Faculty Bibliography

The discrete-time Wright-Fisher (DTWF) model and its diffusion limit are central to population genetics. These models can describe the forward-in-time evolution of allele frequencies in a population resulting from genetic drift, mutation, and selection. Computing likelihoods under the diffusion process is feasible, but the diffusion approximation breaks down for large samples or in the presence of strong selection. Existing methods for computing likelihoods under the DTWF model do not scale to current exome sequencing sample sizes in the hundreds of thousands. Here, we present a scalable algorithm that approximates the DTWF model with provably bounded error. Our approach relies on two key observations about the DTWF model. The first is that transition probabilities under the model are approximately sparse. The second is that transition distributions for similar starting allele frequencies are extremely close as distributions. Together, these observations enable approximate matrix-vector multiplication in linear (as opposed to the usual quadratic) time. We prove similar properties for Hypergeometric distributions, enabling fast computation of likelihoods for subsamples of the population. We show theoretically and in practice that this approximation is highly accurate and can scale to population sizes in the tens of millions, paving the way for rigorous biobank-scale inference. Finally, we use our results to estimate the impact of larger samples on estimating selection coefficients for loss-of-function variants. We find that increasing sample sizes beyond existing large exome sequencing cohorts will provide essentially no additional information except for genes with the most extreme fitness effects.

IMPORTANCE/UNASSIGNED:After the initial disruption from the COVID-19 pandemic, it is unclear how patterns of e-cigarette use in the US have changed. OBJECTIVE/UNASSIGNED:To examine recent patterns in current and daily e-cigarette use among US adults in 2021. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional study used data from the 2021 Behavioral Risk Factor Surveillance System (BRFSS) database. The BRFSS is the largest national telephone-based survey of randomly sampled adults in the US. Adults aged 18 years or older, residing in 49 US states (all except Florida), the District of Columbia, and 3 US territories (Guam, Puerto Rico, and the US Virgin Islands), were included in the data set. Data analysis was performed in January 2023. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The main outcome was age-adjusted prevalence of current and daily e-cigarette use overall and by participant characteristics, state, and territory. Descriptive statistical analysis was conducted, applying weights to account for population representation. RESULTS/UNASSIGNED:This study included 414 755 BRFSS participants with information on e-cigarette use. More than half of participants were women (51.3%). In terms of race and ethnicity, 0.9% of participants were American Indian or Alaska Native, 5.8% were Asian, 11.5% were Black, 17.3% were Hispanic, 0.2% were Native Hawaiian or Other Pacific Islander, 62.2% were White, 1.4% were of multiple races or ethnicities, and 0.6% were of other race or ethnicity. Individuals aged 18 to 24 years comprised 12.4% of the study population. The age-standardized prevalence of current e-cigarette use was 6.9% (95% CI, 6.7%-7.1%), with almost half of participants using e-cigarettes daily (3.2% [95% CI, 3.1%-3.4%]). Among individuals aged 18 to 24 years, there was a consistently higher prevalence of e-cigarette use, with more than 18.6% reporting current use and more than 9.0% reporting daily use. Overall, among individuals reporting current e-cigarette use, 42.2% (95% CI, 40.7%-43.7%) indicated former combustible cigarette use, 37.1% (95% CI, 35.6%-38.6%) indicated current combustible cigarette use, and 20.7% (95% CI, 19.7%-21.8%) indicated never using combustible cigarettes. Although relatively older adults (aged ≥25 years) who reported current e-cigarette use were more likely to report former or current combustible cigarette use, younger adults (aged 18-24 years) were more likely to report never using combustible cigarettes. Notably, the proportion of individuals who reported current e-cigarette use and never using combustible cigarettes was higher in the group aged 18 to 20 years (71.5% [95% CI, 66.8%-75.7%]) compared with those aged 21 to 24 years (53.0% [95% CI, 49.8%-56.1%]). CONCLUSION AND RELEVANCE/UNASSIGNED:These findings suggest that e-cigarette use remained common during the COVID-19 pandemic, particularly among young adults aged 18 to 24 years (18.3% prevalence). Notably, 71.5% of individuals aged 18 to 20 years who reported current e-cigarette use had never used combustible cigarettes. These results underscore the rationale for the implementation and enforcement of public health policies tailored to young adults.

