Daniel Kim

All Publications

• Fine-tuning Large Language Models in Behavioral Psychology for Scalable Physical Activity Coaching. medRxiv : the preprint server for health sciences Mantena, S., Johnson, A., Oppezzo, M., Schuetz, N., Tolas, A., Doijad, R., Mattson, C. M., Lawrie, A., Ramirez-Posada, M., Linos, E., King, A. C., Rodriguez, F., Kim, D. S., Ashley, E. A. 2025

  Abstract

  Personalized, smartphone-based coaching improves physical activity but relies on static, human-crafted messages. We introduce My Heart Counts (MHC)-Coach, a large language model fine-tuned on the Transtheoretical Model of Change. MHC-Coach generates messages tailored to an individual's psychology (their "stage of change"), providing personalized support to foster long-term physical activity behavior change. To evaluate MHC-Coach's efficacy, 632 participants compared human-expert and MHC-Coach text-based interventions encouraging physical activity. Among messages matched to an individual's stage of change, 68.0% (N=430) preferred MHC-Coach-generated messages (P < 0.001). Blinded behavioral science experts (N=2) rated MHC-Coach messages higher than human-expert messages for perceived effectiveness (4.4 vs. 2.8) and Transtheoretical Model alignment (4.1 vs. 3.5) on a 5-point Likert scale. This work demonstrates how language models can operationalize behavioral science frameworks for personalized health coaching, promoting long-term physical activity and potentially reducing cardiovascular disease risk at scale.

  View details for DOI 10.1101/2025.02.19.25322559

  View details for PubMedID 40034753

• Reference equations for peak oxygen uptake for treadmill cardiopulmonary exercise tests based on the NHANES lean body mass equations, a FRIEND registry study. European journal of preventive cardiology Santana, E. J., Kim, D. S., Christle, J. W., Cauwenberghs, N., Celestin, B. E., Tso, J. V., Wheeler, M. T., Ashley, E. A., Peterman, J. E., Gardner, C., Arena, R., Harber, M., Kaminsky, L. A., Kuznetsova, T., Myers, J. N., Haddad, F. 2025

  Abstract

  Cardiorespiratory fitness (CRF), measured by peak oxygen uptake (VO2peak), is a strong predictor of mortality. Despite its widespread clinical use, current reference equations for VO2peak show distorted calibration in obese individuals. Using data from the Fitness Registry and the Importance of Exercise National Database (FRIEND), we sought to develop novel reference equations for VO2peak better calibrated for overweight/obese individuals - in both males and females, by considering body composition metrics.Graded treadmill tests from 6,836 apparently healthy individuals were considered in data analysis. We used the National Health and Nutrition Examination Survey equations to estimate lean body mass (eLBM) and body fat percentage (eBF). Multivariable regression was used to determine sex-specific equations for predicting VO2peak considering age terms, eLBM and eBF.The resultant equations were expressed as VO2peak (male) = 2633.4 + 48.7✕eLBM (kg) - 63.6✕eBF (%) - 0.23✕Age2 (R2=0.44) and VO2peak (female) = 1174.9 + 49.4✕eLBM (kg) - 21.7✕eBF (%) - 0.158✕Age2 (R2=0.53). These equations were well-calibrated in subgroups based on sex, age and body mass index (BMI), in contrast to the Wasserman equation. In addition, residuals for the percent-predicted VO2peak (ppVO2) were stable over the predicted VO2peak range, with low CRF defined as < 70% ppVO2 and average CRF defined between 85-115%.The derived VO2peak reference equations provided physiologically explainable and were well-calibrated across the spectrum of age, sex and BMI. These equations will yield more accurate VO2peak evaluation, particularly in obese individuals.

