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A longitudinal big data approach for precision health

Abstract

Precision health relies on the ability to assess disease risk at an individual level, detect early preclinical conditions and initiate preventive strategies. Recent technological advances in omics and wearable monitoring enable deep molecular and physiological profiling and may provide important tools for precision health. We explored the ability of deep longitudinal profiling to make health-related discoveries, identify clinically relevant molecular pathways and affect behavior in a prospective longitudinal cohort (n = 109) enriched for risk of type 2 diabetes mellitus. The cohort underwent integrative personalized omics profiling from samples collected quarterly for up to 8 years (median, 2.8 years) using clinical measures and emerging technologies including genome, immunome, transcriptome, proteome, metabolome, microbiome and wearable monitoring. We discovered more than 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance by using omics measurements, illustrating their potential to replace burdensome tests. Finally, study participation led the majority of participants to implement diet and exercise changes. Altogether, we conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

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Fig. 1: Study design and data collection.
Fig. 2: Clinical and enhanced phenotyping of glucose metabolism, insulin production and resistance.
Fig. 3: Longitudinal individual phenotyping and multi-omics of glucose metabolism and inflammation.
Fig. 4: Clinical longitudinal cardiovascular health profiling and multi-omics correlation network of adjusted ASCVD risk.
Fig. 5: Oncologic discoveries.
Fig. 6: Summary of major clinically actionable health discoveries and participant health behavior change.

Data availability

Raw omics data (transcriptome, immunome, proteome, metabolome, microbiome) included in this study are hosted on the NIH Human Microbiome 2 project site (https://portal.hmpdacc.org/) under the T2D project along with clinical laboratory data to 2016. Data from participants who have not consented to make their data public are available on dbGAP (accession phs001719.v1.p1). Additional data unique to this manuscript has been provided in the Supplementary Data files.

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Acknowledgements

Our work was supported by grants from the National Institutes of Health (NIH) Human Microbiome Project (HMP) 1U54DE02378901 (G.M.W. and M.P.S.), an NIH grant no. R01 DK110186-03 (T.L.M.), a NIH National Center for Advancing Translational Science Clinical and Translational Science Award (no. UL1TR001085). This work used the Genome Sequencing Service Center by the Stanford Center for Genomics and Personalized Medicine Sequencing Center (supported by NIH grant no. S10OD020141), the Diabetes Genomics Analysis Core and the Clinical and Translational Core of the Stanford Diabetes Research Center (NIH grant no. P30DK116074). S.M.S.-F.R. was supported by a Department of Veteran Affairs Office of Academic Affiliations Advanced Fellowship in Spinal Cord Injury Medicine and a NIH Career Development Award no. K08 ES028825. G.M.S. was supported by NIH grant no. K08 MH103443. D.H. was supported by a Stanford School of Medicine Dean’s Postdoctoral Fellowship and a Stanford Center for Computational, Evolutionary and Human Genomics Fellowship. M.R.S. was supported by grant nos. P300PA_161005 and P2GEP3_151825 from the Swiss National Science Foundation (SNSF). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the Department of Veteran Affairs, or the SNSF. We thank S. Chen and B. Lee for their work in metabolomics data production. A. Breschi generously shared her code for the ISR calculations. Finally, we thank the iPOP participants who generously gave their time and biological samples.

