Faculty Bibliography

Most signals in genome-wide association studies (GWAS) of complex traits implicate noncoding genetic variants with putative gene regulatory effects. However, currently identified regulatory variants, notably expression quantitative trait loci (eQTLs), explain only a small fraction of GWAS signals. Here, we show that GWAS and cis-eQTL hits are systematically different: eQTLs cluster strongly near transcription start sites, whereas GWAS hits do not. Genes near GWAS hits are enriched in key functional annotations, are under strong selective constraint and have complex regulatory landscapes across different tissue/cell types, whereas genes near eQTLs are depleted of most functional annotations, show relaxed constraint, and have simpler regulatory landscapes. We describe a model to understand these observations, including how natural selection on complex traits hinders discovery of functionally relevant eQTLs. Our results imply that GWAS and eQTL studies are systematically biased toward different types of variant, and support the use of complementary functional approaches alongside the next generation of eQTL studies.

Indiscriminate use of predictive models incorporating race can reinforce biases present in source data and lead to an exacerbation of health disparities. In some countries, such as the United States, there is therefore a push to remove race from prediction models; however, there are still many prediction models that use race as an input. Biomedical informaticists who are given the responsibility of using these predictive models in healthcare environments are likely to be faced with questions like how to deal with race covariates in these models. Thus, there is a need for a pragmatic framework to help model users think through how to include race in their chosen model so as to avoid inadvertently exacerbating disparities. In this paper, we use the case study of lung cancer screening to propose a simple framework to guide how model users can approach the use (or non-use) of race inputs in the predictive models they are tasked with leveraging in electronic health records and clinical workflows.

BACKGROUND/UNASSIGNED:Sleep difficulties are common in pregnancy, yet poor prenatal sleep may be related to negative long-term outcomes for the offspring, including risk for attention-deficit/hyperactivity disorder (ADHD). Existing studies are few and have not examined timing of exposure effects or offspring sex moderation. We thus aimed to test the hypotheses that poor sleep health in pregnancy is associated with increased risk for ADHD symptoms and offspring sleep problems at approximately 4 years of age. METHODS/UNASSIGNED:Participants were 794 mother-child dyads enrolled in the NIH Environmental Influences on Child Health Outcomes Study (ECHO). Participants self-reported on sleep duration, quality, and disturbances during pregnancy and on children's ADHD symptoms and sleep problems on the Child Behaviour Checklist. FINDINGS/UNASSIGNED: = 0.026). We did not document substantial offspring sex moderation. INTERPRETATION/UNASSIGNED:Poor prenatal sleep health, particularly quality and duration in the second trimester, may be associated with offspring risk of neurodevelopmental disorders and sleep problems in early childhood. Further research is needed to understand mechanisms, yet our study suggests that prenatal maternal sleep may be a modifiable target for interventions aimed at optimizing early neurodevelopment. FUNDING/UNASSIGNED:NIH grants U2COD023375, U24OD023382, U24OD023319, UH3OD023320, UH3OD023305, UH3OD023349, UH3OD023313, UH3OD023272, UH3OD023328, UH3OD023290, K08MH117452 and NARSAD Young Investigator Award 28545.

Exposure to phthalates, used as plasticizers and solvents in consumer products, is ubiquitous. Despite growing concerns regarding their neurotoxicity, brain differences associated with gestational exposure to phthalates are understudied. We included 775 mother-child pairs from Generation R, a population-based pediatric neuroimaging study with prenatal recruitment, who had data on maternal gestational phthalate levels and T₁-weighted magnetic resonance imaging in children at age 10 years. Maternal urinary concentrations of phthalate metabolites were measured at early, mid-, and late pregnancy. Child IQ was assessed at age 14 years. We investigated the extent to which prenatal exposure to phthalates is associated with brain volumetric measures and whether brain structural measures mediate the association of prenatal phthalate exposure with IQ. We found that higher maternal concentrations of monoethyl phthalate (mEP, averaged across pregnancy) were associated with smaller total gray matter volumes in offspring at age 10 years (β per log10 increase in creatinine adjusted mEP = -10.7, 95%CI: -18.12, -3.28). Total gray matter volumes partially mediated the association between higher maternal mEP and lower child IQ (β for mediated path =-0.31, 95%CI: -0.62, 0.01, p = 0.05, proportion mediated = 18%). An association of higher monoisobutyl phthalate (mIBP) and smaller cerebral white matter volumes was present only in girls, with cerebral white matter volumes mediating the association between higher maternal mIBP and lower IQ in girls. Our findings suggest the global impact of prenatal phthalate exposure on brain volumetric measures that extends into adolescence and underlies less optimal cognitive development.