  View details for DOI 10.1093/eurjpc/zwaf045

  View details for PubMedID 39920345

• Unlocking insights: Clinical associations from the largest 6-minute walk test collection via the my Heart Counts Cardiovascular Health Study, a fully digital smartphone platform. Progress in cardiovascular diseases Kim, D. S., Schuetz, N., Johnson, A., Tolas, A., Mantena, S., O'Sullivan, J. W., Hershman, S. G., Myers, J. N., Christle, J. W., Oppezzo, M., Linos, E., Rodriguez, F., Mattsson, C. M., Wheeler, M. T., King, A. C., Taylor, H. A., Ashley, E. A. 2025

  Abstract

  The six-minute walk test (6MWT) is a prognostic sub-maximal exercise test used clinically as a measure of functional capacity. With the emergence of advanced sensors, 6MWTs are being performed remotely via smartphones and other devices. The My Heart Counts Cardiovascular Health Study is a smartphone application that serves as a digital platform for studies of human cardiovascular health, and has been used to perform 30,475 6MWTs on 8922 unique participants.As our 30,475 6MWTs represent the largest such collection of data available, we sought to identify associations with measured demographic and clinical variables with 6MWT distance at enrollment and separately determine if use of the My Heart Counts smartphone application led to changes in 6MWT distance.We present the public data release of our 30,475 6MWTs and the launch of a webpage-based data viewer of summary-level statistics, to compare the functional capacity of an individual by their age, gender, height, weight, and disease status (https://mhc-6mwts.streamlit.app). Using multivariable regression, we report associations of demographic and clinical variables with baseline 6MWT distance (N = 3606), validating prior associations with age, male gender, height, and baseline physical activity level with 6MWT distance. We also report associations of 6MWT baseline distance with employment status (+12.4 m ±4.9 m, P = 0.011) and feeling depressed (-3.65 m, ±0.79 m, P < 0.001). We separately found that cardiovascular disease status was significantly associated with decreased 6MWT distance for atrial fibrillation (-24.9 m ±7.8 m, P = 0.0013), peripheral artery disease (-41.7 m ±12.5 m, P < 0.001), and pulmonary arterial hypertension (-76.3 m ±24.8 m, P = 0.0022). Heart failure was associated with decreased 6MWT distance but was not statistically significant (-25.5 m ±14.5 m, P = 0.078). In a subset of participants who conducted repeat 6MWTs separated by at least 1 week but no greater than 3 months (N = 1129), we found that use of the My Heart Counts app was associated with a statistically significant increase in 6MWT distance (+17.5 m ±7.85 m, P < 0.001).We validate previously identified associations from clinic-performed 6MWTs, demonstrating the utility of a mobile method in collecting 6MWT data for clinicians and researchers. We also demonstrate that use of the My Heart Counts app is associated with small, but significant increases in 6MWT distance. Given the importance of 6MWTs in assessment of functional capacity, our publicly-available data will serve an important purpose as a health and disease-specific reference for investigators worldwide.

  View details for DOI 10.1016/j.pcad.2025.01.010

  View details for PubMedID 39884325

• Bridging the Gap: How Accounting for Social Determinants of Health Can Improve Digital Health Equity in Cardiovascular Medicine. Current atherosclerosis reports Kim, D. S., Eltahir, A. A., Ngo, S., Rodriguez, F. 2024; 27 (1): 9

  Abstract

  PURPOSE OF REVIEW: In this review, we discuss the importance of digital health equity and how social determinants of health (and intersectionality with race, ethnicity, and gender) affect cardiovascular health-related outcomes in digital health trials. We propose strategies to improve digital health equity as we move to a digitally-connected world for healthcare applications and beyond.RECENT FINDINGS: Digital health has immense promise to improve population health by reaching individuals in their homes, at their preferred times. However, initial data demonstrate decreased patient engagement and worse cardiovascular outcomes for racial and ethnic minorities, leading to unequal uptake of digital health technologies. In addition, while women generally have higher uptake of technology, they are less likely to be referred by clinicians for digital health interventions. We highlight several exemplar trials and analyze their methodology for replication in future digital health research. The promise of digital health equity has not been reached due to exclusionary practices. Specific focus must be placed on societal/governmental policies that enable digital inclusion, particularly of racial and ethnic minority populations and women, to ensure that the expansion of digital health technologies does not exacerbate existing health disparities.

