Stanford Advisors


All Publications


  • Prediction of neuropathologic lesions from clinical data. Alzheimer's & dementia : the journal of the Alzheimer's Association Phongpreecha, T., Cholerton, B., Bhukari, S., Chang, A. L., De Francesco, D., Thuraiappah, M., Godrich, D., Perna, A., Becker, M. G., Ravindra, N. G., Espinosa, C., Kim, Y., Berson, E., Mataraso, S., Sha, S. J., Fox, E. J., Montine, K. S., Baker, L. D., Craft, S., White, L., Poston, K. L., Beecham, G., Aghaeepour, N., Montine, T. J. 2023

    Abstract

    Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life.This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities.Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased.Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

    View details for DOI 10.1002/alz.12921

    View details for PubMedID 36681388

  • In-Silico Generation of High-Dimensional Immune Response Data in Patients using a Deep Neural Network. Cytometry. Part A : the journal of the International Society for Analytical Cytology Fallahzadeh, R., Bidoki, N. H., Stelzer, I. A., Becker, M., Marić, I., Chang, A. L., Culos, A., Phongpreecha, T., Xenochristou, M., De Francesco, D., Espinosa, C., Berson, E., Verdonk, F., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2022

    Abstract

    Technologies for single-cell profiling of the immune system have enabled researchers to extract rich interconnected networks of cellular abundance, phenotypical and functional cellular parameters. These studies can power machine learning approaches to understand the role of the immune system in various diseases. However, the performance of these approaches and the generalizability of the findings have been hindered by limited cohort sizes in translational studies, partially due to logistical demands and costs associated with longitudinal data collection in sufficiently large patient cohorts. An evolving challenge is the requirement for ever-increasing cohort sizes as the dimensionality of datasets grows. We propose a deep learning model derived from a novel pipeline of optimal temporal cell matching and overcomplete autoencoders that uses data from a small subset of patients to learn to forecast an entire patient's immune response in a high dimensional space from one timepoint to another. In our analysis of 1.08 million cells from patients pre- and post-surgical intervention, we demonstrate that the generated patient-specific data are qualitatively and quantitatively similar to real patient data by demonstrating fidelity, diversity, and usefulness. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/cyto.a.24709

    View details for PubMedID 36507780

  • Early prediction and longitudinal modeling of preeclampsia from multiomics. Patterns (New York, N.Y.) Maric, I., Contrepois, K., Moufarrej, M. N., Stelzer, I. A., Feyaerts, D., Han, X., Tang, A., Stanley, N., Wong, R. J., Traber, G. M., Ellenberger, M., Chang, A. L., Fallahzadeh, R., Nassar, H., Becker, M., Xenochristou, M., Espinosa, C., De Francesco, D., Ghaemi, M. S., Costello, E. K., Culos, A., Ling, X. B., Sylvester, K. G., Darmstadt, G. L., Winn, V. D., Shaw, G. M., Relman, D. A., Quake, S. R., Angst, M. S., Snyder, M. P., Stevenson, D. K., Gaudilliere, B., Aghaeepour, N. 2022; 3 (12): 100655

    Abstract

    Preeclampsia is a complex disease of pregnancy whose physiopathology remains unclear. We developed machine-learning models for early prediction of preeclampsia (first 16weeks of pregnancy) and over gestation by analyzing six omics datasets from a longitudinal cohort of pregnant women. For early pregnancy, a prediction model using nine urine metabolites had the highest accuracy and was validated on an independent cohort (area under the receiver-operating characteristic curve [AUC]= 0.88, 95% confidence interval [CI] [0.76, 0.99] cross-validated; AUC= 0.83, 95% CI [0.62,1] validated). Univariate analysis demonstrated statistical significance of identified metabolites. An integrated multiomics model further improved accuracy (AUC= 0.94). Several biological pathways were identified including tryptophan, caffeine, and arachidonic acid metabolisms. Integration with immune cytometry data suggested novel associations between immune and proteomic dynamics. While further validation in a larger population is necessary, these encouraging results can serve as a basis for a simple, early diagnostic test for preeclampsia.

    View details for DOI 10.1016/j.patter.2022.100655

    View details for PubMedID 36569558

  • A data-driven health index for neonatal morbidities. iScience De Francesco, D., Blumenfeld, Y. J., Maric, I., Mayo, J. A., Chang, A. L., Fallahzadeh, R., Phongpreecha, T., Butwick, A. J., Xenochristou, M., Phibbs, C. S., Bidoki, N. H., Becker, M., Culos, A., Espinosa, C., Liu, Q., Sylvester, K. G., Gaudilliere, B., Angst, M. S., Stevenson, D. K., Shaw, G. M., Aghaeepour, N. 2022; 25 (4): 104143

    Abstract

    Whereas prematurity is a major cause of neonatal mortality, morbidity, and lifelong impairment, the degree of prematurity is usually defined by the gestational age (GA) at delivery rather than by neonatal morbidity. Here we propose a multi-task deep neural network model that simultaneously predicts twelve neonatal morbidities, as the basis for a new data-driven approach to define prematurity. Maternal demographics, medical history, obstetrical complications, and prenatal fetal findings were obtained from linked birth certificates and maternal/infant hospitalization records for 11,594,786 livebirths in California from 1991 to 2012. Overall, our model outperformed traditional models to assess prematurity which are based on GA and/or birthweight (area under the precision-recall curve was 0.326 for our model, 0.229 for GA, and 0.156 for small for GA). These findings highlight the potential of using machine learning techniques to predict multiple prematurity phenotypes and inform clinical decisions to prevent, diagnose and treat neonatal morbidities.

