Shyh-Huei Chen

Aging and Physical Function in Type 2 Diabetes: 8 Years of an Intensive Lifestyle Intervention

BACKGROUND Compared with adults without type 2 diabetes mellitus, those with the disease experience more limitations in their physical functioning (PF). Look AHEAD is a large multicenter trial that examined the effects of an intensive lifestyle intervention (ILI) for weight loss on cardiovascular outcomes compared with diabetes support and education (DSE). Although the current study compared treatment differences between ILI and DSE on PF, the primary goal was to examine whether this effect was moderated by age and history of cardiovascular disease at enrollment. METHODS Overweight or obese adults with type 2 diabetes mellitus (n = 5,145) were randomly assigned to either ILI or DSE. The mean (±SD) age and % females in ILI was 58.9 years (±6.9) and 59.8%; it was 58.6 years (6.8) and 59.5% in DSE. Analysis in 4,998 participants assessed the differential rates of decline in PF across a period of 8 years for the ILI and DSE groups. RESULTS ILI resulted in improved PF compared with DSE after 1 year (p < .0001) and was maintained across time. Within the ILI, older adults experienced greater improvements than younger adults (p < .0001). By year 2, persons in ILI with preexisting cardiovascular disease were no different in PF than in DSE participants with preexisting cardiovascular disease. CONCLUSION With the exception of persons who had a history of cardiovascular disease, ILI slowed the decline in PF with type 2 diabetes mellitus despite weight regain, an effect that was stronger for older than younger participants and could translate into reductions in falls and disability.

Insulin Dose and Cardiovascular Mortality in the ACCORD Trial

OBJECTIVE In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality. RESEARCH DESIGN AND METHODS We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment. RESULTS More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation. CONCLUSIONS These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.

Genome-wide two-locus epistasis scans in prostate cancer using two European populations

Approximately 40 single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk have been identified through genome-wide association studies (GWAS). However, these GWAS-identified PCa risk-associated SNPs can explain only a small proportion of heritability (~13%) of PCa risk. Gene–gene interaction is speculated to be one of the major factors contributing to the so-called missing heritability. To evaluate the gene–gene interaction and PCa risk, we performed a two-stage genome-wide gene–gene interaction scan using a novel statistical approach named “Boolean Operation-based Screening and Testing”. In the first stage, we exhaustively evaluated all pairs of SNP–SNP interactions for ~500,000 SNPs in 1,176 PCa cases and 1,101 control subjects from the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) study. No SNP–SNP interaction reached a genome-wide significant level of 4.4E−13. The second stage of the study involved evaluation of the top 1,325 pairs of SNP–SNP interactions (Pinteraction <1.0E−08) implicated in CGEMS in another GWAS population of 1,964 PCa cases from the Johns Hopkins Hospital (JHH) and 3,172 control subjects from the Illumina iControl database. Sixteen pairs of SNP–SNP interactions were significant in the JHH population at a Pinteraction cutoff of 0.01. However, none of the 16 pairs of SNP–SNP interactions were significant after adjusting for multiple tests. The current study represents one of the first attempts to explore the high-dimensional etiology of PCa on a genome-wide scale. Our results suggested a list of SNP–SNP interactions that can be followed in other replication studies.

Gibbs ensembles for nearly compatible and incompatible conditional models

Gibbs sampler has been used exclusively for compatible conditionals that converge to a unique invariant joint distribution. However, conditional models are not always compatible. In this paper, a Gibbs sampling-based approach - Gibbs ensemble -is proposed to search for a joint distribution that deviates least from a prescribed set of conditional distributions. The algorithm can be easily scalable such that it can handle large data sets of high dimensionality. Using simulated data, we show that the proposed approach provides joint distributions that are less discrepant from the incompatible conditionals than those obtained by other methods discussed in the literature. The ensemble approach is also applied to a data set regarding geno-polymorphism and response to chemotherapy in patients with metastatic colorectal.

Factors associated with failure to achieve a glycated haemoglobin target of <8.0% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

The aim of this study was to identify the clinical features of participants in the standard therapy arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) glycaemia trial who failed to reach the glycated haemoglobin (HbA1c) target. We analysed 4685 participants in the standard therapy arm, comparing participants who reached the HbA1c target of <8.0% with those whose HbA1c level was ≥8.0% 12 months after randomization. Baseline and 12‐month clinical characteristics were compared. At 12 months after randomization, 3194 participants had HbA1c <8.0% and 1491 had HbA1c ≥8.0%. Black race [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.61–0.89; p = 0.002], severe hypoglycaemia (OR 0.57, CI 0.37–0.89; p = 0.014) and insulin use (OR 0.51, CI 0.40–0.65; p < 0.001) were associated with failure to reach HbA1c goal at 12 months in the adjusted model. Even with free medications, free visits with clinicians and aggressive titration of medications, >30% of participants in the standard arm of the ACCORD trial had an HbA1c ≥8.0% at 1 year. Participants who were black, had severe hypoglycaemia and were on insulin were more likely to have an above‐target HbA1c concentration after 12 months on the standard protocol.