  View details for DOI 10.1007/s11883-024-01249-9

  View details for PubMedID 39576395

• One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy FRONTIERS IN CARDIOVASCULAR MEDICINE Kim, D., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A., Stanford Ctr Inherited Cardiovasc Dis 2024; 11

  View details for DOI 10.3389/fcvm.2024.1429230

  View details for Web of Science ID 001312496500001

• One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy. Frontiers in cardiovascular medicine Kim, D. S., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I. D., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A. 2024; 11: 1429230

  Abstract

  Mavacamten is a first-in-class cardiac myosin ATPase inhibitor, approved by the United States Food and Drug Administration for the treatment of hypertrophic cardiomyopathy with obstructive physiology (oHCM). Here, we present the real-world use of mavacamten in 50 patients with oHCM at a tertiary care referral center. In both our highlighted case and in our aggregate data, we report significant improvement in wall thickness, mitral regurgitation, left ventricular outflow tract obstruction and New York Heart Association symptom class. Moreover, in our center's experience, neither arrhythmia burden, nor contractility have worsened in the vast majority of patients: we note a clinically insignificant mean decrease in left ventricular ejection fraction (LVEF), with only two patients requiring temporary mavacamten discontinuance for LVEF < 50%. Adverse events were rare, unrelated to mavacamten itself, and seen solely in patients with disease too advanced to have been represented in clinical trials. Moreover, our multidisciplinary pathway enabled us to provide a large number of patients with a novel closely-monitored therapeutic within just a few months of commercial availability. These data lead us to conclude that mavacamten, as a first-in-class cardiac myosin inhibitor, is safe and efficacious in real-world settings.

  View details for DOI 10.3389/fcvm.2024.1429230

  View details for PubMedID 39314763

  View details for PubMedCentralID PMC11417615

• Classification of Premature Ventricular Contractions in Athletes During Routine Preparticipation Exams. Circulation. Arrhythmia and electrophysiology Gomez, S. E., Perez, M. V., Wheeler, M. T., Hadley, D., Hwang, C. E., Kussman, A., Kim, D. S., Froelicher, V. 2024: e012835

  Abstract

  Large-scale data on incidental premature ventricular contraction (PVC) prevalence and morphologies have been lacking, leaving many providers without guidance on further cardiac testing for patients with incidental PVCs on ECG. Athletes offer an intriguing cohort to understand the clinical significance, prevalence, and common morphologies of incidental PVCs because they often undergo ECG screening during preparticipation exams.Digital ECGs were obtained from 10 728 screened athletes aged 14 to 35 years during mass screenings in schools and professional sports teams between 2014 and 2021. A retrospective analysis of ECGs with PVCs was performed using the simultaneous display of frontal (limb) and horizontal (precordial) plane leads. PVCs were coded for morphology and categorized as benign or nonbenign using recommended criteria.Twenty-six athletes (0.24%) were found to have at least 1 PVC. Among these, 50% were female, 65% were White, 8% were Asian, 4% were Hispanic, and 23% were Black. Nineteen of the 26 (73%) ECGs had PVCs with a left bundle branch block pattern compared with 7 (27%) with a right bundle branch block pattern. Twenty-four ECGs (96%) had PVCs with benign patterns, including 18 with right ventricular outflow tract, 5 with left anterior fascicle, and 2 with left posterior fascicle morphology.There is a low prevalence of PVCs on routine ECG screening of young athletes, and most PVCs are of benign morphology in this population. This study highlights the value of using digital ECG recorders with simultaneous lead display to guide decision-making about further cardiac testing and referrals in young athletes with PVCs. Using our results and review of the literature, we propose methods and algorithms of PVC evaluation on screening ECGs to help guide many providers with risk stratification and decision-making about further cardiac testing and electrophysiology referrals in young athletes with PVCs.

  View details for DOI 10.1161/CIRCEP.124.012835

  View details for PubMedID 39193774

• Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study. European heart journal. Digital health Javed, A., Kim, D. S., Hershman, S. G., Shcherbina, A., Johnson, A., Tolas, A., O'Sullivan, J. W., McConnell, M. V., Lazzeroni, L., King, A. C., Christle, J. W., Oppezzo, M., Mattsson, C. M., Harrington, R. A., Wheeler, M. T., Ashley, E. A. 2023; 4 (5): 411-419

  Abstract

  Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity.We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with ClinicalTrials.gov, NCT03090321.Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.

