Faculty Bibliography

Time is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID-19. There are currently 876 randomized clinical trials (phase 2 and 3) of treatments for COVID-19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal, and time-to-event) that are common in COVID-19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two-arm, randomized trials comparing a hypothetical COVID-19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time-to-event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital and a Centers for Disease Control and Prevention preliminary description of 2449 cases. In simulated trials with sample sizes ranging from 100 to 1000 participants, we found substantial precision gains from using covariate adjustment-equivalent to 4-18% reductions in the required sample size to achieve a desired power. This was the case for a variety of estimands (targets of inference). From these simulations, we conclude that covariate adjustment is a low-risk, high-reward approach to streamlining COVID-19 treatment trials. We provide an R package and practical recommendations for implementation.

BACKGROUND:Relapse rates during opioid use disorder (OUD) treatment remain unacceptably high. It is possible that optimally matching patients with medication type would reduce risk of relapse. Our objective was to learn a rule by which to assign type of medication for OUD to reduce risk of relapse, and to estimate the extent to which risk of relapse would be reduced if such a rule were used. METHODS:This was a secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial of injection extended-release naltrexone (XR-NTX), delivered approximately every 28 days, or daily sublingual buprenorphine-naloxone (BUP-NX) for treating OUD, 2014-2017 (N = 570). Outcome was a binary indicator of relapse to regular opioid use during the 24 weeks of outpatient treatment. RESULTS:We found that applying an estimated individualized treatment rule-i.e., a rule that assigns patients with OUD to either XR-NTX or BUP-NX based on their individual characteristics in such a way that risk of relapse is minimized-would reduce risk of relapse by 24 weeks by 12% compared to randomly assigned treatment. CONCLUSIONS:The number-needed-to-treat with the estimated treatment rule to prevent a single relapse is 14. A simpler, alternative estimated rule in which homeless participants would be treated with XR-NTX and stably housed participants would be treated with BUP-NX performed similarly. These results provide an estimate of the amount by which a relatively simple change in clinical practice could be expected to improve prevention of OUD relapse.

BACKGROUND AND AIMS:A recent study found that homeless individuals with opioid use disorder (OUD) had a lower risk of relapse on extended-release naltrexone (XR-NTX) versus buprenorphine-naloxone (BUP-NX), whereas non-homeless individuals had a lower risk of relapse on BUP-NX. This secondary study examined differences in mediation pathways to medication effect between homeless and non-homeless participants. DESIGN:Secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial, 2014-17. SETTING:Eight community addiction treatment programs in the United States. PARTICIPANTS:English-speaking adults with DSM-5 OUD, recruited during inpatient admission (n = 570). INTERVENTION(S):Randomization to monthly injection of XR-NTX or daily sublingual BUP-NX. MEASUREMENTS(S):Mediation analysis estimated the direct effect of XR-NTX versus BUP-NX on relapse and indirect effect through mediators of medication adherence, use of illicit opioids, depressive symptoms and pain, separately by homeless status. FINDINGS:For the homeless subgroup, the protective indirect path contributed a 3.4 percentage point reduced risk of relapse [95% confidence interval (CI) = -12.0, 5.3] comparing XR-NTX to BUP-NX (explaining 21% of the total effect). For the non-homeless subgroup, the indirect path contributed a 9.4 percentage point increased risk of relapse (95% CI = 3.1, 15.7) comparing XR-NTX to BUP-NX (explaining 57% of the total effect). CONCLUSIONS:A novel approach to mediation analysis shows that much of the difference in medication effectiveness (extended-release naltrexone versus buprenorphine-naloxone) on opioid relapse among non-homeless adults with opioid use disorder appears to be explained by mediators of adherence, illicit opioid use, depressive symptoms and pain.

Background and Purpose:Mechanical thrombectomy helps prevent disability in patients with acute ischemic stroke involving occlusion of a large cerebral vessel. Thrombectomy requires procedural expertise and not all hospitals have the staff to perform this intervention. Few population-wide data exist regarding access to mechanical thrombectomy. Methods:We examined access to thrombectomy for ischemic stroke using discharge data from calendar years 2016 to 2018 from all nonfederal emergency departments and acute care hospitals across 11 US states encompassing 80 million residents. Facilities were classified as hubs if they performed mechanical thrombectomy, gateways if they transferred patients who ultimately underwent mechanical thrombectomy, and gaps otherwise. We used standard descriptive statistics and unadjusted logistic regression models in our primary analyses. Results:Among 205 681 patients with ischemic stroke, 100 139 (48.7% [95% CI, 48.5%–48.9%]) initially received care at a thrombectomy hub, 72 534 (35.3% [95% CI, 35.1%–35.5%]) at a thrombectomy gateway, and 33 008 (16.0% [95% CI, 15.9%–16.2%]) at a thrombectomy gap. Patients who initially received care at thrombectomy gateways were substantially less likely to ultimately undergo thrombectomy than patients who initially received care at thrombectomy hubs (odds ratio, 0.27 [95% CI, 0.25–0.28]). Rural patients had particularly limited access: 27.7% (95% CI, 26.9%–28.6%) of such patients initially received care at hubs versus 69.5% (95% CI, 69.1%–69.9%) of urban patients. For 93.8% (95% CI, 93.6%–94.0%) of patients with stroke at gateways, their initial facility was capable of delivering intravenous thrombolysis, compared with 76.3% (95% CI, 75.8%–76.7%) of patients at gaps. Our findings were unchanged in models adjusted for demographics and comorbidities and persisted across multiple sensitivity analyses, including analyses adjusting for estimated stroke severity. Conclusions:We found that a substantial proportion of patients with ischemic stroke across the United States lacked access to thrombectomy even after accounting for interhospital transfers. US systems of stroke care require further development to optimize thrombectomy access.

Importance:Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown. Objective:To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction. Design, Setting, and Participants:An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020. Exposure:Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria. Main Outcomes and Measures:The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications. Results:Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1). Conclusions and Relevance:This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

BACKGROUND:Interventions can have harmful effects among subgroups they intend to help. The Moving To Opportunity experiment, in which families were randomized to receive a Section 8 housing voucher, was one example. Voucher receipt generally resulted in better long-term mental health and lower substance use and risk behavior outcomes among adolescent girls, but resulted in worse outcomes among adolescent boys. Reasons for this discrepancy and the unintended harmful health effects for boys are unclear. We used mediation analysis to estimate processes through which voucher receipt was hypothesized to affect adolescent mental health and substance use. METHODS:We used longitudinal data (10-15 years) on boys enrolled in Moving To Opportunity. We estimated interventional (also known as stochastic) indirect effects of voucher receipt on mental health and substance use outcomes through mediators capturing aspects of the school environment, neighborhood poverty, and instability of the social environment. We also estimated interventional direct effects not operating through these mediators. We used a robust, efficient, nonparametric substitution estimator in the targeted minimum loss-based framework. RESULTS:Housing voucher receipt increased long-term risk of any diagnostic statistical manual disorder, any mood disorder, any externalizing disorder, and cigarette smoking among boys. The majority (between 69% and 90%) of the total negative long-term effects could be explained by indirect effects through the mediators considered. CONCLUSIONS:This evidence suggests that, even though the intervention had the desired effects on neighborhood poverty and the school environment, these "positives" ultimately negatively impacted the long-term mental health and behaviors of boys.

BACKGROUND:There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. METHODS:P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. RESULTS:P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. CONCLUSION/CONCLUSIONS:In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. TRIAL REGISTRATION/BACKGROUND: ClinicalTrials.gov NCT01969344 (SPIROMICS).