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S.M.S.-F.R., M.P.S., F.H., K.C., K.M., T.M. and W.Z. contributed to the conceptualization. S.M.S.-F.R., K.C., F.H., M.P.S., T.M., K.M., S.M., W.Z. and S.R. contributed to the methodology. K.C. (ASCVD biomarkers), D.H. (Lipidomics), A.B.G. (Microbiome DADA2 processing), T.M., M.A. and W.Z. (OGTT C-peptide and insulin) contributed to omics generation and/or processing. S.M.S.-F.R., K.C., T.M., W.Z., J.D., M.A., J.W.C., E.S. and P.L. contributed to data curation. K.C., S.M.S.-F.R., T.M., K.M., F.H. and M.P.S. contributed to visualization. S.M.S.-F.R., K.C., T.M., S.M., K.M., O.D.-R., S.R., J.C. and C.R. contributed to formal analysis. S.M.S.-F.R., K.C. and M.P.S. contributed to project administration. M.P.S. and F.H. contributed to supervision. S.M.S.-F.R., F.H., K.C., K.M. and M.P.S. contributed to writing and preparing the original draft. S.M.S.-F.R., K.C., K.M., F.H., M.P.S., W.Z., A.B.G., D.H., J.D., G.M.S, T.M., M.T., D.P., T.L.M., A.J.B., M.R.S. and S.A. contributed to review and editing. K.M., F.H. and J.W.C. contributed to cardiovascular clinical data collection and investigation. W.Z., S.R., M.A., P.L., D.P., M.T., T.L.M. and S.M.S.-F.R. contributed to iPOP/iHMP clinical data collection/investigation. W.Z., S.R.L, M.P.S., T.L.M., E.S. and G.M.W. contributed to iPOP/iHMP project administration. K.C. (metabolomics), S.A. (proteomics), M.R.S. (DNA, RNA-seq), W.Z. (microbiome, cytokines, and overall omics data), Y.Z. (microbiome), T.M. and D.H. (batch correction methodology for proteomics) contributed to iPOP/iHMP omics raw data processing. M.P.S., G.M.W., T.L.M. and E.S. contributed to iPOP/iHMP funding acquisition.

Corresponding authors

Correspondence to Francois Haddad or Michael P. Snyder.

Ethics declarations

Competing interests

M.P.S. is a cofounder of Personalis, SensOmics, January, Filtricine, Qbio and Akna and an inventor on provisional patent number 62/814,746 ‘Methods for evaluation and treatment of glycemic dysregulation and applications thereof’. S.M.S.-F.R., K.C., W.Z., T.M. and S.M. are also listed as inventors. A.J.B. reports grants and non-financial support from Progenity, grants and personal fees from NIH (multiple institutes) and Genentech, and grants from L’Oreal, personal fees from NuMedii, Personalis, Lilly, Assay Depot, Geisinger Health, GNS Healthcare, uBiome, Roche, Wilson Sonsini Goodrich & Rosati, Orrick, Herrington & Sutcliffe, Verinata, 10x Genomics, Pathway Genomics, Guardant Health, Gerson Lehrman Group, Nuna Health, Samsung, Capital Royalty Group, Optum Labs, Pfizer, AbbVie, Bayer, Three Lakes Partners, HudsonAlpha, Tensegrity, Westat, FH Foundation, WuXi, FlareCapital, Helix, Roam Insights, Autodesk, Regenstrief Institute, American Medical Association, Precision Medicine World Conference, and Mars during the conduct of the study. A.J.B. has pending patent Atul J. Butte, Keiichi Kodama, Methods for diagnosis and treatment of non-insulin dependent diabetes mellitus, published August 4, 2011, WO2011094731 and US20130071408; patent Joel T. Dudley, Atul J. Butte, Method and System for Computing and Integrating Genetic and Environmental Health Risks for a Personal Genome, published April 26, 2012, US20120101736 with royalties paid to Personalis; patent Joel T. Dudley, Atul J. Butte, Method And System For Functional Evolutionary Assessment Of Genetic Variants, published April 11, 2013, US20130090909 with royalties paid to Personalis; patent Konrad Karczewski, Michael Snyder, Atul J. Butte, Joel T. Dudley, Eurie Hong, Alan Boyle, J. Michael Cherry, Method and System for Assessment of Regulatory Variants in a Genome, published May 9, 2013, US20130116931 with royalties paid to Personalis; and patent Frederick Dewey, Euan Ashley, Carlos Daniel Bustamante, Atul Butte, Jake Byrnes, Rong Chen, Phased Whole Genome Genetic Risk In A Family Quartet, published March 28, 2013, US20130080068, with royalties paid to Personalis; Stanford University pays royalties each year on licensed intellectual property.