  View details for DOI 10.1093/ehjdh/ztad047

  View details for PubMedID 37794870

  View details for PubMedCentralID PMC10545510

• Premature ventricular contractions (PVCs) in young athletes. Progress in cardiovascular diseases Gomez, S. E., Hwang, C. E., Kim, D. S., Froelicher, V. F., Wheeler, M. T., Perez, M. V. 2022

  Abstract

  There is a growing body of literature focusing on the morphology, management, and outcomes of PVCs in athletes. This review summarizes this literature and establishes recommendations on management, treatment, and indications for specialist referral in this patient population. The sports medicine physician's responses and recommendation should be made in conjunction with the athletes wishes. Medications or ablations are not always necessary in all athletes if they are followed with regular evaluations.

  View details for DOI 10.1016/j.pcad.2022.10.011

  View details for PubMedID 36309100

• Mind the Gap: The Complete Human Genome Unlocks Benefits for Clinical Genomics. Clinical chemistry Kim, D. S., Wiel, L., Ashley, E. A. 2022

  View details for DOI 10.1093/clinchem/hvac133

  View details for PubMedID 36112529

• Lipoprotein(a) and Incident Atrial Fibrillation: Leveraging Nature's Randomization to Identify Novel Causal Associations. Journal of the American College of Cardiology Kim, D. S., Khandelwal, A. 2022; 79 (16): 1591-1593

  View details for DOI 10.1016/j.jacc.2022.02.026

  View details for PubMedID 35450576

• The genetics of human performance. Nature reviews. Genetics Kim, D. S., Wheeler, M. T., Ashley, E. A. 2021

  Abstract

  Human physiology is likely to have been selected for endurance physical activity. However, modern humans have become largely sedentary, with physical activity becoming a leisure-time pursuit for most. Whereas inactivity is a strong risk factor for disease, regular physical activity reduces the risk of chronic disease and mortality. Although substantial epidemiological evidence supports the beneficial effects of exercise, comparatively little is known about the molecular mechanisms through which these effects operate. Genetic and genomic analyses have identified genetic variation associated with human performance and, together with recent proteomic, metabolomic and multi-omic analyses, are beginning to elucidate the molecular genetic mechanisms underlying the beneficial effects of physical activity on human health.

  View details for DOI 10.1038/s41576-021-00400-5

  View details for PubMedID 34522035

• Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar. Journal of the American College of Cardiology Kim, D. S., Gloyn, A. L., Knowles, J. W. 2021; 78 (5): 496-512

  Abstract

  Type 2 diabetes (T2D) is highly prevalent and is a strong contributor for cardiovascular disease. However, there is significant heterogeneity in disease pathogenesis and the risk of complications. Enormous progress has been made in our ability to catalog genetic variation associated with T2D risk and variation in disease-relevant quantitative traits. These discoveries hold the potential to shed light on tractable targets and pathways for safe and effective therapeutic development, but the promise of precision medicine has been slow to be realized. Recent studies have identified subgroups of individuals with differential risk for intermediate phenotypes (eg, lipid levels, fasting insulin, body mass index) that contribute to T2D risk, helping to account for the observed clinical heterogeneity. These "partitioned genetic risk scores" not only have the potential to identify patients at greatest risk of cardiovascular disease and rapid disease progression, but also could aid patient stratification bridging the gap toward precision medicine for T2D.

  View details for DOI 10.1016/j.jacc.2021.03.346

  View details for PubMedID 34325839

• Actionable exomic incidental findings in 6503 participants: challenges of variant classification GENOME RESEARCH Amendola, L. M., Dorschner, M. O., Robertson, P. D., Salama, J. S., Hart, R., Shirts, B. H., Murray, M. L., Tokita, M. J., Gallego, C. J., Kim, D. S., Bennett, J. T., Crosslin, D. R., Ranchalis, J., Jones, K. L., Rosenthal, E. A., Jarvik, E. R., Itsara, A., Turner, E. H., Herman, D. S., Schleit, J., Burt, A., Jamal, S. M., Abrudan, J. L., Johnson, A. D., Conlin, L. K., Dulik, M. C., Santani, A., Metterville, D. R., Kelly, M., Foreman, A. K., Lee, K., Taylor, K. D., Guo, X., Crooks, K., Kiedrowski, L. A., Raffe, L. J., Gordon, O., Machini, K., Desnick, R., Biesecker, L. G., Lubitz, S. A., Mulchandani, S., Cooper, G. M., Joffe, S., Richards, C. S., Yang, Y., Rotter, J. I., Rich, S. S., O'Donne, C. J., Berg, J. S., Spinner, N. B., Evans, J. P., Fullerton, S. M., Leppig, K. A., Bennett, R. L., Bird, T., Sybert, V. P., Grady, W. M., Tabor, H. K., Kim, J. H., Bamshad, M. J., Wilfond, B., Motulsky, A. G., Scott, R., Pritchard, C. C., Walsh, T. D., Burke, W., Raskind, W. H., Byers, P., Hisama, F. M., Rehm, H., Nickerson, D. A., Jarvik, G. P. 2015; 25 (3): 305-315