CONTEXT/BACKGROUND:Children with medical complexity (CMC) are at risk for adverse outcomes after discharge. Difficulties with comprehension of and adherence to discharge instructions contribute to these errors. Comprehensive reviews of patient-, caregiver-, provider-, and system-level characteristics and interventions associated with discharge instruction comprehension and adherence for CMC are lacking. OBJECTIVE:To systematically review the literature related to factors associated with comprehension of and adherence to discharge instructions for CMC. DATA SOURCES/METHODS:PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, Web of Science (database initiation until March 2023), and OAIster (gray literature) were searched. STUDY SELECTION/METHODS:Original studies examining caregiver comprehension of and adherence to discharge instructions for CMC (Patient Medical Complexity Algorithm) were evaluated. DATA EXTRACTION/METHODS:Two authors independently screened titles/abstracts and reviewed full-text articles. Two authors extracted data related to study characteristics, methodology, subjects, and results. RESULTS:Fifty-one studies were included. More than half were qualitative or mixed methods studies. Few interventional studies examined objective outcomes. More than half of studies examined instructions for equipment (eg, tracheostomies). Common issues related to access, care coordination, and stress/anxiety. Facilitators included accounting for family context and using health literacy-informed strategies. LIMITATIONS/CONCLUSIONS:No randomized trials met inclusion criteria. Several groups (eg, oncologic diagnoses, NICU patients) were not examined in this review. CONCLUSIONS:Multiple factors affect comprehension of and adherence to discharge instructions for CMC. Several areas (eg, appointments, feeding tubes) were understudied. Future work should focus on design of interventions to optimize transitions.

BACKGROUND:Drinking water is a common source of exposure to inorganic arsenic. In the US, the Safe Drinking Water Act (SDWA) was enacted to protect consumers from exposure to contaminants, including arsenic, in public water systems (PWS). The reproductive effects of preconception and prenatal arsenic exposure in regions with low to moderate arsenic concentrations are not well understood. OBJECTIVES:This study examined associations between preconception and prenatal exposure to arsenic violations in water, measured via residence in a county with an arsenic violation in a regulated PWS during pregnancy, and five birth outcomes: birth weight, gestational age at birth, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). METHODS:Data for arsenic violations in PWS, defined as concentrations exceeding 10 parts per billion, were obtained from the Safe Drinking Water Information System. Participants of the Environmental influences on Child Health Outcomes Cohort Study were matched to arsenic violations by time and location based on residential history data. Multivariable, mixed effects regression models were used to assess the relationship between preconception and prenatal exposure to arsenic violations in drinking water and birth outcomes. RESULTS:Compared to unexposed infants, continuous exposure to arsenic from three months prior to conception through birth was associated with 88.8 g higher mean birth weight (95% CI: 8.2, 169.5), after adjusting for individual-level confounders. No statistically significant associations were observed between any preconception or prenatal violations exposure and gestational age at birth, preterm birth, SGA, or LGA. CONCLUSIONS:Our study did not identify associations between preconception and prenatal arsenic exposure, defined by drinking water exceedances, and adverse birth outcomes. Exposure to arsenic violations in drinking water was associated with higher birth weight. Future studies would benefit from more precise geodata of water system service areas, direct household drinking water measurements, and exposure biomarkers.