OBJECTIVES:Few studies have considered how trends in opioid poisonings have changed among older adults. The objective of this study was to examine trends in fatal and nonfatal opioid-related poisonings ("exposures") among older adults. METHODS:National poison center data were used to examine trends in characteristics of reported exposures to commonly prescribed opioids between 2015 and 2021 among adults 60 years or older. We estimated the proportion of opioid exposures by demographic characteristics, the specific opioid(s) involved, exposure type, route of administration, other substances co-used, and medical outcomes for each calendar year. We estimated whether there were linear changes in prevalence by year using logistic regression. RESULTS:Although there was a decrease in the number of opioid exposures within the study population from 7706 in 2015 to 7337 in 2021 (a 4.8% decrease, P = 0.04), exposures increased for adults aged 70 to 79 years (a 14.0% increase, P < 0.001). The proportion classified as "abuse" increased by 63.3% ( P < 0.001). There were significant decreases in the proportion involving hydromorphone (a 23.3% decrease, P < 0.001) and morphine (a 22.0% decrease, P < 0.001), with an increase involving buprenorphine (a 216.0% increase, P < 0.001). The proportion increased for co-use of cocaine (a 488.9% increase, P < 0.001) and methamphetamine (a 220.0% increase, P = 0.02), with a decrease in co-use of benzodiazepines (a 25.5% decrease, P < 0.001). The proportion of major medical outcomes increased by 93.9% ( P < 0.001). CONCLUSIONS:National patterns of opioid-related poisonings are shifting among older adults, including the types of opioids involved and co-use of other drugs. These results can inform prevention and harm reduction efforts aimed at older adults.

BACKGROUND:Cannabis use disorder is associated with considerable comorbidity and impairment in functioning, and prevalence is increasing among adults with chronic pain. We aimed to assess the effect of introduction of medical cannabis laws (MCL) and recreational cannabis laws (RCL) on the increase in cannabis use disorder among patients in the US Veterans Health Administration (VHA). METHODS:Data from patients with one or more primary care, emergency, or mental health visit to the VHA in 2005-19 were analysed using 15 repeated cross-sectional VHA electronic health record datasets (ie, one dataset per year). Patients in hospice or palliative care were excluded. Patients were stratified as having chronic pain or not using an American Pain Society taxonomy of painful medical conditions. We used staggered-adoption difference-in-difference analyses to estimate the role of MCL and RCL enactment in the increases in prevalence of diagnosed cannabis use disorder and associations with presence of chronic pain, accounting for the year that state laws were enacted. We did this by fitting a linear binomial regression model stratified by pain, with time-varying cannabis law status, fixed effects for state, categorical year, time-varying state-level sociodemographic covariates, and patient covariates (age group [18-34 years, 35-64 years, and 65-75 years], sex, and race and ethnicity). FINDINGS:Between 2005 and 2019, 3 234 382-4 579 994 patients were included per year. Among patients without pain in 2005, 5·1% were female, mean age was 58·3 (SD 12·6) years, and 75·7%, 15·6%, and 3·6% were White, Black, and Hispanic or Latino, respectively. In 2019, 9·3% were female, mean age was 56·7 (SD 15·2) years, and 68·1%, 18·2%, and 6·5% were White, Black, and Hispanic or Latino, respectively. Among patients with pain in 2005, 7·1% were female, mean age was 57·2 (SD 11·4) years, and 74·0%, 17·8%, and 3·9% were White, Black, and Hispanic or Latino, respectively. In 2019, 12·4% were female, mean age was 57·2 (SD 13·8) years, and 65·3%, 21·9%, and 7·0% were White, Black, and Hispanic or Latino, respectively. Among patients with chronic pain, enacting MCL led to a 0·135% (95% CI 0·118-0·153) absolute increase in cannabis use disorder prevalence, with 8·4% of the total increase in MCL-enacting states attributable to MCL. Enacting RCL led to a 0·188% (0·160-0·217) absolute increase in cannabis use disorder prevalence, with 11·5% of the total increase in RCL-enacting states attributable to RCL. In patients without chronic pain, enacting MCL and RCL led to smaller absolute increases in cannabis use disorder prevalence (MCL: 0·037% [0·027-0·048], 5·7% attributable to MCL; RCL: 0·042% [0·023-0·060], 6·0% attributable to RCL). Overall, associations of MCL and RCL with cannabis use disorder were greater in patients with chronic pain than in patients without chronic pain. INTERPRETATION:Increasing cannabis use disorder prevalence among patients with chronic pain following state legalisation is a public health concern, especially among older age groups. Given cannabis commercialisation and widespread public beliefs about its efficacy, clinical monitoring of cannabis use and discussion of the risk of cannabis use disorder among patients with chronic pain is warranted. FUNDING:NIDA grant R01DA048860, New York State Psychiatric Institute, and the VA Centers of Excellence in Substance Addiction Treatment and Education.

Enhancing access to care using telehealth is a priority for improving outcomes among older adults with heart failure, increasing quality of care, and decreasing costs. Telehealth has the potential to increase access to care for patients who live in underresourced geographic regions, have physical disabilities or poor access to transportation, and may not otherwise have access to cardiologists with expertise in heart failure. During the COVID-19 pandemic, access to telehealth expanded, and yet barriers to access, including broadband inequality, low digital literacy, and structural barriers, prevented many of the disadvantaged patients from getting equitable access. Using a health equity lens, this scientific statement reviews the literature on telehealth for older adults with heart failure; provides an overview of structural, organizational, and personal barriers to telehealth; and presents novel interventions that pair telemedicine with in-person services to mitigate existing barriers and structural inequities.

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10^-5 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p_prefrailty  = 1 × 10^-15 , p_frailty  = 2 × 10^-19 ), transgelin (TAGLN; p_prefrailty  = 2 × 10^-12 , p_frailty  = 6 × 10^-22 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p_prefrailty  = 5 × 10^-15 , p_frailty  = 1 × 10^-15 ) and with a lower level of growth hormone receptor (GHR, p_prefrailty  = 3 × 10^-16 , p_frailty  = 2 × 10^-18 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10^-5 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.