  Abstract

  Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

  View details for DOI 10.1101/gr.183483.114

  View details for Web of Science ID 000350526700001

  View details for PubMedID 25637381

  View details for PubMedCentralID PMC4352885

• Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Human molecular genetics Schick, U. M., Auer, P. L., Bis, J. C., Lin, H., Wei, P., Pankratz, N., Lange, L. A., Brody, J., Stitziel, N. O., Kim, D. S., Carlson, C. S., Fornage, M., Haessler, J., Hsu, L., Jackson, R. D., Kooperberg, C., Leal, S. M., Psaty, B. M., Boerwinkle, E., Tracy, R., Ardissino, D., Shah, S., Willer, C., Loos, R., Melander, O., Mcpherson, R., Hovingh, K., Reilly, M., Watkins, H., Girelli, D., Fontanillas, P., Chasman, D. I., Gabriel, S. B., Gibbs, R., Nickerson, D. A., Kathiresan, S., Peters, U., Dupuis, J., Wilson, J. G., Rich, S. S., Morrison, A. C., Benjamin, E. J., Gross, M. D., Reiner, A. P. 2015; 24 (2): 559-71

  Abstract

  C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

  View details for DOI 10.1093/hmg/ddu450

  View details for PubMedID 25187575

  View details for PubMedCentralID PMC4334838

• Genetic variation in the HLA region is associated with susceptibility to herpes zoster GENES AND IMMUNITY Crosslin, D. R., Carrell, D. S., Burt, A., Kim, D. S., Underwood, J. G., Hanna, D. S., Comstock, B. A., Baldwin, E., de Andrade, M., Kullo, I. J., Tromp, G., Kuivaniemi, H., Borthwick, K. M., McCarty, C. A., Peissig, P. L., Doheny, K. F., Pugh, E., Kho, A., Pacheco, J., Hayes, M. G., Ritchie, M. D., Verma, S. S., Armstrong, G., Stallings, S., Denny, J. C., Carroll, R. J., Crawford, D. C., Crane, P. K., Mukherjee, S., Bottinger, E., Li, R., Keating, B., Mirel, D. B., Carlson, C. S., Harley, J. B., Larson, E. B., Jarvik, G. P. 2015; 16 (1): 1-7

  Abstract

  Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

  View details for DOI 10.1038/gene.2014.51

  View details for Web of Science ID 000348358100001

  View details for PubMedID 25297839

  View details for PubMedCentralID PMC4308645

• Design and Anticipated Outcomes of the eMERGE-PGx Project: A Multicenter Pilot for Preemptive Pharmacogenomics in Electronic Health Record Systems CLINICAL PHARMACOLOGY & THERAPEUTICS Rasmussen-Torvik, L. J., Stallings, S. C., Gordon, A. S., Almoguera, B., Basford, M. A., Bielinski, S. J., Brautbar, A., Brilliant, M. H., Carrell, D. S., Connolly, J. J., Crosslin, D. R., Doheny, K. F., Gallego, C. J., Gottesman, O., Kim, D. S., Leppig, K. A., Li, R., Lin, S., Manzi, S., Mejia, A. R., Pacheco, J. A., Pan, V., Pathak, J., Perry, C. L., Peterson, J. F., Prows, C. A., Ralston, J., Rasmussen, L. V., Ritchie, M. D., Sadhasivam, S., Scott, S. A., Smith, M., Vega, A., Vinks, A. A., Volpi, S., Wolf, W. A., Bottinger, E., Chisholm, R. L., Chute, C. G., Haines, J. L., Harley, J. B., Keating, B., Holm, I. A., Kullo, I. J., Jarvik, G. P., Larson, E. B., Manolio, T., McCarty, C. A., Nickerson, D. A., Scherer, S. E., Williams, M. S., Roden, D. M., Denny, J. C. 2014; 96 (4): 482–89