BACKGROUND:Sickle cell trait affects approximately 8% of Black individuals in the United States, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests that sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including kidney failure. The mechanisms underlying these associations remain poorly understood. We used proteomic profiling to gain insight into the pathobiology of sickle cell trait. METHODS:We measured proteomics ( N =1285 proteins assayed by Olink Explore) using baseline plasma samples from 592 Black participants with sickle cell trait and 1:1 age-matched Black participants without sickle cell trait from the prospective Women's Health Initiative cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait. RESULTS:In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in Black participants from two independent cohorts (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are known biomarkers of kidney function or injury ( e.g. , hepatitis A virus cellular receptor 1 [HAVCR1]/kidney injury molecule-1 [KIM-1], uromodulin [UMOD], ephrins), related to red cell physiology or hemolysis (erythropoietin [EPO], heme oxygenase 1 [HMOX1], and α -hemoglobin stabilizing protein) and/or inflammation (fractalkine, C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 [MCP-1], and urokinase plasminogen activator surface receptor [PLAUR]). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during Women's Health Initiative follow-up (odds ratio, 1.32; 95% confidence interval, 1.10 to 1.58). CONCLUSIONS:We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.

BACKGROUND:Reporting race and ethnicity in clinical trial publications is critical for determining the generalizability and effectiveness of new treatments. This is particularly important for breast cancer, in which Black women have been shown to have between 40 and 100% higher mortality rate yet are underrepresented in trials. Our objective was to describe changes over time in the reporting of race/ethnicity in breast trial publications. PATIENTS AND METHODS/METHODS:We searched ClinicalTrials.gov to identify the primary publication linked to trials with results posted from May 2010-2022. Statistical analysis included summed frequencies and a linear regression model of the proportion of articles reporting race/ethnicity and the proportion of non-White enrollees over time. RESULTS:A proportion of 72 of the 98 (73.4%) studies that met inclusion criteria reported race/ethnicity. In a linear regression model of the proportion of studies reporting race/ethnicity as a function of time, there was no statistically significant change, although we detected a signal toward a decreasing trend (coefficient for quarter = -2.2, p = 0.2). Among all studies reporting race and ethnicity over the study period, the overall percentage of non-White enrollees during the study period was 21.9%, [standard error (s.e.) 1.8, 95% confidence interval (CI) 18.4, 25.5] with a signal towards a decreasing trend in Non-White enrollment [coefficient for year-quarter = -0.8 (p = 0.2)]. CONCLUSION/CONCLUSIONS:Our data demonstrate that both race reporting and overall representation of minority groups in breast cancer clinical trials did not improve over the last 12 years and may have, in fact, decreased. Increased reporting of race and ethnicity data forces the medical community to confront disparities in access to clinical trials. This may improve efforts to recruit and retain members of minority groups in clinical trials, and over time, reduce racial disparities in oncologic outcomes.

Despite higher chronic disease prevalence, minoritized populations live in highly walkable neighborhoods in US cities more frequently than non-minoritized populations. We investigated whether city-level racial residential segregation (RRS) was associated with city-level walkability, stratified by population density, possibly explaining this counterintuitive association. RRS for Black-White and Latino-White segregation in large US cities was calculated using the Index of Dissimilarity (ID), and walkability was measured using WalkScore. Median walkability increased across increasing quartiles of population density, as expected. Higher ID was associated with higher walkability; associations varied in strength across strata of population density. RRS undergirds the observed association between walkability and minoritized populations, especially in higher population density cities.

BACKGROUND:The projected increase in extreme heat days is a growing public health concern. While exposure to extreme heat has been shown to negatively affect mortality and physical health, very little is known about its long-term consequences for late-life cognitive function. We examined whether extreme heat exposure is associated with cognitive decline among older adults and whether this association differs by race/ethnicity and neighbourhood socioeconomic status. METHODS:Data were drawn from seven waves of the Health and Retirement Study (2006-2018) merged with historical temperature data. We used growth curve models to assess the role of extreme heat exposure on trajectories of cognitive function among US adults aged 52 years and older. RESULTS:We found that high exposure to extreme heat was associated with faster cognitive decline for blacks and residents of poor neighbourhoods, but not for whites, Hispanics or residents of wealthier neighbourhoods. CONCLUSION/CONCLUSIONS:Extreme heat exposure can disproportionately undermine cognitive health in later life for socially vulnerable populations. Our findings underscore the need for policy actions to identify and support high-risk communities for increasingly warming temperatures.