 categories with functional decline. In conclusion, in participants with peripheral arterial disease, persistently high IL-6 levels are associated with faster functional decline compared to those with fluctuating or persistently low IL-6 levels.

  View details for DOI 10.1016/j.amjcard.2011.01.007

  View details for Web of Science ID 000290605600023

  View details for PubMedID 21371679

• Superficial Femoral Artery Plaque, the Ankle-Brachial Index, and Leg Symptoms in Peripheral Arterial Disease The Walking and Leg Circulation Study (WALCS) III CIRCULATION-CARDIOVASCULAR IMAGING McDermott, M. M., Liu, K., Carr, J., Criqui, M. H., Tian, L., Li, D., Ferrucci, L., Guralnik, J. M., Kramer, C. M., Yuan, C., Kibbe, M., Pearce, W. H., Berry, J., McCarthy, W., Liao, Y., Xu, D., Orozco, J., Carroll, T. J. 2011; 4 (3): 246-252

  Abstract

  The clinical significance of magnetic resonance-imaged plaque characteristics in the superficial femoral artery (SFA) is not well established. We studied associations of the ankle-brachial index (ABI) and leg symptoms with MRI-measured plaque area and percent lumen area in the SFA in participants with and without lower-extremity peripheral arterial disease (PAD).Four hundred twenty-seven participants (393 with PAD) underwent plaque imaging of the first 30 mm of the SFA. Twelve 2.5-mm cross-sectional images of the SFA were obtained. Outcomes were normalized plaque area, adjusted for artery size (0 to 1 scale, 1=greatest plaque), and lumen area, expressed as a percent of the total artery area. Adjusting for age, sex, race, smoking, statins, cholesterol, and other covariates, lower ABI values were associated with higher normalized mean plaque area (ABI <0.50:0.79; ABI 0.50 to 0.69:0.73; ABI 0.70 to 0.89:0.65; ABI 0.90 to 0.99:0.62; ABI 1.00 to 1.09:0.48; ABI 1.10 to 1.30:0.47 (P trend <0.001)) and smaller mean percent lumen area (P trend <0.001). Compared with PAD participants with intermittent claudication, asymptomatic PAD participants had lower normalized mean plaque area (0.72 versus 0.65, P=0.005) and larger mean percent lumen area (0.30 versus 0.36, P=0.01), adjusting for the ABI and other confounders.Lower ABI values are associated with greater MRI-measured plaque burden and smaller lumen area in the first 30 mm of the SFA. Compared with PAD participants with claudication, asymptomatic PAD participants have smaller plaque area and larger lumen area in the SFA. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520312.

  View details for DOI 10.1161/CIRCIMAGING.110.962183

  View details for Web of Science ID 000290715800010

  View details for PubMedID 21436300

• Regulation of T cell receptor signaling by activation-induced zinc influx JOURNAL OF EXPERIMENTAL MEDICINE Yu, M., Lee, W., Tomar, D., Pryshchep, S., Czesnikiewicz-Guzik, M., Lamar, D. L., Li, G., Singh, K., Tian, L., Weyand, C. M., Goronzy, J. J. 2011; 208 (4): 775-785

  Abstract

  Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.

  View details for DOI 10.1084/jem.20100031

  View details for PubMedID 21422171

• Analysis of randomized comparative clinical trial data for personalized treatment selections BIOSTATISTICS Cai, T., Tian, L., Wong, P. H., Wei, L. J. 2011; 12 (2): 270-282

  Abstract

  Suppose that under the conventional randomized clinical trial setting, a new therapy is compared with a standard treatment. In this article, we propose a systematic, 2-stage estimation procedure for the subject-level treatment differences for future patient's disease management and treatment selections. To construct this procedure, we first utilize a parametric or semiparametric method to estimate individual-level treatment differences, and use these estimates to create an index scoring system for grouping patients. We then consistently estimate the average treatment difference for each subgroup of subjects via a nonparametric function estimation method. Furthermore, pointwise and simultaneous interval estimates are constructed to make inferences about such subgroup-specific treatment differences. The new proposal is illustrated with the data from a clinical trial for evaluating the efficacy and toxicity of a 3-drug combination versus a standard 2-drug combination for treating HIV-1-infected patients.

