Objective

Depression is a prevalent disorder difficult to diagnose and treat. In particular, depressed patients exhibit largely unpredictable responses to treatment. Toward the goal of personalizing treatment for depression, we develop and evaluate computational models that use electronic health record (EHR) data for predicting the diagnosis and severity of depression, and response to treatment.

Materials and methods

We develop regression-based models for predicting depression, its severity, and response to treatment from EHR data, using structured diagnosis and medication codes as well as free-text clinical reports. We used two datasets: 35,000 patients (5000 depressed) from the Palo Alto Medical Foundation and 5651 patients treated for depression from the Group Health Research Institute.

Results

Our models are able to predict a future diagnosis of depression up to 12 months in advance (area under the receiver operating characteristic curve (AUC) 0.70-0.80). We can differentiate patients with severe baseline depression from those with minimal or mild baseline depression (AUC 0.72). Baseline depression severity was the strongest predictor of treatment response for medication and psychotherapy.

Conclusions

It is possible to use EHR data to predict a diagnosis of depression up to 12 months in advance and to differentiate between extreme baseline levels of depression. The models use commonly available data on diagnosis, medication, and clinical progress notes, making them easily portable. The ability to automatically determine severity can facilitate assembly of large patient cohorts with similar severity from multiple sites, which may enable elucidation of the moderators of treatment response in the future.

Background

Web-based collaborative approaches to managing chronic illness show promise for both improving health outcomes and increasing the efficiency of the healthcare system.

Objective

Analyze the cost-effectiveness of the Electronic Communications and Home Blood Pressure Monitoring to Improve Blood Pressure Control (e-BP) study, a randomized controlled trial that used a patient-shared electronic medical record, home blood pressure (BP) monitoring, and web-based pharmacist care to improve BP control (<140/90 mm Hg).

Study design

Incremental cost-effectiveness analysis conducted from a health plan perspective.

Methods

Cost-effectiveness of home BP monitoring and web-based pharmacist care estimated for percent change in patients with controlled BP and cost per mm Hg in diastolic and systolic BP relative to usual care and home BP monitoring alone.

Results

A 1% improvement in number of patients with controlled BP using home BP monitoring and web-based pharmacist care-the e-BP program-costs $16.65 (95% confidence interval: 15.37- 17.94) relative to home BP monitoring and web training alone. Each mm HG reduction in systolic and diastolic BP achieved through the e-BP program costs $65.29 (59.91-70.67) relativeto home BP monitoring and web tools only. Life expectancy was increased at an incremental cost of $1850 (1635-2064) and $2220 (1745-2694) per year of life saved for men and women, respectively.

Conclusions

Web-based collaborative care can be used to achieve BP control at a relatively low cost. Future research should examine the cost impact of potential long-term clinical improvements.

A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with mechanistic phenotypes, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fishers p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects and complex disease associations in the same locus.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10^-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10^-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10^-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)_cases = 0.0059, MAF_controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10^-10, OR = 1.43, MAF_cases = 0.011, MAF_controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10^-14, OR = 1.67, MAF_cases = 0.0143, MAF_controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.