A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers.

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.

Temporal Poisson Square Root Graphical Models.

We propose temporal Poisson square root graphical models (TPSQRs), a generalization of Poisson square root graphical models (PSQRs) specifically designed for modeling longitudinal event data. By estimating the temporal relationships for all possible pairs of event types, TPSQRs can offer a holistic perspective about whether the occurrences of any given event type could excite or inhibit any other type. A TPSQR is learned by estimating a collection of interrelated PSQRs that share the same template parameterization. These PSQRs are estimated jointly in a pseudo-likelihood fashion, where Poisson pseudo-likelihood is used to approximate the original more computationally-intensive pseudo-likelihood problem stemming from PSQRs. Theoretically, we demonstrate that under mild assumptions, the Poisson pseudo-likelihood approximation is sparsistent for recovering the underlying PSQR. Empirically, we learn TPSQRs from Marshfield Clinic electronic health records (EHRs) with millions of drug prescription and condition diagnosis events, for adverse drug reaction (ADR) detection. Experimental results demonstrate that the learned TPSQRs can recover ADR signals from the EHR effectively and efficiently.