  View details for DOI 10.1093/biostatistics/kxq060

  View details for Web of Science ID 000288800600007

  View details for PubMedID 20876663

• Predictors of Clinical and Angiographic Outcome After Surgical or Endovascular Therapy of Very Large and Giant Intracranial Aneurysms NEUROSURGERY Darsaut, T. E., Darsaut, N. M., Chang, S. D., Silverberg, G. D., Shuer, L. M., Tian, L., Dodd, R. L., Do, H. M., Marks, M. P., Steinberg, G. K. 2011; 68 (4): 903-915

  Abstract

  Risk factors for poor outcome in the treatment of very large (≥20-24 mm) and giant (≥25 mm) intracranial aneurysms remain incompletely defined.To present an aggregate clinical series detailing a 24-year experience with very large and giant aneurysms to identify and assess the relative importance of various patient, aneurysm, and treatment-specific characteristics associated with clinical and angiographic outcomes.The authors retrospectively identified 184 aneurysms measuring 20 mm or larger (85 very large, 99 giant) treated at Stanford University Medical Center between 1984 and 2008. Clinical data including age, presentation, and modified Rankin Scale (mRS) score were recorded, along with aneurysm size, location, and morphology. Type of treatment was noted and clinical outcome measured using the mRS score at final follow-up. Angiographic outcomes were completely occluded, occluded with residual neck, partly obliterated, or patent with modified flow.After multivariate analysis, risk factors for poor clinical outcome included a baseline mRS score of 2 or higher (odds ratio [OR], 0.23; 95% confidence interval [CI]: 0.08-0.66; P = .01), aneurysm size of 25 mm or larger (OR, 3.32; 95% CI: 1.51-7.28; P < .01), and posterior circulation location (OR, 0.18; 95% CI: 0.07-0.43; P < .01). Risk factors for incomplete angiographic obliteration included fusiform morphology (OR, 0.25; 95% CI: 0.10-0.66; P < .01), posterior circulation location (OR, 0.33; 95% CI: 0.13-0.83; P = .02), and endovascular treatment (OR, 0.14; 95% CI: 0.06-0.32; P < .01). Patients with incompletely occluded aneurysms experienced higher rates of posttreatment subarachnoid hemorrhage and had increased mortality compared with those with completely obliterated aneurysms.Our results suggest that patients with poor baseline functional status, giant aneurysms, and aneurysms in the posterior circulation had a significantly higher proportion of poor outcomes at final follow-up. Fusiform morphology, posterior circulation location, and endovascular treatment were risk factors for incompletely obliterated aneurysms.

  View details for DOI 10.1227/NEU.0b013e3182098ad0

  View details for PubMedID 21221025

• Assessment and Monitoring Tumor Vascularity With Contrast-Enhanced Ultrasound Maximum Intensity Persistence Imaging INVESTIGATIVE RADIOLOGY Pysz, M. A., Foygel, K., Panje, C. M., Needles, A., Tian, L., Willmann, J. K. 2011; 46 (3): 187-195

  Abstract

  Contrast-enhanced ultrasound imaging is increasingly being used in the clinic for assessment of tissue vascularity. The purpose of our study was to evaluate the effect of different contrast administration parameters on the in vivo ultrasound imaging signal in tumor-bearing mice using a maximum intensity persistence (MIP) algorithm and to evaluate the reliability of in vivo MIP imaging in assessing tumor vascularity. The potential of in vivo MIP imaging for monitoring tumor vascularity during antiangiogenic cancer treatment was further evaluated.In intraindividual experiments, varying contrast microbubble concentrations (5 × 10⁵, 5 × 10⁶, 5 × 10⁷, 5 × 10⁸ microbubbles in 100 μL saline) and contrast injection rates (0.6, 1.2, and 2.4 mL/min) in subcutaneous tumor-bearing mice were applied and their effects on in vivo contrast-enhanced ultrasound MIP imaging plateau values were obtained using a dedicated small animal ultrasound imaging system (40 MHz). Reliability of MIP ultrasound imaging was tested following 2 injections of the same microbubble concentration (5 × 10⁷ microbubbles at 1.2 mL/min) in the same tumors. In mice with subcutaneous human colon cancer xenografts, longitudinal contrast-enhanced ultrasound MIP imaging plateau values (baseline and at 48 hours) were compared between mice with and without antiangiogenic treatment (antivascular endothelial growth factor antibody). Ex vivo CD31 immunostaining of tumor tissue was used to correlate in vivo MIP imaging plateau values with microvessel density analysis.In vivo MIP imaging plateau values correlated significantly (P = 0.001) with contrast microbubble doses. At 3 different injection rates of 0.6, 1.2, and 2.4 mL/min, MIP imaging plateau values did not change significantly (P = 0.61). Following 2 injections with the same microbubble dose and injection rate, MIP imaging plateau values were obtained with high reliability with an intraclass correlation coefficient of 0.82 (95% confidence interval: 0.64, 0.94). In addition, in vivo MIP imaging plateau values significantly correlated (P = 0.01; R² = 0.77) with ex vivo microvessel density analysis. Tumor volumes in treated and nontreated mice did not change significantly (P = 0.22) within 48 hours. In contrast, the change of in vivo MIP imaging plateau values from baseline to 48 hours was significantly different (P = 0.01) in treated versus nontreated mice.Contrast-enhanced ultrasound MIP imaging allows reliable assessment of tumor vascularity and monitoring of antiangiogenic cancer therapy in vivo, provided that a constant microbubble dose is administered.

