Caffo, Brian S.

Background: Individualized diabetes management would benefit from prospectively identifying well-controlled patients at risk of losing glycemic control. Objectives: To identify patterns of hemoglobin A1c (HbA1c) change among patients with stable controlled diabetes. Research Design: Cohort study using OptumLabs Data Warehouse, 2001–2013. We develop and apply a machine learning framework that uses a Bayesian estimation of the mixture of generalized linear mixed effect models to discover glycemic trajectories, and a random forest feature contribution method to identify patient characteristics predictive of their future glycemic trajectories. Subjects: The study cohort consisted of 27,005 US adults with type 2 diabetes, age 18 years and older, and stable index HbA1c <7.0%. Measures: HbA1c values during 24 months of observation. Results: We compared models with k=1, 2, 3, 4, 5 trajectories and baseline variables including patient age, sex, race/ethnicity, comorbidities, medications, and HbA1c. The k=3 model had the best fit, reflecting 3 distinct trajectories of glycemic change: (T1) rapidly deteriorating HbA1c among 302 (1.1%) youngest (mean, 55.2 y) patients with lowest mean baseline HbA1c, 6.05%; (T2) gradually deteriorating HbA1c among 902 (3.3%) patients (mean, 56.5 y) with highest mean baseline HbA1c, 6.53%; and (T3) stable glycemic control among 25,800 (95.5%) oldest (mean, 58.5 y) patients with mean baseline HbA1c 6.21%. After 24 months, HbA1c rose to 8.75% in T1 and 8.40% in T2, but remained stable at 6.56% in T3. Conclusions: Patients with controlled type 2 diabetes follow 3 distinct trajectories of glycemic control. This novel application of advanced analytic methods can facilitate individualized and population diabetes care by proactively identifying high risk patients.

Preexposure prophylaxis (PrEP) of HIV infection with tenofovir-containing regimens is effective, but plagued by poor adherence in some studies. Options for safe, effective, and acceptable PrEP products, especially for men and women at risk of HIV via receptive anal intercourse (RAI), are needed. We performed a randomized, partially blinded, first-in-human evaluation of four candidate rectal microbicide vehicles—aqueous gel, aqueous fluid, lipid gel, and lipid fluid—to select a prototype for further clinical development. Eight seronegative participants received three doses of each product with each dose separated by at least 2 weeks: one dose was given alone without simulated RAI in clinic, another dose was followed by simulated RAI in clinic, and another dose was self-administered at home in the context of RAI with a partner. Assessments included safety, acceptability, colon histology, ex vivo HIV infectivity of colon tissue explants, and colonic luminal distribution of vehicle and HIV surrogates. Adverse events were all mild and mainly sigmoidoscopy associated. There were minor differences in colon distribution of products and little effect of RAI. Vehicle distribution covered 95% (±7% standard deviation) of the distribution of an HIV surrogate in the colonic lumen. The lipid fluid vehicle increased HIV colon tissue infectability 5-fold [log 10 p24 0.68 (95% confidence interval 0.08, 1.28)] and aqueous gel provided 6-fold protection [log 10 p24 0.80 (95% confidence interval 0.20, 1.41)] compared to no product baseline. Colon permeability of lipid vehicles was more than 10-fold greater than aqueous vehicles. All products received similar acceptability ratings, though trends favored the gel products. Intensive simultaneous assessment of safety and toxicity, luminal and tissue distribution, ex vivo HIV infectivity, and product acceptability in relevant sexual contexts provided clear differentiation among candidate gels very early in product development. We selected the aqueous gel for further development as a rectal microbicide vehicle.