A multigenic approach to evaluating prostate cancer risk in a systematic replication study.

Although it is well known that multiple genes may influence prostate cancer risk, most current efforts at identifying prostate cancer risk variants rely on single-gene approaches. In previous work using mostly single-gene approaches, we observed significant associations (P < 0.05) for 6 of 46 polymorphisms in five genes in a Swedish prostate cancer case-control study population. We now report on the higher-order gene-gene interactions among those 46 genetic variants and the combined effect of the six polymorphisms with significant main effects for association with prostate cancer risk in 795 controls and 1,461 cases. Classification and regression tree analysis was used to evaluate higher-order gene-gene interactions. No interactions were confirmed by the result from logistic regressions. For the combined analysis, we tested the hypothesis that individuals carrying multiple copies of risk variants are at increased risk for prostate cancer. Individuals carrying more than eight copies of any risk variant were almost twofold more likely to get prostate cancer (OR = 1.99, P = 0.0014). A significant trend relationship was observed (P < 0.0001). In the present study, additive effects but not multiplicative effects among these six polymorphisms with significant main effects were observed.

Assessment of a Short Diabetes Knowledge Instrument for Older and Minority Adults

Purpose The purpose of the study was to assess the performance of a Short Diabetes Knowledge Instrument (SDKI) in a large multi-ethnic sample of older adults with diabetes and to identify possible modifications to improve its ability to document diabetes knowledge. Research Design and Methods A sample of 593 African American, American Indian, and white female and male adults 60 years and older, with diabetes diagnosed at least 2 years prior, was recruited from 8 North Carolina counties. All completed an interview that included a 16-item questionnaire to assess diabetes knowledge. A subsample of 46 completed the questionnaire a second time at a subsequent interview. Item-response analysis was used to refine the instrument to well-performing items. The instrument consisting of the remaining items was subjected to analyses to assess validity and test-retest reliability. Results Three items were removed after item-response analysis. Scores for the resulting instrument were lower among minority and older participants, as well as those with lower educational attainment and income. Scores for test-retest were highly correlated. Conclusions The SDKI (13-item questionnaire) appears to be a valid and reliable instrument to evaluate knowledge about diabetes. Assessment in a multi-ethnic sample of older adults suggests that this instrument can be used to measure diabetes knowledge in diverse populations. Further evaluation is needed to determine whether or not this instrument can detect changes in knowledge resulting from diabetes education or other interventions.

Behavior of the Gibbs Sampler When Conditional Distributions Are Potentially Incompatible.

The Gibbs sampler has been used extensively in the statistics literature. It relies on iteratively sampling from a set of compatible conditional distributions and the sampler is known to converge to a unique invariant joint distribution. However, the Gibbs sampler behaves rather differently when the conditional distributions are not compatible. Such applications have seen increasing use in areas such as multiple imputation. In this paper, we demonstrate that what a Gibbs sampler converges to is a function of the order of the sampling scheme. Besides providing the mathematical background of this behaviour, we also explain how that happens through a thorough analysis of the examples.

Risk profiles of lipids, blood pressure, and anthropometric measures in childhood and adolescence: project heartBeat!

BackgroundMany common risk factors for cardiovascular disease (CVD) originate in childhood and adolescence. There is a lack of literature examining variability within study populations, as well as a shortage of simultaneous analyses of CVD risk factors operating in tandem.MethodsWe used data from Project HeartBeat!-a multi-cohort longitudinal growth study of children and adolescents in the US - for assessing multiple profiles for lipids, blood pressure, and anthropometric measures. Principal component functional curve analysis methods were used to summarize trajectories of multiple measurements. Subsequently less favorable health (high risk) and more favorable (low risk) groups from both female and male cohorts were identified and compared to US national norms.ResultsCompared to national norms, the high risk groups have increased waist circumference, body mass index, and percent body fat as well as higher low-density lipoprotein cholesterol and triglyceride levels, and lower high-density lipoprotein cholesterol. The risk profiles also exhibit patterns of convergence and divergence across the high and low risk groups as a function of age.ConclusionsThese observations may have clinical and public health implications in identifying groups of children at high risk of CVD for earlier interventions.

Device‐Measured Physical Activity As a Predictor of Disability in Mobility‐Limited Older Adults

To examine associations between objectively measured physical activity (PA) and incidence of major mobility disability (MMD) and persistent MMD (PMMD) in older adults in the Lifestyle Interventions and Independence for Elders (LIFE) Study.