  View details for DOI 10.1097/RLI.0b013e3181f9202d

  View details for Web of Science ID 000286971700006

  View details for PubMedID 21150790

• Decline in Functional Performance Predicts Later Increased Mobility Loss and Mortality in Peripheral Arterial Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McDermott, M. M., Liu, K., Ferrucci, L., Tian, L., Guralnik, J. M., Liao, Y., Criqui, M. H. 2011; 57 (8): 962-970

  Abstract

  We hypothesized that a greater 2-year decline in office-based functional performance measures would be associated with greater mobility loss and mortality in people with peripheral arterial disease (PAD).Associations of decline in functional performance with clinically important outcomes in patients with PAD are unknown.A total of 440 men and women with PAD completed the 6-min walk test and measures of walking velocity at baseline and annually for 2 years. Participants were categorized into tertiles according to their functional decline between baseline and 2-year follow-up and were followed annually after the functional change assessment. Cox proportional hazard models were used to assess relations between the 2-year change in functional performance with later mortality and mobility loss, with adjustments for age, sex, race, ankle brachial index, comorbidities, and other confounders.A total of 102 participants (23.2%) died during a median follow-up of 44.5 months after functional change was assessed. Of 319 participants without baseline mobility disability, 60 (18.8%) developed mobility loss after functional change was assessed. Participants in the tertile with the greatest 6-min walk decline had the highest subsequent mobility loss (hazard ratio [HR]: 3.50; 95% confidence interval [CI]: 1.56 to 7.85; p = 0.002), all-cause mortality (HR: 2.16; 95% CI: 1.28 to 3.64; p = 0.004), and cardiovascular disease mortality (HR: 2.45; 95% CI: 1.08 to 5.54; p = 0.031), compared with those with the smallest 6-min walk decline. Greater declines in fastest-paced 4-m walking velocity were associated with higher mobility loss (p trend = 0.018), all-cause mortality (p trend = 0.01), and cardiovascular mortality (p trend = 0.004).Participants with PAD with declining functional performance are at increased risk for later mobility loss and mortality.

  View details for DOI 10.1016/j.jacc.2010.09.053

  View details for Web of Science ID 000287650900012

  View details for PubMedID 21329843

• Women With Peripheral Arterial Disease Experience Faster Functional Decline Than Men With Peripheral Arterial Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McDermott, M. M., Ferrucci, L., Liu, K., Guralnik, J. M., Tian, L., Kibbe, M., Liao, Y., Tao, H., Criqui, M. H. 2011; 57 (6): 707-714

  Abstract

  We hypothesized that women with lower extremity peripheral arterial disease (PAD) would have greater mobility loss and faster functional decline than men with PAD.Whether rates of mobility loss or functional decline differ between men and women with PAD is currently unknown.Three hundred eighty men and women with PAD completed the 6-min walk, were assessed for mobility disability, and underwent measures of 4-m walking velocity at baseline and annually for up to 4 years. Computed tomography-assessed calf muscle characteristics were measured biannually. Outcomes included becoming unable to walk for 6 min continuously among participants who walked continuously for 6 min at baseline. Mobility loss was defined as becoming unable to walk for a quarter mile or to walk up and down 1 flight of stairs without assistance among those without baseline mobility disability. Results were adjusted for age, race, body mass index, physical activity, the ankle brachial index, comorbidities, and other confounders.At 4 years of follow-up, women were more likely to become unable to walk for 6 min continuously (hazard ratio: 2.30, 95% confidence interval: 1.30 to 4.06, p = 0.004), more likely to develop mobility disability (hazard ratio: 1.79, 95% confidence interval: 1.30 to 3.03, p = 0.030), and had faster declines in walking velocity (p = 0.022) and the distance achieved in the 6-min walk (p = 0.041) compared with men. Sex differences in functional decline were attenuated after additional adjustment for baseline sex differences in calf muscle area.Women with PAD have faster functional decline and greater mobility loss than men with PAD. These sex differences may be attributable to smaller baseline calf muscle area among women with PAD.

