Faculty Bibliography

Copula-based approaches can be useful in multivariate modeling settings where multivariate dependency is of primary interest, such as estimating the reliability of self-reported sexual behavior assessed independently for male and female partners (dyad) in a couple-based HIV risk reduction study. Specifically, we investigate the reliability of couple reports using copulas, adjusting for key individual baseline covariates. We propose applying a copula modeling approach to measure the reliability of self-reported, shared sexual behaviors from couples where measures are assessed independently from male and female partners. In particular, we estimate measures of dependence, such as the odds ratios and binary correlations, using mixtures of max-infinitely divisible copulas with a bivariate logit model. This approach is flexible in measuring the effect of covariates on dependence parameters and for estimating marginal probabilities for multiple outcomes simultaneously. In this paper, we focus on estimating these two dependencies and explore the influences of additional covariate information on the copula parameter. We provide simulation results comparing copula-based estimates to moment estimates of the generalized estimating equation (GEE) for the correlation coefficients with respect to bias and 95% coverage probability. We illustrate that copulas have better performance in terms of bias, while their performance is similar with respect to efficiency. The estimator of the marginal probability using copula methods is robust to the choice of copula family. The choice of copula may affect the estimator of dependency when the dependency of the outcomes is very low. We apply these methods to data from the Multisite HIV/STD Prevention Trial for African American Couples (AAC) Study.

Introduction. High BMI is a risk factor for upper body breast cancer-related lymphedema (BCRL) onset. Black cancer survivors are more likely to have high BMI than White cancer survivors. While observational analyses suggest up to 2.2 times increased risk of BCRL onset for Black breast cancer survivors, no studies have explored race or other social factors that may affect BCRL severity, operationalized by interlimb volume difference (ILD). Materials and Methods. ILD was measured by perometry for 296 overweight (25 > BMI < 50) Black (n = 102) or White (n = 194) breast cancer survivors (>6 months from treatment) in the WISER Survivor trial. Multivariable linear regression examined associations between social and physical factors and ILD. Results. Neither Black race (-0.26, p = 0.89) nor BMI (0.22, p = 0.10) was associated with ILD. Attending college (-4.89, p = 0.03) was the strongest factor associated with ILD, followed by having more lymph nodes removed (4.75, p = 0.01), >25% BCRL care adherence (4.10, p = 0.01), and years since treatment (0.55, p < 0.001). Discussion. Neither race nor BMI was associated with ILD among overweight cancer survivors. Education, a proxy for resource level, was the strongest factor associated with greater ILD. Tailoring physical activity and weight loss interventions designed to address BCRL severity by resource rather than race should be considered.

IMPORTANCE: Financial incentives to physicians or patients are increasingly used, but their effectiveness is not well established. OBJECTIVE: To determine whether physician financial incentives, patient incentives, or shared physician and patient incentives are more effective than control in reducing levels of low-density lipoprotein cholesterol (LDL-C) among patients with high cardiovascular risk. DESIGN, SETTING, AND PARTICIPANTS: Four-group, multicenter, cluster randomized clinical trial with a 12-month intervention conducted from 2011 to 2014 in 3 primary care practices in the northeastern United States. Three hundred forty eligible primary care physicians (PCPs) were enrolled from a pool of 421. Of 25,627 potentially eligible patients of those PCPs, 1503 enrolled. Patients aged 18 to 80 years were eligible if they had a 10-year Framingham Risk Score (FRS) of 20% or greater, had coronary artery disease equivalents with LDL-C levels of 120 mg/dL or greater, or had an FRS of 10% to 20% with LDL-C levels of 140 mg/dL or greater. Investigators were blinded to study group, but participants were not. INTERVENTIONS: Primary care physicians were randomly assigned to control, physician incentives, patient incentives, or shared physician-patient incentives. Physicians in the physician incentives group were eligible to receive up to $1024 per enrolled patient meeting LDL-C goals. Patients in the patient incentives group were eligible for the same amount, distributed through daily lotteries tied to medication adherence. Physicians and patients in the shared incentives group shared these incentives. Physicians and patients in the control group received no incentives tied to outcomes, but all patient participants received up to $355 each for trial participation. MAIN OUTCOMES AND MEASURES: Change in LDL-C level at 12 months. RESULTS: Patients in the shared physician-patient incentives group achieved a mean reduction in LDL-C of 33.6 mg/dL (95% CI, 30.1-37.1; baseline, 160.1 mg/dL; 12 months, 126.4 mg/dL); those in physician incentives achieved a mean reduction of 27.9 mg/dL (95% CI, 24.9-31.0; baseline, 159.9 mg/dL; 12 months, 132.0 mg/dL); those in patient incentives achieved a mean reduction of 25.1 mg/dL (95% CI, 21.6-28.5; baseline, 160.6 mg/dL; 12 months, 135.5 mg/dL); and those in the control group achieved a mean reduction of 25.1 mg/dL (95% CI, 21.7-28.5; baseline, 161.5 mg/dL; 12 months, 136.4 mg/dL; P < .001 for comparison of all 4 groups). Only patients in the shared physician-patient incentives group achieved reductions in LDL-C levels statistically different from those in the control group (8.5 mg/dL; 95% CI, 3.8-13.3; P = .002). CONCLUSIONS AND RELEVANCE: In primary care practices, shared financial incentives for physicians and patients, but not incentives to physicians or patients alone, resulted in a statistically significant difference in reduction of LDL-C levels at 12 months. This reduction was modest, however, and further information is needed to understand whether this approach represents good value. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01346189.