  Abstract

  We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

  View details for DOI 10.1038/clpt.2014.137

  View details for Web of Science ID 000342675400027

  View details for PubMedID 24960519

  View details for PubMedCentralID PMC4169732

• Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci. American journal of human genetics Tragante, V., Barnes, M. R., Ganesh, S. K., Lanktree, M. B., Guo, W., Franceschini, N., Smith, E. N., Johnson, T., Holmes, M. V., Padmanabhan, S., Karczewski, K. J., Almoguera, B., Barnard, J., Baumert, J., Chang, Y. C., Elbers, C. C., Farrall, M., Fischer, M. E., Gaunt, T. R., Gho, J. M., Gieger, C., Goel, A., Gong, Y., Isaacs, A., Kleber, M. E., Mateo Leach, I., McDonough, C. W., Meijs, M. F., Melander, O., Nelson, C. P., Nolte, I. M., Pankratz, N., Price, T. S., Shaffer, J., Shah, S., Tomaszewski, M., van der Most, P. J., van Iperen, E. P., Vonk, J. M., Witkowska, K., Wong, C. O., Zhang, L., Beitelshees, A. L., Berenson, G. S., Bhatt, D. L., Brown, M., Burt, A., Cooper-DeHoff, R. M., Connell, J. M., Cruickshanks, K. J., Curtis, S. P., Davey-Smith, G., Delles, C., Gansevoort, R. T., Guo, X., Haiqing, S., Hastie, C. E., Hofker, M. H., Hovingh, G. K., Kim, D. S., Kirkland, S. A., Klein, B. E., Klein, R., Li, Y. R., Maiwald, S., Newton-Cheh, C., O'Brien, E. T., Onland-Moret, N. C., Palmas, W., Parsa, A., Penninx, B. W., Pettinger, M., Vasan, R. S., Ranchalis, J. E., M Ridker, P., Rose, L. M., Sever, P., Shimbo, D., Steele, L., Stolk, R. P., Thorand, B., Trip, M. D., van Duijn, C. M., Verschuren, W. M., Wijmenga, C., Wyatt, S., Young, J. H., Zwinderman, A. H., Bezzina, C. R., Boerwinkle, E., Casas, J. P., Caulfield, M. J., Chakravarti, A., Chasman, D. I., Davidson, K. W., Doevendans, P. A., Dominiczak, A. F., FitzGerald, G. A., Gums, J. G., Fornage, M., Hakonarson, H., Halder, I., Hillege, H. L., Illig, T., Jarvik, G. P., Johnson, J. A., Kastelein, J. J., Koenig, W., Kumari, M., März, W., Murray, S. S., O'Connell, J. R., Oldehinkel, A. J., Pankow, J. S., Rader, D. J., Redline, S., Reilly, M. P., Schadt, E. E., Kottke-Marchant, K., Snieder, H., Snyder, M., Stanton, A. V., Tobin, M. D., Uitterlinden, A. G., van der Harst, P., van der Schouw, Y. T., Samani, N. J., Watkins, H., Johnson, A. D., Reiner, A. P., Zhu, X., de Bakker, P. I., Levy, D., Asselbergs, F. W., Munroe, P. B., Keating, B. J. 2014; 94 (3): 349-360

  Abstract

  Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

  View details for DOI 10.1016/j.ajhg.2013.12.016

  View details for PubMedID 24560520

• Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes AMERICAN JOURNAL OF HUMAN GENETICS Dorschner, M. O., Amendola, L. M., Turner, E. H., Robertson, P. D., Shirts, B. H., Gallego, C. J., Bennett, R. L., Jones, K. L., Tokita, M. J., Bennett, J. T., Kim, J. H., Rosenthal, E. A., Kim, D. S., Tabor, H. K., Bamshad, M. J., Motulsky, A. G., Scott, C. R., Pritchard, C. C., Walsh, T., Burke, W., Raskind, W. H., Byers, P., Hisama, F. M., Nickerson, D. A., Jarvik, G. P. 2013; 93 (4): 631-640

  Abstract

  The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants' pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.