  View details for DOI 10.1016/j.jacc.2010.09.042

  View details for Web of Science ID 000286880100011

  View details for PubMedID 21292130

• Associations of calf skeletal muscle characteristics and peripheral nerve function with self-perceived physical functioning and walking ability in persons with peripheral artery disease VASCULAR MEDICINE Evans, N. S., Liu, K., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Tian, L., Liao, Y., McDermott, M. M. 2011; 16 (1): 3-11

  Abstract

  We determined whether more adverse calf muscle characteristics and poorer peripheral nerve function were associated with impairments in self-perceived physical functioning and walking ability in persons with lower extremity peripheral artery disease (PAD). Participants included 462 persons with PAD; measures included the ankle-brachial index (ABI), medical history, electrophysiologic characteristics of nerves, and computed tomography of calf muscle. Self-perceived physical functioning and walking ability were assessed using the 36-Item Short Form Health Survey (SF-36) and the Walking Impairment Questionnaire (WIQ). Results were adjusted for age, sex, race, ABI, body mass index, comorbidities, and other confounders. Lower calf muscle area was associated with a poorer SF-36 physical function (PF) score (overall p-trend < 0.001, 33.76 PF score for the lowest quartile versus 59.74 for the highest, pairwise p < 0.001) and a poorer WIQ walking distance score (p-trend = 0.001, 29.71 WIQ score for the lowest quartile versus 48.43 for the highest, pairwise p < 0.001). Higher calf muscle percent fat was associated with a poorer SF-36 PF score (p-trend < 0.001, 53.76 PF score for the lowest quartile versus 40.28 for the highest, pairwise p = 0.009). Slower peroneal nerve conduction velocity was associated with a poorer WIQ speed score ( p-trend = 0.023, 30.49 WIQ score for the lowest quartile versus 40.48 for the highest, pairwise p = 0.031). In summary, adverse calf muscle characteristics and poorer peripheral nerve function are associated significantly and independently with impairments in self-perceived physical functioning and walking ability in PAD persons.

  View details for DOI 10.1177/1358863X10395656

  View details for Web of Science ID 000289198700001

  View details for PubMedID 21471147

• Adaptive index models for marker-based risk stratification BIOSTATISTICS Tian, L., Tibshirani, R. 2011; 12 (1): 68-86

  Abstract

  We use the term "index predictor" to denote a score that consists of K binary rules such as "age > 60" or "blood pressure > 120 mm Hg." The index predictor is the sum of these binary scores, yielding a value from 0 to K. Such indices as often used in clinical studies to stratify population risk: They are usually derived from subject area considerations. In this paper, we propose a fast data-driven procedure for automatically constructing such indices for linear, logistic, and Cox regression models. We also extend the procedure to create indices for detecting treatment-marker interactions. The methods are illustrated on a study with protein biomarkers as well as a large microarray gene expression study.

  View details for DOI 10.1093/biostatistics/kxq047

  View details for Web of Science ID 000285625800005

  View details for PubMedID 20663850

  View details for PubMedCentralID PMC3006126

• The Walking Impairment Questionnaire Stair-Climbing Score Predicts Mortality in Patients With Peripheral Arterial Disease Jain, A., Liu, K., Ferrucci, L., Criqui, M. H., Tian, L., Guralnik, J. M., Tao, H., McDermott, M. M. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231602418

• Men with Peripheral Arterial Disease Have Greater Deterioration in Calf Muscle Characteristics and Function than Women with Peripheral Arterial Disease: A Longitudinal Study Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology McDermott, M. M., Ferrucci, L., Liu, K., Guralnik, J. M., Tian, L., Liao, Y., Criqui, M. H. LIPPINCOTT WILLIAMS & WILKINS. 2010: E235–E235