BACKGROUND: To examine the feasibility of implementing clinician-supported inpatient self-managed insulin to aid in the planning of a randomized clinical trial. RESULTS: We conducted a proof-of-concept interventional study of inpatients with diabetes mellitus who had hospital orders for basal-bolus or sliding scale insulin. Patients meeting inclusion criteria were offered the opportunity to manage their own basal-bolus insulin with support from a diabetes nurse practitioner. Over a three-month screening period, we conducted 361 screens in 336 patients, only eleven of whom met all inclusion criteria. None of these eleven eligible patients elected to enroll. The most common reason for refusal was lack of interest in self-managing insulin while acutely ill (36 %). DISCUSSION: Future studies of patient-managed in-hospital insulin should consider enrolling less acutely ill patients with longer anticipated lengths of stay. TRIALS REGISTRATION: NCT02144441.

Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients. This trial was registered at www.clinicaltrials.gov as #NCT813320.

Over the last decade a large body of epidemiological, translational, and animal model research has suggested that psoriasis may be a risk factor for cardiovascular and metabolic disease. Outcome based studies often suggest that patients with more severe psoriasis have an increased risk of major cardiovascular events independent of traditional risk factors that are captured in electronic health data. The study by Parisi and colleagues finds that incident severe psoriasis is associated with a non-statistically significant increased risk of major cardiovascular events, HR 1.28 (95% CI 0.96-1.69) in their primary model and a statistically significant increased risk, HR 1.46 (95% CI 1.11, 1.92), in a sensitivity analysis that excludes patients with inflammatory arthritis. These results are usefully consistent with prior studies published using the same or similar databases. Here we review three key biostatistical and epidemiological principles that are commonly misunderstood (over reliance on P-values, confounding versus effect modification, and inception versus prevalent cohort design) and often lead to controversy in analyzing and interpreting results.

The prerequisite for an 'undetectable' HIV viral load has restricted access to transplantation for HIV-infected kidney recipients. However, HCV-infected recipients, owing to the historic limitations of HCV therapy in patients with renal disease, are commonly viremic at transplant and have universal access. To compare the effect of HIV, HCV, and HIV/HCV coinfection on kidney transplant patient and allograft outcomes, we performed a retrospective study of kidney recipients transplanted from January 1996 through December 2013. In multivariable analysis, patient (hazard ratio 0.90, 95% confidence interval 0.66-1.24) and allograft survival (0.60, 40-0.88) in 492 HIV patients did not differ significantly from the 117,791 patient-uninfected reference group. This was superior to outcomes in both the 5605 patient HCV group for death (1.44, 1.33-1.56) and graft loss (1.43, 1.31-1.56), as well as the 147 patient HIV/HCV coinfected group for death (2.26, 1.45-3.52) and graft loss (2.59, 1.60-4.19). HIV infection did not adversely affect recipient or allograft survival and was associated with superior outcomes compared with both HCV infection and HIV/HCV coinfection in this population. Thus, pretransplant viral eradication and/or immediate posttransplant eradication should be studied as potential strategies to improve posttransplant outcomes in HCV-infected kidney recipients.

