Specifying uniform eligibility criteria to strengthen causal inference studies of long-term outcomes of COVID-19 (preprint)

Background: Causal interpretation of findings from existing epidemiological studies on long-term clinical outcomes of coronavirus disease 2019 (COVID-19) may be limited by the choice of comparator (control) group. Objective: We compare two approaches to control group selection (based on requirement for negative SARS-CoV-2 test for eligibility) in long-term clinical outcomes after COVID-19 in patients with history of heart failure (HF). Design: Retrospective cohort study using data from February 1, 2020 to July 31, 2021. Setting: Veteran Health Administration (VHA). Participants: We studied two cohorts of Veterans with COVID-19 and history of HF which selected comparison group using two different approaches. In Cohort I, Veterans with HF who tested for positive for SARS-CoV-2 were age, sex, and race matched to Veterans with no evidence of COVID-19 in 1:5 ratio. In Cohort II Veterans with HF who tested positive for SARS-CoV-2 were age, sex, and race matched with Veterans with HF who tested negative for SARS-CoV-2 within +/-15 days of the positive test date within the same VHA facility. Exposure: COVID-19 as determined by a positive SARS-CoV-2 test. Main Outcomes and Measures: 1-year all-cause mortality and hospital admissions beyond the first 30 days after COVID-19 diagnosis. Adjusted hazard ratios (HRs) accounting for comorbidity and 95% confidence intervals were calculated. Results: Cohort I comprised 13,722 Veterans with HF with COVID-19 (mean [SD] age 72.0 [10.2] years, 2.4% female, 71.1% White) and 60,956 matched controls not known to have COVID-19. Cohort II comprised 6,725 Veterans with HF with COVID-19 (mean [SD] age 72.5 [7.5] years, 0.1% female, 80.8% White) and 6,726 matched controls with negative SARS-CoV-2 test. The adjusted HRs for 1-year mortality and hospital admission beyond the first 30 days after diagnosis of COVID-19 were 1.40 (1.32-1.49) and 1.34 (1.28-1.41), respectively, in analysis of Cohort-I (where the comparator group was not required to test negative for SARS-CoV-2). However, in Cohort-II (using the second comparator group specifying negative SARS-CoV-2 test for eligibility), the associations were markedly attenuated; adjusted HRs 1.05 (0.95-1.17) and 1.07 (0.96-1.19), respectively. Conclusions: We found significant attenuation of associations between COVID-19 and long-term risk of mortality and hospital admissions beyond the first 30 days among patient with existing HF, when comparing with a control group selected based on a negative SARS-CoV-2 test versus control group not known to have COVID-19. The findings have implications for the design of studies of long-term CVD (and non-CVD) outcome of COVID-19.

Polygenic predisposition to venous thromboembolism is associated with increased COVID-19 positive testing rates (preprint)

Genetic predisposition to venous thrombosis may impact COVID-19 infection and its sequelae. Participants in the ongoing prospective cohort study, Million Veteran Program (MVP), who were tested for COVID-19, with European ancestry, were evaluated for associations with polygenic venous thromboembolic risk, Factor V Leiden mutation (FVL) (rs6025) and prothrombin gene 3 -UTR mutation (F2 G20210A)(rs1799963), and their interactions. Logistic regression models assessed genetic associations with VTE diagnosis, COVID-19 (positive) testing rates and outcome severity (modified WHO criteria), and post-test conditions, adjusting for outpatient anticoagulation medication usage, age, sex, and genetic principal components. 108,437 out of 464,961 European American MVP participants were tested for COVID-19 with 9786 (9%) positive. PRS(VTE), FVL, F2 G20210A were not significantly associated with the propensity of being tested for COVID-19. PRS(VTE) was significantly associated with a positive COVID-19 test in F5 wild type (WT) individuals (OR 1.05; 95% CI [1.02-1.07]), but not in FVL carriers (0.97, [0.91-1.94]). There was no association with severe outcome for FVL, F2 G20210A or PRS(VTE). Outpatient anticoagulation usage in the two years prior to testing was associated with worse clinical outcomes. PRS(VTE) was associated with prevalent VTE diagnosis among both FVL carriers or F5 wild type individuals as well as incident VTE in the two years prior to testing. Increased genetic propensity for VTE in the MVP was associated with increased COVID-19 positive testing rates, suggesting a role of coagulation in the initial steps of COVID-19 infection. Key PointsO_LIIncreased genetic predisposition to venous thrombosis is associated with increased COVID-19 positive testing rates. C_LIO_LIPRS for VTE further risk stratifies factor V Leiden carriers regarding their VTE risk. C_LI

A MUC5B gene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection (preprint)

RationaleA common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear. ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI). MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of a MUC5B rs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2, and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions. Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 x 10-5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 x 10-6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement. ConclusionsThe MUC5B variant rs35705950-T is protective in COVID-19 infection.