  View details for Web of Science ID 000283234800240

• Leg strength predicts mortality in men but not in women with peripheral arterial disease JOURNAL OF VASCULAR SURGERY Singh, N., Liu, K., Tian, L., Criqui, M. H., Guralnik, J. M., Ferrucci, L., Liao, Y., McDermott, M. M. 2010; 52 (3): 624-631

  Abstract

  To establish associations between leg strength and mortality in men and women with lower extremity peripheral arterial disease (PAD).This was an observational, prospective study of 410 men and women with PAD aged 55 and older recruited from Chicago-area medical centers and followed for a mean of 60 months. The participants were followed for a mean of 60.0 months. Isometric knee extension, knee flexion, hip extension, and hip flexion were measured at baseline. Primary outcomes were all-cause and cardiovascular disease mortality. Cox proportional hazards models were used to assess relations between leg strength and all-cause and cardiovascular disease mortality among men and women, adjusting for age, race, comorbidities, physical activity, smoking, body mass index, and the ankle brachial index.Among the 246 male participants, poorer baseline strength for knee flexion (P trend = .029), knee extension (P trend =.010), and hip extension (P trend = .013) were each associated independently with higher all-cause mortality. Poorer strength for knee flexion (P trend = .042) and hip extension (P trend = .029) were associated with higher cardiovascular mortality. Compared with those in the fourth (best) baseline knee flexion quartile, hazard ratios for all-cause and cardiovascular disease mortality among men in the first (poorest) knee flexion quartile were 2.23 (95% confidence interval [CI], 1.02-4.87; P = .045) and 4.20 (95% CI, 1.12-15.79; P = .044), respectively. No significant associations of leg strength and all-cause mortality were identified among women.Poorer leg strength is associated with increased mortality in men, but not women, with PAD. Future study is needed to determine whether interventions that increase leg strength improve survival in men with PAD.

  View details for DOI 10.1016/j.jvs.2010.03.066

  View details for Web of Science ID 000281570100013

  View details for PubMedID 20598471

• Leg Symptom Categories and Rates of Mobility Decline in Peripheral Arterial Disease 32nd Annual National Meeting of the Society-for-General-Internal-Medicine McDermott, M. M., Ferrucci, L., Liu, K., Guralnik, J. M., Tian, L., Liao, Y., Criqui, M. H. WILEY-BLACKWELL. 2010: 1256–62

  Abstract

  To determine whether asymptomatic lower extremity peripheral arterial disease (PAD) and leg symptoms other than intermittent claudication (IC) in PAD are associated with faster functional decline than in people with both PAD and IC.Prospective, observational study.Chicago-area medical center.Four hundred fifteen people with PAD followed annually for up to 7 years.At baseline, patients with PAD were categorized into symptom categories, including IC; leg pain on exertion and rest; participants who could walk through exertional leg pain (pain/carry on); and participants who never experienced exertional leg pain, even during the 6-minute walk (always asymptomatic). Outcomes included mobility loss (becoming unable to walk one-quarter of a mile or walk up and down one flight of stairs without assistance) and becoming unable to complete the 6-minute walk without stopping. Analyses adjusted for age, sex, comorbidities, ankle brachial index, and other confounders.Always-asymptomatic participants (hazard ratio (HR)=2.94, 95% confidence interval (CI)=1.39-6.19, P=.005) and those with leg pain on exertion and rest (HR=2.89, 95% CI=1.47-5.68, P=.002) had greater mobility loss than participants with IC. Participants with PAD with leg pain/carry on were less likely (P=.047) to become unable to walk for 6 minutes continuously without stopping than participants with IC.The ABI identifies patients with asymptomatic PAD and those with atypical leg symptoms who are at risk for greater mobility decline than participants without PAD and participants with PAD with IC.

