Glycemic Measures in Childhood as Predictors of Future Diabetes-Related Microvascular Complications in an Indigenous American Population.

OBJECTIVE: To examine the role of glycemic measures performed during childhood in predicting future diabetes-related nephropathy and retinopathy in a high-risk indigenous American cohort. RESEARCH DESIGN AND METHODS: We studied associations between glycated hemoglobin (HbA1c) and 2-h plasma glucose (PG), measured during childhood (age 5 to <20 years) in a longitudinal observational study of diabetes and its complications (1965-2007), and future albuminuria (albumin creatinine ratio [ACR] ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), and retinopathy (at least one microaneurysm or hemorrhage or proliferative retinopathy on direct ophthalmoscopy). Areas under the receiver operating characteristic curve (AUCs) for childhood glycemic measures when predicting nephropathy and retinopathy were compared. RESULTS: Higher baseline levels of HbA1c and 2-h PG significantly increased the risk of future severe albuminuria (HbA1c: hazard ratio [HR] 1.45 per %; 95% CI 1.02-2.05 and 2-h PG: HR 1.21 per mmol/L; 95% CI 1.16-1.27). When categorized by baseline HbA1c, children with prediabetes had a higher incidence of albuminuria (29.7 cases per 1,000 person-years [PY]), severe albuminuria (3.8 cases per 1,000 PY), and retinopathy (7.1 cases per 1,000 PY) than children with normal HbA1c levels (23.8, 2.4, and 1.7 cases per 1,000 PY, respectively); children with diabetes at baseline had the highest incidence of the three complications. No significant differences were observed between AUCs for models with HbA1c, 2-h PG, and fasting PG when predicting albuminuria, severe albuminuria, or retinopathy. CONCLUSIONS: In this study, higher glycemia levels ascertained by HbA1c and 2-h PG during childhood were associated with future microvascular complications; this demonstrates the potential utility of screening tests performed in high-risk children in predicting long-term health outcomes.

Effects of the ABCC8 R1420H loss-of-function variant on beta-cell function, diabetes incidence, and retinopathy.

INTRODUCTION: The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. The effects of an ABCC8 R1420H loss-of-function variant on beta-cell function, incidence of type 2 diabetes, and age-at-onset, prevalence, and progression of diabetes complications were assessed in a longitudinal study in American Indians. RESEARCH DESIGN AND METHODS: We analyzed beta-cell function through the relationship between insulin secretion and insulin sensitivity in members of this population without diabetes aged ≥5 years using standard major axis regression. We used hierarchical logistic regression models to study cross-sectional associations with diabetes complications including increased albuminuria (albumin-to-creatinine ratio (ACR) ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2), and retinopathy. This study included 7675 individuals (254 variant carriers) previously genotyped for the R1420H with available phenotypic data and with a median follow-up time of 13.5 years (IQR 4.5-26.8). RESULTS: Variant carriers had worse beta-cell function than non-carriers (p=0.0004; on average estimated secretion was 22% lower, in carriers), in children and adults, with no difference in insulin sensitivity (p=0.50). At any body mass index and age before 35 years, carriers had higher type 2 diabetes incidence. This variant did not associate with prevalence of increased albuminuria (OR 0.87, 95% CI 0.66 to 1.16), severe albuminuria (OR 0.96, 95% CI 0.55 to 1.68), or reduced eGFR (OR 0.44, 95% CI 0.18 to 1.06). By contrast, the variant significantly associated with higher retinopathy prevalence (OR 1.74, 95% CI 1.19 to 2.53) and this association was only partially mediated (<11%) by glycemia, duration of diabetes, risk factors of retinopathy, or insulin use. Retinopathy prevalence in carriers was higher regardless of diabetes presence. CONCLUSIONS: The ABCC8 R1420H variant is associated with increased risks of diabetes and of retinopathy, which may be partially explained by higher glycemia levels and worse beta-cell function.

Weight Loss, Lifestyle Intervention, and Metformin Affect Longitudinal Relationship of Insulin Secretion and Sensitivity.

