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      A Longitudinal Big Data Approach for Precision Health

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          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 impact behavior in a prospective longitudinal cohort ( n = 109) enriched for risk of type 2 diabetes mellitus (DM). The cohort underwent integrative Personalized Omics Profiling (iPOP) 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 over 67 clinically actionable health discoveries and identified multiple molecular pathways associated with metabolic, cardiovascular and oncologic pathophysiology. We developed prediction models for insulin resistance using omics measurements illustrating their potential to replace burdensome tests. Finally, study participation lead 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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          Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.

          Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.
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            Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis

            OBJECTIVE To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes. RESEARCH DESIGN AND METHODS We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite. RESULTS We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24–1.48]; I 2 = 9.5%), 36% for leucine (1.36 [1.17–1.58]; I 2 = 37.4%), 35% for valine (1.35 [1.19–1.53]; I 2 = 45.8%), 36% for tyrosine (1.36 [1.19–1.55]; I 2 = 51.6%), and 26% for phenylalanine (1.26 [1.10–1.44]; I 2 = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81–0.96] and 0.85 [0.82–0.89], respectively; both I 2 = 0.0%). CONCLUSIONS In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes.
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              The max-min hill-climbing Bayesian network structure learning algorithm

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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                20 May 2019
                08 May 2019
                May 2019
                08 November 2019
                : 25
                : 5
                : 792-804
                Affiliations
                [1 ]Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
                [2 ]Spinal Cord Injury Service, Veteran Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
                [3 ]Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
                [4 ]Stanford Cardiovascular Institute, Stanford University, Stanford, CA, 94305 USA.
                [5 ]Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305 USA
                [6 ]Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Australia
                [7 ]Department of Electrical Engineering and Computer Sciences, University of California - Berkeley, Berkeley, CA 94720
                [8 ]Department of Bioengineering, University of California - Berkeley, Berkeley, CA 94720
                [9 ]Mobilize Center, Stanford University, Stanford, California, USA, 94305
                [10 ]The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
                [11 ]Department of Medicine, University of Connecticut Health, Farmington, CT 06030, USA
                [12 ]Bakar Computational Health Sciences Institute and Department of Pediatrics, University of California, San Francisco, California 94143, USA
                [13 ]Department of Bioengineering, Stanford University, Stanford CA, 94305, USA
                [14 ]Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA
                [15 ]Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA
                Author notes
                [** ]To whom correspondence should be addressed: mpsnyder@ 123456stanford.edu or fhaddad@ 123456stanford.edu

                Author Contributions

                S.M.S.-F.R., M.P.S., F.H., K.C., K.M., T.M., W.Z. contributed to conceptualization. S.M.S.-F.R., K.C., F.H., M.P.S., T.M., K.M., S.M., W.Z., S.R. contributed to methodology. K.C. (ASCVD biomarkers), D.H. (Lipidomics), A.B.G. (Microbiome DADA2 processing), T.M., M.A., 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., P.L. contributed to data curation. K.C., S.M.S.-F.R., T.M., K.M., F.H., 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., C.R. contributed to formal analysis. S.M.S.-F.R., K.C., M.P.S. contributed to project administration. M.P.S., F.H. contributed to supervision. S.M.S.-F.R., F.H., K.C., K.M., 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., S.A. contributed to review and editing. K.M., F.H., 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., 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., 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. & D.H. (batch correction methodology for proteomics) contributed to iPOP/iHMP omics raw data processing. M.P.S., G.M.W., T.L.M., E.S. contributed to iPOP/iHMP funding acquisition.

                [*]

                These authors contributed equally to this work

                Article
                NIHMS1523412
                10.1038/s41591-019-0414-6
                6713274
                31068711
                29beaa92-a5a2-4a94-a4da-aa73b618a696

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