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Extended data

Extended Data Fig. 1 Integrated personalized omics profiling cohort flow chart and genetic ancestry.

a, The flow chart demonstrates recruitment and enrollment of the iPOP cohort. b, PCA plot showing the ancestries of 72 participants. The reference includes 2,504 samples from the 1,000GP11. Each filled circle is a 1,000GP sample, colored by the super-population of ancestral origin, namely African (AFR; red), admixed American (AMR; purple), East Asian (EAS; green), European (EUR; cyan) and South Asian (SAS; orange). Each black symbol is an individual from the study, which we categorized by self-reported ethnicity consistent with the 1,000GP super-population definitions, namely AFR (black filled circle), AMR (black filled triangle), EAS (black filled square), EUR (black plus sign) and South Asian (a checked box). We see that the individuals in our study have self-reported ancestries generally clustering in the super-population reference panel from the 1,000GP. Source Data

Extended Data Fig. 2 Comparison of diabetic metrics in categorizing individuals when performed at the same time and HbA1C trajectories.

a, Overlap of FPG and hemoglobin A1C (HbA1C) categories when simultaneously measured. FPG impaired: 1.0 mg ml−1 ≤ FPG < 1.26 mg ml−1; diabetic range: FPG ≥ 1.26 mg ml−1; HbA1C impaired: 5.7% ≤ HbA1C < 6.5%; diabetic range: HbA1C ≥ 6.5%. b, Overlap of FPG and 2-hour OGTT when simultaneously measured. FPG ranges as above. OGTT impaired: 1.40 mg ml−1 ≤ OGTT < 2.00 mg ml−1; diabetic range ≥2.00 mg ml−1. c, Longitudinal patterns of changes in Hemoglobin A1C (HbA1C) over time. Six different patterns could be characterized including: 1, participants who remained in the normal range the entire study (Group 1, n = 51); 2, participants who progressed from normal to prediabetic (Group 2, n = 5); 3, participants who went from prediabetic to normal (Group 3, n = 10); 4, participants whose HbA1C went back and forth from normal to prediabetic (Group 4, n = 21); 5, participants whose HbA1C laboratory results were predominantly in the prediabetic range (Group 5, n = 14) and 6, participants whose HbA1C crossed into the diabetic range (Group 6, n = 8). The red lines represent the overall penalized b-spline of participants’ data in each category. Source Data

Extended Data Fig. 3 Additional individual longitudinal trajectories for diabetic measures.

Diabetic-range metrics are indicated in red. ae, Diabetic-range OGTT (a), Diabetic-range FPG (b,c), undiagnosed DM at study entry (HbA1C) (d), Initial abnormality HbA1C (e). Note this person had two HbA1C measurements on the same day at two different laboratories and was started on medication based on the higher measurement. f,g, Bouncer with diabetic-range HbA1C and OGTT (f) and SSPG decrease with lifestyle change (g). Source Data

Extended Data Fig. 4 Longitudinal microbiome trajectories in diabetes.

a,b, Longitudinal weight, gut microbial Shannon diversity and phylum proportion changes in participants ZNDMXI3 (a) and ZNED4XZ (b). c, Longitudinal changes in genus proportion (ZNDMXI3). d,e, Microbiome outliers (95th percentile) at the latest microbiome sample time point in participants ZNDMXI3 (d) and ZNED4XZ (e). Microbial abundance is scaled by row with low (blue) and high (red) abundance. Source Data

Extended Data Fig. 5 Multi-omics of glucose metabolism and inflammation.