CONTEXT: Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies leading to diabetes. OBJECTIVE: We investigated effects of weight loss, an intensive lifestyle intervention (ILS), and metformin on the relationship between insulin secretion and sensitivity using repository data from 2931 participants in the Diabetes Prevention Program clinical trial in adults at high risk of developing type 2 diabetes. METHODS: Insulin secretion and sensitivity were estimated from insulin and glucose concentrations in fasting and 30-minute postload serum samples at baseline and 1, 2, and 3 years after randomization, during the active intervention phase. The nonlinear relationship of secretion and sensitivity was evaluated by standardized major axis regression to account for variability in both variables. Insulin secretory demand and compensatory insulin secretion were characterized by distances along and away from the regression line, respectively. RESULTS: ILS and metformin decreased secretory demand while increasing compensatory insulin secretion, with greater effects of ILS. Improvements were directly related to weight loss; decreased weight significantly reduced secretory demand (b=-0.144 SD; 95% CI (-0.162, -0.125)/5 kg loss) and increased compensatory insulin secretion (b = 0.287 SD, 95% CI (0.261, 0.314)/5 kg loss). In time-dependent hazard models, increasing compensatory insulin secretion (hazard ratio [HR] = 0.166 per baseline SD, 95% CI 0.133, 0.206) and weight loss (HR = 0.710 per 5 kg loss, 95% CI 0.613, 0.819) predicted lower diabetes risk. CONCLUSION: Diabetes risk reduction was directly related to the amount of weight loss, an effect mediated by lowered insulin secretory demand (due to increased insulin sensitivity) coupled with improved compensatory insulin secretion.

Cardiorespiratory Fitness, BMI, Mortality, and Cardiovascular Disease in Adults with Overweight/Obesity and Type 2 Diabetes.

INTRODUCTION: We estimated the effects of cardiorespiratory fitness (CRF) and body mass index (BMI) at baseline on mortality and cardiovascular disease events in people with type 2 diabetes who participated in the Look AHEAD randomized clinical trial. METHODS: Look AHEAD compared effects of an intensive lifestyle intervention with diabetes support and education on cardiovascular disease events in 5145 adults age 45-76 yr with overweight/obesity and type 2 diabetes. In 4773 participants, we performed a secondary analysis of the association of baseline CRF during maximal treadmill test (expressed as metabolic equivalents (METs)) on mortality and cardiovascular disease events during a mean follow-up of 9.2 yr. RESULTS: The mean (SD) CRF was 7.2 (2.0) METs. Adjusted for age, sex, race/ethnicity, BMI, intervention group, and ß-blocker use, all-cause mortality rate was 30% lower per SD greater METs (hazard ratio (HR) = 0.70 (95% confidence interval, 0.60 to 0.81); rate difference (RD), -2.71 deaths/1000 person-years (95% confidence interval, -3.79 to -1.63)). Similarly, an SD greater METs predicted lower cardiovascular disease mortality (HR, 0.45; RD, -1.65 cases/1000 person-years) and a composite cardiovascular outcome (HR, 0.72; RD, -6.38). Effects of METs were homogeneous on the HR scale for most baseline variables and outcomes but heterogeneous for many on the RD scale, with greater RD in subgroups at greater risk of the outcomes. For example, all-cause mortality was lower by 7.6 deaths/1000 person-years per SD greater METs in those with a history of cardiovascular disease at baseline but lower by only 1.6 in those without such history. BMI adjusted for CRF had little or no effect on these outcomes. CONCLUSIONS: Greater CRF is associated with reduced risks of mortality and cardiovascular disease events.

Patient Service Utilization Among Individuals with Co-occurring Disorders: A Comparison of Two Models of Care Coordination.

Healthcare systems have increasingly adopted integrated care models with demonstrated effectiveness. However, few studies examine integrated care for individuals with co-morbid mental illness and medical conditions. This quasi-experimental study compared service use for two integrated care models for patients with co-occurring conditions. We used hierarchical negative binomial and logistic regressions with random effects to test the relationship between integration and service use. Patients treated at co-located agencies had significantly higher odds of inpatient hospitalization compared to those in fully integrated settings. Additionally, some comorbidities had significantly different levels of service use. Patients at co-located agencies had more outpatient and emergency visits, but was not statistically significant. Our findings provide evidence that the model of care may impact service use for patients experiencing co-occurring conditions, however, variations in service use for specific co-morbid conditions highlight the need to examine the specific needs and characteristics of this population.

Relationship Between Insulin Secretion and Insulin Sensitivity and its Role in Development of Type 2 Diabetes Mellitus: Beyond the Disposition Index.

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia.

Relationship Between Insulin Secretion and Insulin Sensitivity and its Role in Development of Type 2 Diabetes Mellitus: Beyond the Disposition Index.

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia.

A two-stage Generalized Method of Moments model for feedback with time-dependent covariates.