  View details for DOI 10.1111/j.1532-5415.2010.02941.x

  View details for Web of Science ID 000279448500005

  View details for PubMedID 20550604

• Calibrating parametric subject-specific risk estimation BIOMETRIKA Cai, T., Tian, L., Uno, H., Solomon, S. D., Wei, L. J. 2010; 97 (2): 389-404

  View details for DOI 10.1093/biomet/asq012

  View details for Web of Science ID 000280559700010

• Comparison of Effects of Statin Use on Mortality in Patients With Peripheral Arterial Disease With Versus Without Elevated C-Reactive Protein and D-Dimer Levels AMERICAN JOURNAL OF CARDIOLOGY Vidula, H., Tian, L., Liu, K., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Green, D., Ridker, P., McDermott, M. M. 2010; 105 (9): 1348-1352

  Abstract

  We determined whether statin use was associated with lower all-cause and cardiovascular disease (CVD) mortality in 579 participants with lower extremity peripheral arterial disease (PAD) according to the presence and absence of elevated C-reactive protein (CRP) and D-dimer levels. Statin use was determined at baseline and at each annual visit. The CRP and D-dimer levels were measured at baseline. The mean follow-up was 3.7 years. The analyses were adjusted for age, gender, race, co-morbidities, ankle brachial index, cholesterol, and other confounders. Of the 579 participants, 242 (42%) were taking a statin at baseline and 129 (22%) died during follow-up. Statin use was associated with lower all-cause mortality (hazard ratio 0.51, 95% confidence interval [CI] 0.30 to 0.86, p = 0.012) and CVD mortality (hazard ratio 0.36, 95% CI 0.14 to 0.89, p = 0.027) compared to statin nonuse. No statistically significant interaction was found for the baseline CRP or D-dimer level with the association of statin use and mortality. However, statin therapy was associated with significantly lower all-cause and total mortality only among participants with baseline CRP values greater than the median and not among those with CRP values less than the median (hazard ratio 0.44, 95% CI 0.23 to 0.88 vs hazard ratio 0.73, 95% CI 0.31 to 1.75 for all-cause mortality and hazard ratio 0.20, 95% CI 0.063 to 0.65 vs hazard ratio 0.59, 95% CI 0.093 to 3.79 for CVD mortality). In conclusion, among those with PAD, statin use was associated with lower all-cause and CVD mortality compared to no statin use. The favorable association of statin use with mortality was not influenced significantly by the baseline CRP or D-dimer level.

  View details for DOI 10.1016/j.amjcard.2009.12.054

  View details for Web of Science ID 000277579600025

  View details for PubMedID 20403491

• NONPARAMETRIC INFERENCE PROCEDURE FOR PERCENTILES OF THE RANDOM EFFECTS DISTRIBUTION IN META-ANALYSIS ANNALS OF APPLIED STATISTICS Wang, R., Tian, L., Cai, T., Wei, L. J. 2010; 4 (1): 520-532

  Abstract

  To investigate whether treating cancer patients with erythropoiesis-stimulating agents (ESAs) would increase the mortality risk, Bennett et al. [Journal of the American Medical Association299 (2008) 914-924] conducted a meta-analysis with the data from 52 phase III trials comparing ESAs with placebo or standard of care. With a standard parametric random effects modeling approach, the study concluded that ESA administration was significantly associated with increased average mortality risk. In this article we present a simple nonparametric inference procedure for the distribution of the random effects. We re-analyzed the ESA mortality data with the new method. Our results about the center of the random effects distribution were markedly different from those reported by Bennett et al. Moreover, our procedure, which estimates the distribution of the random effects, as opposed to just a simple population average, suggests that the ESA may be beneficial to mortality for approximately a quarter of the study populations. This new meta-analysis technique can be implemented with study-level summary statistics. In contrast to existing methods for parametric random effects models, the validity of our proposal does not require the number of studies involved to be large. From the results of an extensive numerical study, we find that the new procedure performs well even with moderate individual study sample sizes.

  View details for DOI 10.1214/09-AOAS280

  View details for Web of Science ID 000283528300023

  View details for PubMedCentralID PMC4321956

• Posttransplant Hyperglycemia is Associated With Increased Risk of Liver Allograft Rejection TRANSPLANTATION Wallia, A., Parikh, N. D., Molitch, M. E., Mahler, E., Tian, L., Huang, J. J., Levitsky, J. 2010; 89 (2): 222-226