a, Proteins and metabolites associated with HbA1C, FPG and hsCRP using healthy-baseline and dynamic linear mixed models. Healthy-baseline models (HbA1C n = 101, samples 560; FPG n = 101, samples 563; hsCRP n = 98, samples 518) account for repeated measures at healthy time points. Dynamic models are similar models except that analytes are normalized across individuals to the first measurement and all time points in the study are used (HbA1C n = 94, samples = 836; FPG n = 94, samples = 843; hsCRP n = 92, samples 777). Individual analyte P values were determined using a two-sided t-test. Multiple testing correction was performed and molecules were considered significant when Benjamini–Hochberg FDR < 0.2. Model estimates were normalized in each condition so the maximum value equal to 1 and the minimal value equal to −1. b, Integrative pathway analysis using IMPaLa67 of proteins and metabolites associated with HbA1C (n = 101, samples 560), FPG (n = 101, samples 563) and hsCRP (n = 98, samples 518) as determined by the healthy-baseline models (Benjamini–Hochberg FDR < 0.2 at molecule level) that matched to known pathways. Significance of pathways for proteins and metabolites separately is determined by the hypergeometric test (one-sided) followed by Fisher’s combined probability test (one-sided) to determine combined pathway significance (Benjamini–Hochberg FDR < 0.05; n’s of proteins and metabolites for each pathway are provided in Supplementary Tables 9, 11 and 13).

Extended Data Fig. 6 Outlier Analysis of RNA-seq data.

a, Number of outlier RNA molecules (95th percentile) in each participant. Outlier analysis was performed on Z scores calculated on the median expression level of each gene at healthy visits in individuals with at least three healthy visits (n = 63). The box is defined as 25th and 75th quartile. The upper whisker extends to 1.5 times the interquartile range from the box and the lower whisker to the lowest data point. The horizontal bar in the box is the median value. b, Selected clinical laboratory and metabolite trajectories (seven measurement time points) for participant ZJTKAE3 showing a concomitant increase of bile acids and glutamyl dipeptides with ALT (alanine aminotransferase) and AST (aspartate aminotransferase). Source Data

Extended Data Fig. 7 Multidimensional cardiac risk assessment.

a, Distribution of ASCVD risk scores (n = 35 participants, 36 measurements) and cardiovascular imaging and physiology measures that have been established as cardiovascular risk markers. (Abbreviations: RWT-relative wall thickness, LV GLS-left ventricular global longitudinal strain, E/e’ - ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e’), PWV-pulse wave velocity). Please note that thresholds for PWV are age-related. Box plots were derived to display quartiles (Q1, median, Q3) with the upper whisker being Q3 + 1.5 × (interquartile range) and the lower whisker extending to Q1 − 1.5 × (interquartile range) or the lowest data point. b, Ultrasound of carotid plaque (6 participants out of 35 had an ultrasound finding of carotid plaque) and relative distribution of ASCVD risk score, HbA1C and LV GLS in function of presence or absence of carotid plaque (Student’s t-test (two-sided) was used to evaluate differences between groups; n = 35, 36 measurements) (Abbreviations: CCA-common carotid artery; IJV-internal jugular vein). Error bars represent one standard deviation from the mean (upper edge of box). c, Correlation network of selected metrics collected during cardiovascular assessment (Spearman correlation (two-sided) with q < 0.2; n = 35 participants with 36 measurements). d, Composite Z score of ZOBX723 (unstable angina with stent placement) and ZNED4XZ (mild stroke with full recovery and transition to diabetes). For ZOBX723, day 829 occurred 3 weeks post-stent placement. Day 679 was a mid-infection time point. For ZNED4XZ, day 699 was the time point before the participant’s transition to diabetes and day 846 was the first diabetic time point. The stroke occurred on day 307 for this individual. Gray dots represent Z scores of other participants (n = 101 with 859 samples). e, Violin plot showing the same data as d (n = 101 with 859 samples). The box plot shows the first (lower edge of box), median (middle line) and third (upper edge of box) quartiles. The upper whisker is the third quartile + 1.5 × (interquartile range) and the lower whisker is the lowest data point. Source Data

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Supplementary Tables 0–28

Supplementary Data

Data Tables 1–24

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Schüssler-Fiorenza Rose, S.M., Contrepois, K., Moneghetti, K.J. et al. A longitudinal big data approach for precision health. Nat Med 25, 792–804 (2019). https://doi.org/10.1038/s41591-019-0414-6

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