OBJECTIVES: Efforts to improve adherence by reducing co-payments through value-based insurance design are become more prevalent despite limited evidence of improved health outcomes. The objective of this study was to determine whether eliminating patient co-payments for blood pressure medications improves blood pressure control. STUDY DESIGN: Randomized controlled trial. METHODS: The Collaboration to Reduce Disparities in Hypertension (CHORD) was a randomized controlled trial with 12 months' follow-up conducted among patients from the Philadelphia and Pittsburgh Veterans Administration Medical Centers. We enrolled 479 patients with poorly controlled systolic blood pressure. Participants were randomly assigned to: a) receive reductions in co-payments from $8 to $0 per medication per month for each antihypertensive prescription filled, b) a computerized behavioral intervention (CBI), c) both co-pay reduction and CBI, or d) usual care. Our main outcome measure was change in systolic blood pressure from enrollment to 12 months post enrollment. We also measured adherence using the medication possession ratio in a subset of participants. RESULTS: There were no significant interactions between the co-payment interventions and the CBI interventions. There was no relative difference in the change in medication possession ratio between baseline and 12 months (0.05% and -.90% in control and incentive groups, respectively; P = .74) or in continuous medication gaps of 30, 60, or 90 days. Blood pressure decreased among all participants, but to a similar degree between the financial incentive and control groups. Systolic pressure within the incentive group dropped 13.2 mm Hg versus 15.2 mm Hg for the control group (difference = 2.0; 95% CI, -2.3 to 6.3; P = .36). The proportion of patients with blood pressure under control at 12 months was 29.5% in the incentive group versus 33.9 in the control group (odds ratio, 0.8; 95% CI, 0.5-1.3; P = .36). CONCLUSIONS: Among patients with poorly controlled blood pressure, financial incentives--as implemented in this trial--that reduced patient cost sharing for blood pressure medications did not improve medication adherence or blood pressure control.

OBJECTIVES: Value-based insurance designs are being widely used. We undertook this study to examine whether a financial incentive that lowered co-payments for blood pressure medications below $0 improved blood pressure control among patients with poorly controlled hypertension. STUDY DESIGN: Randomized controlled trial. METHODS: Participants from 3 Pennsylvania hospitals (n = 337) were randomly assigned to: a) be paid $8 per medication per month for filling blood pressure prescriptions, b) a computerized behavioral intervention (CBI), c) both payment and CBI, or d) usual care. The primary outcome was change in blood pressure between baseline and 12 months post enrollment. We also measured adherence using the medication possession ratio in a subset of participants. RESULTS: There were no significant interactions between the incentive and the CBI interventions. There were no significant changes in medication possession ratio in the treatment group. Blood pressure decreased among all participants, but to a similar degree between the financial incentive and control groups. Systolic blood pressure (SBP) dropped 13.7 mm Hg for the incentive group versus 10.0 mm Hg for the control group (difference = -3.7; 95% CI, -9.0 to 1.6; P = .17). The proportion of patients with blood pressure under control 12 months post enrollment was 35.6% of the incentive group versus 27.7% of the control group (odds ratio, 1.4; 95% CI, 0.8-2.5; P = .19). Diabetics in the incentive group had an average drop in SBP of 12.7 mm Hg between baseline and 12 months compared with 4.0 mm Hg in the control group (P = .02). Patients in the incentive group without diabetes experienced average SBP reductions of 15.0 mm Hg, compared with 16.3 mm Hg for control group nondiabetics (P = .71). CONCLUSIONS: Among patients with poorly controlled blood pressure, financial incentives-as implemented in this trial-did not improve blood pressure control or adherence except among patients with diabetes.

BACKGROUND: Recently investigators have used analysis of administrative/billing datasets to answer clinical and pharmacoepidemiology questions in pediatric oncology. However, the accuracy of pharmacy data from administrative/billing datasets have not yet been evaluated. The primary objective of this study was to determine the concordance of Pediatric Health Information System (PHIS) administrative/billing chemotherapy data with Children's Oncology Group (COG) protocol-mandated chemotherapy and to assess the implications of this level of concordance for further PHIS research. PROCEDURE: Data from 384 pediatric patients (1,060 courses of chemotherapy) with acute myeloid leukemia treated on COG clinical trial AAML0531 were previously merged with PHIS data. PHIS chemotherapy administrative/billing data were reviewed for the first three courses of chemotherapy. Accuracy was assessed using three metrics: recognizability of chemotherapy pattern by course, chemotherapy administration pattern by individual medication, and concordance with the number of days of protocol-defined chemotherapy. RESULTS: The chemotherapy pattern was recognizable in 87.3% of courses when course-wide accuracy was assessed. Chemotherapy administration pattern varied by medication. Cytarabine had perfect concordance 70.9% of the time, daunorubicin had perfect concordance 77.4% of the time, and etoposide had perfect concordance 67.8% of the time. CONCLUSIONS: The accuracy of chemotherapy administrative/billing data supports the continued use of PHIS data for epidemiology studies as long as investigators perform data quality control checks and evaluate each specific medication prior to undertaking definitive analyses.