  Abstract

  Intensive glycemic control has been shown to positively impact outcomes in an intensive care setting. Whether this practice is beneficial after liver transplantation (LT) is not known.A retrospective review of patients undergoing LT from February 2002 to July 2007 was conducted to analyze the association between perioperative hyperglycemia and outcomes after LT. Covariates included preexisting diabetes, mean glucose 3 months pre-LT, need for insulin drip post-LT, mean total glucose during the post-LT hospitalization, age, sex, type of transplant, and model for end-stage liver disease score. Outcomes within 1 year of LT included rejection, infection, rehospitalization, prolonged ventilation, and patient/graft survival.One hundred thirteen LT and 31 liver-kidney recipients were included. By multivariate logistic regression adjusting for covariates, the rejection rate was significantly lower for patients with postoperative glucose levels less than 200 mg/dL (n=114) vs. more than 200 mg/dL (n=30) (odds ratio: 0.055; 95% confidence interval: 0.0154-0.200; P<0.001). The need for prolonged ventilation was more common in patients with glucose less than 200 vs. more than 200 mg/dL (odds ratio: 4.30; 95% confidence interval: 1.284-14.388; P=0.018). Although other outcomes, infection, rehospitalization, patient/graft survival, were not different among the glucose control groups, rejection was associated with increased rehospitalizations and infections.Our data demonstrate an association between the immediate posttransplant glycemic control and the development of subsequent rejection. Prospective trials investigating the effects of perioperative glycemic control on outcomes and morbidity after LT are warranted.

  View details for DOI 10.1097/TP.0b013e3181c3c2ff

  View details for Web of Science ID 000274253700014

  View details for PubMedID 20098286

  View details for PubMedCentralID PMC2946243

• NONPARAMETRIC INFERENCE PROCEDURE FOR PERCENTILES OF THE RANDOM EFFECTS DISTRIBUTION IN META-ANALYSIS. The annals of applied statistics Wang, R., Tian, L., Cai, T., Wei, L. J. 2010; 4 (1): 520-532

  Abstract

  To investigate whether treating cancer patients with erythropoiesis-stimulating agents (ESAs) would increase the mortality risk, Bennett et al. [Journal of the American Medical Association299 (2008) 914-924] conducted a meta-analysis with the data from 52 phase III trials comparing ESAs with placebo or standard of care. With a standard parametric random effects modeling approach, the study concluded that ESA administration was significantly associated with increased average mortality risk. In this article we present a simple nonparametric inference procedure for the distribution of the random effects. We re-analyzed the ESA mortality data with the new method. Our results about the center of the random effects distribution were markedly different from those reported by Bennett et al. Moreover, our procedure, which estimates the distribution of the random effects, as opposed to just a simple population average, suggests that the ESA may be beneficial to mortality for approximately a quarter of the study populations. This new meta-analysis technique can be implemented with study-level summary statistics. In contrast to existing methods for parametric random effects models, the validity of our proposal does not require the number of studies involved to be large. From the results of an extensive numerical study, we find that the new procedure performs well even with moderate individual study sample sizes.

  View details for DOI 10.1214/09-AOAS280SUPP

  View details for PubMedID 25678939

  View details for PubMedCentralID PMC4321956

• Baseline Lower Extremity Strength and Subsequent Decline in Functional Performance at 6-Year Follow-Up in Persons with Lower Extremity Peripheral Arterial Disease JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Herman, S. D., Liu, K., Tian, L., Guralnik, J. M., Ferrucci, L., Criqui, M. H., Liao, Y., McDermott, M. M. 2009; 57 (12): 2246-2252

  Abstract

  To evaluate associations between baseline lower extremity strength and decline in functional performance over 6 years of follow-up in men and women with lower extremity peripheral arterial disease (PAD).Prospective observational study.Three Chicago-area hospitals.Three hundred seventy-four men and women with PAD.Baseline isometric hip extension, hip flexion, knee flexion, and knee extension strength were measured using a musculoskeletal fitness evaluation chair. Usual and fastest-paced 4-m walking speed, 6-minute walk, and Short Physical Performance Battery (SPPB) were assessed at baseline and annually thereafter. Analyses were adjusted for age, sex, race, ankle-brachial index (ABI), comorbidities, and other confounders.In women with PAD, weaker baseline hip and knee flexion strength were associated with faster average annual decline in usual-pace 4-m walking speed (P trend <.001 and .02, respectively) and SPPB (P trend=.02 and .01, respectively). In women, weaker hip extension strength was associated with faster decline in usual-pace 4-m walking speed and SPPB (P trend=.01 and <.01, respectively). There were no significant associations between baseline strength and decline in 6-minute walk in women. There were no significant associations between any baseline strength measure and functional decline in men.Weaker baseline leg strength is associated with faster functional decline in nonendurance measures of functional performance in women with PAD but not in men with PAD.