    View details for DOI 10.1016/j.isci.2022.104143

    View details for PubMedID 35402862

  • Revealing the impact of lifestyle stressors on the risk of adverse pregnancy outcomes with multitask machine learning. Frontiers in pediatrics Becker, M., Dai, J., Chang, A. L., Feyaerts, D., Stelzer, I. A., Zhang, M., Berson, E., Saarunya, G., De Francesco, D., Espinosa, C., Kim, Y., Maric, I., Mataraso, S., Payrovnaziri, S. N., Phongpreecha, T., Ravindra, N. G., Shome, S., Tan, Y., Thuraiappah, M., Xue, L., Mayo, J. A., Quaintance, C. C., Laborde, A., King, L. S., Dhabhar, F. S., Gotlib, I. H., Wong, R. J., Angst, M. S., Shaw, G. M., Stevenson, D. K., Gaudilliere, B., Aghaeepour, N. 2022; 10: 933266

    Abstract

    Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches.Objectives: The primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions.Materials and Methods: In a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF).Results: Jointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs.Conclusions: Elucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics.

    View details for DOI 10.3389/fped.2022.933266

    View details for PubMedID 36582513

  • Data-Driven Modeling of Pregnancy-Related Complications. Trends in molecular medicine Espinosa, C. n., Becker, M. n., Marić, I. n., Wong, R. J., Shaw, G. M., Gaudilliere, B. n., Aghaeepour, N. n., Stevenson, D. K. 2021

    Abstract

    A healthy pregnancy depends on complex interrelated biological adaptations involving placentation, maternal immune responses, and hormonal homeostasis. Recent advances in high-throughput technologies have provided access to multiomics biological data that, combined with clinical and social data, can provide a deeper understanding of normal and abnormal pregnancies. Integration of these heterogeneous datasets using state-of-the-art machine-learning methods can enable the prediction of short- and long-term health trajectories for a mother and offspring and the development of treatments to prevent or minimize complications. We review advanced machine-learning methods that could: provide deeper biological insights into a pregnancy not yet unveiled by current methodologies; clarify the etiologies and heterogeneity of pathologies that affect a pregnancy; and suggest the best approaches to address disparities in outcomes affecting vulnerable populations.

    View details for DOI 10.1016/j.molmed.2021.01.007

    View details for PubMedID 33573911

  • Objective Activity Parameters Track Patient-Specific Physical Recovery Trajectories After Surgery and Link With Individual Preoperative Immune States. Annals of surgery Fallahzadeh, R., Verdonk, F., Ganio, E., Culos, A., Stanley, N., Marić, I., Chang, A. L., Becker, M., Phongpreecha, T., Xenochristou, M., De Francesco, D., Espinosa, C., Gao, X., Tsai, A., Sultan, P., Tingle, M., Amanatullah, D. F., Huddleston, J. I., Goodman, S. B., Gaudilliere, B., Angst, M. S., Aghaeepour, N. 2021

    Abstract

    The longitudinal assessment of physical function with high temporal resolution at a scalable and objective level in patients recovering from surgery is highly desirable to understand the biological and clinical factors that drive the clinical outcome. However, physical recovery from surgery itself remains poorly defined and the utility of wearable technologies to study recovery after surgery has not been established.Prolonged postoperative recovery is often associated with long-lasting impairment of physical, mental, and social functions. While phenotypical and clinical patient characteristics account for some variation of individual recovery trajectories, biological differences likely play a major role. Specifically, patient-specific immune states have been linked to prolonged physical impairment after surgery. However, current methods of quantifying physical recovery lack patient specificity and objectivity.Here, a combined high-fidelity accelerometry and state-of-the-art deep immune profiling approach was studied in patients undergoing major joint replacement surgery. The aim was to determine whether objective physical parameters derived from accelerometry data can accurately track patient-specific physical recovery profiles (suggestive of a 'clock of postoperative recovery'), compare the performance of derived parameters with benchmark metrics including step count, and link individual recovery profiles with patients' preoperative immune state.The results of our models indicate that patient-specific temporal patterns of physical function can be derived with a precision superior to benchmark metrics. Notably, six distinct domains of physical function and sleep are identified to represent the objective temporal patterns: "activity capacity" and "moderate and overall activity" (declined immediately after surgery); "sleep disruption and sedentary activity" (increased after surgery); "overall sleep", "sleep onset", and "light activity" (no clear changes were observed after surgery). These patterns can be linked to individual patients' preoperative immune state using cross-validated canonical-correlation analysis. Importantly, the pSTAT3 signal activity in M-MDSCs predicted a slower recovery.Accelerometry-based recovery trajectories are scalable and objective outcomes to study patient-specific factors that drive physical recovery.

    View details for DOI 10.1097/SLA.0000000000005250

    View details for PubMedID 35129529