  View details for DOI 10.1016/j.ajhg.2013.08.006

  View details for Web of Science ID 000326305600005

  View details for PubMedID 24055113

  View details for PubMedCentralID PMC3791261

• The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future GENETICS IN MEDICINE Gottesman, O., Kuivaniemi, H., Tromp, G., Faucett, W., Li, R., Manolio, T. A., Sanderson, S. C., Kannry, J., Zinberg, R., Basford, M. A., Brilliant, M., Carey, D. J., Chisholm, R. L., Chute, C. G., Connolly, J. J., Crosslin, D., Denny, J. C., Gallego, C. J., Haines, J. L., Hakonarson, H., Harley, J., Jarvik, G. P., Kohane, I., Kullo, I. J., Larson, E. B., McCarty, C., Ritchie, M. D., Roden, D. M., Smith, M. E., Bottinger, E. P., Williams, M. S., eMerge Network 2013; 15 (10): 761–71

  Abstract

  The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute-funded consortium engaged in the development of methods and best practices for using the electronic medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine.

  View details for DOI 10.1038/gim.2013.72

  View details for Web of Science ID 000325665000002

  View details for PubMedID 23743551

  View details for PubMedCentralID PMC3795928

• Results of genome-wide analyses on neurodevelopmental phenotypes at four-year follow-up following cardiac surgery in infancy. PloS one Kim, D. S., Stanaway, I. B., Rajagopalan, R., Bernbaum, J. C., Solot, C. B., Burnham, N., Zackai, E. H., Clancy, R. R., Nicolson, S. C., Gerdes, M., Nickerson, D. A., Hakonarson, H., Gaynor, J. W., Jarvik, G. P. 2012; 7 (9): e45936

  Abstract

  Adverse neurodevelopmental sequelae are reported among children who undergo early cardiac surgery to repair congenital heart defects (CHD). APOE genotype has previously been determined to contribute to the prediction of these outcomes. Understanding further genetic causes for the development of poor neurobehavioral outcomes should enhance patient risk stratification and improve both prevention and treatment strategies.We performed a prospective observational study of children who underwent cardiac surgery before six months of age; this included a neurodevelopmental evaluation between their fourth and fifth birthdays. Attention and behavioral skills were assessed through parental report utilizing the Attention Deficit-Hyperactivity Disorder-IV scale preschool edition (ADHD-IV), and Child Behavior Checklist (CBCL/1.5-5), respectively. Of the seven investigated, three neurodevelopmental phenotypes met genomic quality control criteria. Linear regression was performed to determine the effect of genome-wide genetic variation on these three neurodevelopmental measures in 316 subjects.This genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with three neurobehavioral phenotypes in the postoperative children ADHD-IV Impulsivity/Hyperactivity, CBCL/1.5-5 PDPs, and CBCL/1.5-5 Total Problems. The most predictive SNPs for each phenotype were: a LGALS8 intronic SNP, rs4659682, associated with ADHD-IV Impulsivity (P=1.03 × 10(-6)); a PCSK5 intronic SNP, rs2261722, associated with CBCL/1.5-5 PDPs (P=1.11 × 10(-6)); and an intergenic SNP, rs11617488, 50 kb from FGF9, associated with CBCL/1.5-5 Total Problems (P=3.47 × 10(-7)). 10 SNPs (3 for ADHD-IV Impulsivity, 5 for CBCL/1.5-5 PDPs, and 2 for CBCL/1.5-5 Total Problems) had p<10(-5).No SNPs met genome-wide significance for our three neurobehavioral phenotypes; however, 10 SNPs reached a threshold for suggestive significance (p<10(-5)). Given the unique nature of this cohort, larger studies and/or replication are not possible. Studies to further investigate the mechanisms through which these newly identified genes may influence neurodevelopment dysfunction are warranted.

  View details for DOI 10.1371/journal.pone.0045936

  View details for PubMedID 23049896

  View details for PubMedCentralID PMC3457986