  View details for DOI 10.1111/j.1532-5415.2009.02562.x

  View details for Web of Science ID 000272976400009

  View details for PubMedID 19874404

• Pathophysiological Changes in Calf Muscle Predict Mobility Loss at 2-Year Follow-Up in Men and Women With Peripheral Arterial Disease CIRCULATION McDermott, M. M., Ferrucci, L., Guralnik, J., Tian, L., Liu, K., Hoff, F., Liao, Y., Criqui, M. H. 2009; 120 (12): 1048-1055

  Abstract

  Associations of pathophysiological calf muscle characteristics with functional decline in people with lower extremity peripheral arterial disease are unknown.Three hundred seventy participants with peripheral arterial disease underwent baseline measurement of calf muscle area, density, and percent fat with the use of computed tomography. Participants were followed up annually for 2 years. The outcome of mobility loss was defined as becoming unable to walk 1/4 mile or walk up and down 1 flight of stairs without assistance among those without baseline mobility limitations. Additional outcomes were > or =20% decline in 6-minute walk distance and becoming unable to walk for 6 minutes continuously among participants who walked continuously for 6 minutes at baseline. With adjustment for age, sex, race, body mass index, the ankle-brachial index, smoking, physical activity, relevant medications, and comorbidities, lower calf muscle density (P for trend <0.001) and lower calf muscle area (P for trend=0.039) were each associated with increased mobility loss rates. Compared with participants in the highest baseline tertiles, participants in the lowest tertile of calf muscle percent fat had a hazard ratio of 0.18 for incident mobility loss (95% confidence interval, 0.06 to 0.55; P=0.003), and participants in the lowest tertile of muscle density had a 3.50 hazard ratio for incident mobility loss (95% confidence interval, 1.28 to 9.57; P=0.015). No significant associations of calf muscle characteristics with 6-minute walk outcomes were observed.Our findings suggest that interventions to prevent mobility loss in peripheral arterial disease should focus on reversing pathophysiological findings in calf muscle.

  View details for DOI 10.1161/CIRCULATIONAHA.108.842328

  View details for Web of Science ID 000270015600006

  View details for PubMedID 19738138

• Obesity, weight change, and functional decline in peripheral arterial disease Annual Meeting of the Midwest-Society-of-General-Internal-Medicine McDermott, M. M., Criqui, M. H., Ferrucci, L., Guralnik, J. M., Tian, L., Liu, K., Greenland, P., Tan, J., Schneider, J. R., Clark, E., Pearce, W. H. MOSBY-ELSEVIER. 2006: 1198–1204

  Abstract

  Our objectives were to determine whether obesity is associated with a greater functional decline compared with the ideal body mass index (BMI) among persons with peripheral arterial disease (PAD) and to determine the associations between weight gain and loss and functional declines in PAD. We hypothesized that baseline obesity and weight gain during follow-up would each be associated with functional declines in persons with PAD.The design was a prospective cohort study. The subjects were 389 men and women with PAD (mean ankle-brachial index, 0.65 +/- 0.14) who were followed up prospectively for a median of 48 months. The main outcome measures were functional assessments (6-minute walk, usual- and rapid-paced 4-m walking speed, and summary performance score). Weight and height were measured at baseline and annually. Results were adjusted for age, sex, race, comorbidities, ankle-brachial index, education, leg symptoms, exercise status, depressive symptoms, pack-years of cigarette smoking, prior-year functioning, and patterns of missing data.Compared with those with a baseline BMI between 20 and 25 kg/m2, PAD participants with baseline BMI greater than 30 kg/m2 had a significantly greater average annual decline in 6-minute walk performance (-13.1 vs -26.5 m/y; P = .004), usual-paced 4-m walking velocity (-0.028 vs -0.055 m/s per year; P = .024), and fast-paced 4-m walking velocity (-0.053 vs -0.086 m/s per year; P = .012). Persons with weight gain between 5 and 10 pounds after baseline who walked for exercise regularly had significantly less decline in the 6-minute walk than persons without significant weight change who did not walk for exercise (P = .04).Obesity is associated with functional decline in persons with PAD. Walking exercise may protect against functional decline in PAD persons with modest weight gain.

  View details for DOI 10.1016/j.jvs.2006.02.036

  View details for Web of Science ID 000238046700025

  View details for PubMedID 16765239

  View details for PubMedCentralID PMC2645620