Data_Sheet_1_The Laboratory-Based Intermountain Validated Exacerbation (LIVE) Score Identifies Chronic Obstructive Pulmonary Disease Patients at High Mortality Risk.docx

<p>Background: Identifying COPD patients at high risk for mortality or healthcare utilization remains a challenge. A robust system for identifying high-risk COPD patients using Electronic Health Record (EHR) data would empower targeting interventions aimed at ensuring guideline compliance and multimorbidity management. The purpose of this study was to empirically derive, validate, and characterize subgroups of COPD patients based on routinely collected clinical data widely available within the EHR.</p><p>Methods: Cluster analysis was used in 5,006 patients with COPD at Intermountain to identify clusters based on a large collection of clinical variables. Recursive Partitioning (RP) was then used to determine a preferred tree that assigned patients to clusters based on a parsimonious variable subset. The mortality, COPD exacerbations, and comorbidity profile of the identified groups were examined. The findings were validated in an independent Intermountain cohort and in external cohorts from the United States Veterans Affairs (VA) and University of Chicago Medicine systems.</p><p>Measurements and Main Results: The RP algorithm identified five LIVE Scores based on laboratory values: albumin, creatinine, chloride, potassium, and hemoglobin. The groups were characterized by increasing risk of mortality. The lowest risk, LIVE Score 5 had 8% 4-year mortality vs. 56% in the highest risk LIVE Score 1 (p < 0.001). These findings were validated in the VA cohort (n = 83,134), an expanded Intermountain cohort (n = 48,871) and in the University of Chicago system (n = 3,236). Higher mortality groups also had higher COPD exacerbation rates and comorbidity rates.</p><p>Conclusions: In large clinical datasets across different organizations, the LIVE Score utilizes existing laboratory data for COPD patients, and may be used to stratify risk for mortality and COPD exacerbations.</p

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship

<div><p>Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate <i>LSAMP</i> SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two <i>LSAMP</i> SNPs—rs1462845 and rs6788787—using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; <i>n</i> = 2,224) and the Intermountain Heart Collaborative Study (IMHC; <i>n</i> = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (<i>HR</i> = 1.11, 95%<i>CI</i> = 1.01–1.22, <i>p</i> = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (<i>HR</i> = 0.80, 95% <i>CI</i> = 0.69–0.92, <i>p</i> = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (<i>HR</i> = 1.29, <i>95% CI</i> = 1.08–1.55, <i>p</i> = 0.00456; replication <i>HR</i> = 1.25, <i>95% CI</i> = 1.05–1.49, <i>p</i> = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype (‘A/A’) fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.</p></div

Kaplan–Meier survival curves for CATHGEN males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). Only after controlling for covariates was this model significant for reduced hazards of death by genotype (<i>HR</i> = 0.71, <i>95% CI</i> = 0.54–0.93, <i>p</i> = 0.0148, additive genetic model).</p

Hazards of Death in Caucasian Control Subjects.

<p>Hazards of Death in Caucasian Control Subjects.</p

Post-hoc Power Analyses.

<p>Post-hoc Power Analyses.</p

Kaplan–Meier survival curves for IMHC males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). This model did not demonstrate significant genotype effects on survival probability (<i>HR</i> = 1.04, <i>95% CI</i> = 0.83–1.29, <i>p</i> = 0.752, additive genetic model).</p

Kaplan–Meier survival curves for CATHGEN males with severe CAD by genotype for <i>LSAMP</i> SNP rs1462845.

<p><i>X</i>-axis displays the number of days from index catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan-Meier survival probability by genotype. G is the minor allele; AA, wild-type genotype (reference; black curve); AG, heterozygous genotype (blue curve); and GG, risk homozygous genotype (red curve). Hazards of all-cause mortality were significant for each addition of the G risk allele (<i>HR</i> = 1.39, <i>95% CI</i> = 1.16–1.66, <i>p</i> = 0.0003, additive genetic model).</p

Kaplan–Meier survival curves for 5a) CATHGEN and 5b) IMHC Caucasian control subjects by genotype for LSAMP SNP rs1462845.

<p><i>X</i>-axis displays the number of days from index catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan-Meier survival probability by genotype. G is the minor allele; AA, wild-type genotype (reference; black curve); AG, heterozygous genotype (blue curve); and GG, risk homozygous genotype (red curve). No significant differences were found in any statistical modeling (data not shown).</p

Kaplan–Meier survival curves for IMHC males with severe CAD by genotype for <i>LSAMP</i> SNP rs6788787.

<p><i>X</i>-axis displays the number of days from catheterization to death (all-cause mortality). <i>Y</i>-axis displays the Kaplan–Meier survival probability by genotype. A is the minor allele; GG, wild-type genotype (reference; black curve); GA, heterozygous genotype; and AA, risk homozygous genotype (red curve). No significant differences were found in any statistical modeling (data not shown).</p

Hazards of Death by SNP (Additive) in Caucasian Males with Severe Burden of CAD.

<p>Hazards of Death by SNP (Additive) in Caucasian Males with Severe Burden of CAD.</p