“Association between Median Household Income, State Medicaid Expansion Status, and COVID-19 Outcomes Across US Counties” (preprint)

Objective The relationship between socioeconomic status and its interaction with State’s Medicaid-expansion policies on COVID-19 outcomes across United States (US) counties are uncertain. To determine the association between median-household-income and its interaction with State Medicaid-expansion status on COVID-19 incidence and mortality in US counties Methods Longitudinal, retrospective analysis of 3142 US counties (including District of Columbia) to study the relationship between County-level median-household-income (defined by US Census Bureau’s Small-Area-Income-and-Poverty-Estimates) and COVID-19 incidence and mortality per 100000 of the population in US counties from January 20, 2020 through December 6, 2020. County median-household-income was log-transformed and stratified by quartiles. Medicaid-expansion status was defined by US State’s Medicaid-expansion adoption as of first reported US COVID-19 infection, January 20, 2020. Multilevel mixed-effects generalized-linear-model with negative binomial distribution and log link function compared quartiles of median-household-income and COVID-19 incidence and mortality, reported as incidence-risk-ratio (IRR) and mortality-risk-ratio (MRR), respectively. Models adjusted for county socio-demographic and comorbidity conditions, population density, and hospitals, with a random intercept for states. Multiplicative interaction tested for Medicaid-expansion*income quartiles on COVID-19 incidence and mortality. Results There was no significant difference in COVID-19 incidence across counties by income quartiles or by Medicaid expansion status. Conversely, significant differences exist between COVID-19 mortality by income quartiles and by Medicaid expansion status. The association between income quartiles and COVID-19 mortality was significant only in counties from non-Medicaid-expansion states but not significant in counties from Medicaid-expansion states (P<0.01 for interaction). For non-Medicaid-expansion states, counties in the lowest income quartile had a 41% increase in COVID-19 mortality compared to counties in the highest income quartile (MRR 1.41, 95% CI: 1.25-1.59). Conclusions and Relevance Median-household-income was not related to COVID-19 incidence but negatively related to COVID-19 mortality in US counties of states without Medicaid-expansion. It was unrelated to COVID-19 mortality in counties of states that adopted Medicaid-expansion. These findings suggest that expanded healthcare coverage should be investigated further to attenuate the excessive COVID-19 mortality risk associated with low-income communities. Key Findings Question Is there a relationship between COVID-19 outcomes (incidence and mortality) and household income and status of Medicaid expansion of US counties? Findings In this longitudinal, retrospective analysis of 3142 US counties, we found no significant difference in COVID-19 incidence across US counties by quartiles of household income. However, counties with lower median household income had a higher risk of COVID-19 mortality, but only in non-Medicaid expansion states. This relationship was not significant in Medicaid expansion states. Meaning Expanded healthcare coverage through Medicaid expansion should be investigated as an avenue to attenuate the excessive COVID-19 mortality risk associated with low-income communities.

Association of Poor Housing Conditions with COVID-19 Incidence and Mortality Across US Counties (preprint)

ObjectivePoor housing conditions have been linked with worse health outcomes and infectious spread in communities but its relationship with incidence and mortality of COVID-19 is unknown. Therefore, we undertook this study to determine the association between poor housing condition and COVID-19 incidence and mortality in US counties. MethodsWe conducted cross-sectional analysis of county-level data from the US Centers for Disease Control, US Census Bureau and John Hopkins Coronavirus Resource Center for 3141 US counties. The exposure of interest was percentage of households with poor housing conditions (one or more of: overcrowding, high housing cost, incomplete kitchen facilities, or incomplete plumbing facilities). Outcomes were incidence rate ratios (IRR) and mortality rate ratios (MRR) of COVID-19 across US counties through 4/21/2020. Multilevel generalized linear modeling was utilized with adjustment for population density and county characteristics including demographics, income, education, prevalence of medical comorbidities, access to healthcare insurance and emergency rooms, and state-level COVID-19 test density. ResultsAcross 3135 US counties, the mean percentage of households with poor housing conditions was 14.2% (range 2.7% to 60.2%). The mean (SD) incidence and mortality of COVID-19 were 255.68 (2877.03) cases and 13.90 (272.22) deaths per county, respectively. In the fully adjusted models, with each 5% increase in percent households with poor housing conditions, there was a 50% higher risk of COVID-19 incidence (IRR 1.50, 95% CI: 1.38 - 1.62) and a 42% higher risk of COVID-19 mortality (MRR 1.42, 95% CI: 1.25 - 1.61). Results remained similar using earlier timepoints (3/31/2020 and 4/10/2020). Conclusions and RelevanceCounties with a higher percentage of households with poor housing had higher incidence of, and mortality associated with, COVID-19. These findings suggest targeted health policies to support individuals living in poor housing conditions should be considered in further efforts to mitigate adverse outcomes associated with COVID-19.