Correlated observations in longitudinal studies are often due to repeated measures on the subjects. Additionally, correlation may be realized due to the association between responses at a particular time and the predictors at earlier times. There are also feedback effects (relation between responses in the present and the covariates at a later time), though these are not always relevant and are often ignored. All these cases of correlation must be accounted for as they can have different effects on the regression coefficients. Several authors have provided models that reflect the direct and delayed impact of covariates on the response, utilizing valid moment conditions to estimate the relevant regression coefficients. However, there are applications when one cannot ignore the effect of the responses on future covariates. A two-stage model to account for the feedback, modeling the direct as well as the delayed effects of the covariates on future responses and vice versa is presented. The use of the two-stage model is demonstrated by revisiting child morbidity and its impact on future values of body mass index using Philippines health data. Also, obesity status and its feedback effects on physical activity and depression levels using the Add Health dataset are analyzed.

Analysis of correlated data with feedback for time-dependent covariates in psychiatry research.

In studies on psychiatry and neurodegenerative diseases, it is common to have data that are correlated due to the hierarchical structure in data collection or to repeated measures on the subject longitudinally. However, the feedback effect created due to time-dependent covariates in these studies is often overlooked and seldom modelled. This article reviews the methodological development of feedback effects with marginal models for longitudinal data and discusses their implementation.

Use of partitioned GMM marginal regression model with time-dependent covariates: analysis of Chinese Longitudinal Healthy Longevity Study.

BACKGROUND: Elderly population's health is a major concern for most industrial nations. National health surveys provide a measure of the state of elderly health. One such survey is the Chinese Longitudinal Healthy Longevity Survey. It collects data on risk factors and outcomes on the elderly. We examine these longitudinal survey data to determine the changes in health and to identify risk factors as they impact health outcomes including the elderly's ability to do a physical check. METHODS: We use a Partitioned GMM logistic regression model to identify risk factors. The model also accounts for the correlation between lagged time-dependent covariates and the outcomes. It addresses present and past measures of time-dependent covariates on simultaneous outcomes. The relation produces additional regression coefficients as byproduct of the Partitioned model, identifying the immediate, delayed effects (lag - 1), further delayed (lag-2), etc. Therefore, the model presents the opportunity for decision makers to monitor the covariate over time. This technique is particularly useful in healthcare and health related research. We use the Chinese Longitudinal Health Longevity Survey data to identify those risk factors and to display the utility of the model. RESULTS: We found that one's ability to make own decisions, frequently consuming vegetables, exercise frequently, one's ability to transfer without assistance, having visual difficulties and being able to pick book from floor while standing had varying effects of significance on one's health and ability to complete physical checks as they get older. CONCLUSIONS: The partitioning of the covariates as immediate effect, delayed effect or further delayed effect are important measures in a declining population.

Staff and Organizational Capacity in the Implementation of Coordinated Care: an Examination of 10 Behavioral Health Agencies in Rural Communities.

Providing primary care services in behavioral health settings has become more common and necessary given the needs of individuals with serious mental illness (SMI). In this exploratory study, we developed a survey to assess agency and professional staff and practitioner capacity for coordinated care. The survey provides a feedback mechanism for agencies to target staff and organizational needs related to building capacity to provide coordinated care. Logistic regressions compared differences in 24 dimensions of coordinated care specifically comparing capacity based on professional role (behavioral health and medical), model of coordination (co-located and fully integrated), and time of model adoption (early and late adopters). Findings indicated that all three were significant predictors of capacity in multiple dimensions suggesting the need for training and planning around inter-professional and inter-agency coordination.

Gender Differences in Alzheimer Disease: Brain Atrophy, Histopathology Burden, and Cognition.

Multiple studies suggest that females are affected by Alzheimer disease (AD) more severely and more frequently than males. Other studies have failed to confirm this and the issue remains controversial. Difficulties include differences in study methods and male versus female life expectancy. Another element of uncertainty is that the majority of studies have lacked neuropathological confirmation of the AD diagnosis. We compared clinical and pathological AD severity in 1028 deceased subjects with full neuropathological examinations. The age of dementia onset did not differ by gender but females were more likely to proceed to very severe clinical and pathological disease, with significantly higher proportions having a Mini-Mental State Examination score of 5 or less and Braak stage VI neurofibrillary degeneration. Median neuritic plaque densities were similar in females and males with AD but females had significantly greater tangle density scores. In addition, we found that AD-control brain weight differences were significantly greater for females, even after adjustment for age, disease duration, and comorbid conditions. These findings suggest that when they are affected by AD, females progress more often to severe cognitive dysfunction, due to more severe neurofibrillary degeneration, and greater loss of brain parenchyma.