Qing Pan

Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study.

BACKGROUNDnOur objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) in participants who returned to normal glucose regulation at least once during the Diabetes Prevention Program (DPP) compared with those who consistently met criteria for prediabetes.nnnMETHODSnDPPOS is an ongoing observational study of participants from the DPP randomised trial. For this analysis, diabetes cumulative incidence in DPPOS was calculated for participants with normal glucose regulation or prediabetes status during DPP with and without stratification by previous randomised treatment group. Cox proportional hazards modelling and generalised linear mixed models were used to quantify the effect of previous (DPP) glycaemic status on risk of later (DPPOS) diabetes and normal glucose regulation status, respectively, per SD in change. Included in this analysis were 1990 participants of DPPOS who had been randomly assigned to treatment groups during DPP (736 intensive lifestyle intervention, 647 metformin, 607 placebo). These studies are registered at ClinicalTrials.gov, NCT00004992 (DPP) and NCT00038727 (DPPOS).nnnFINDINGSnDiabetes risk during DPPOS was 56% lower for participants who had returned to normal glucose regulation versus those who consistently had prediabetes (hazard ratio [HR] 0·44, 95% CI 0·37-0·55, p<0·0001) and was unaffected by previous group assignment (interaction test for normal glucose regulation and lifestyle intervention, p=0·1722; normal glucose regulation and metformin, p=0·3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of a participant reaching normal glucose regulation status in DPPOS. Specifically, previous achievement of normal glucose regulation (odds ratio [OR] 3·18, 95% CI 2·71-3·72, p<0·0001), increased β-cell function (OR 1·28; 95% CI 1·18-1·39, p<0·0001), and insulin sensitivity (OR 1·16, 95% CI 1·08-1·25, p<0·0001) were associated with normal glucose regulation in DPPOS, whereas the opposite was true for prediction of diabetes, with increased β-cell function (HR 0·80, 95% CI 0·71-0·89, p<0·0001) and insulin sensitivity (HR 0·83, 95% CI 0·74-0·94, p=0·0001) having a protective effect. Among participants who did not return to normal glucose regulation in DPP, those assigned to the intensive lifestyle intervention had a higher diabetes risk (HR 1·31, 95% CI 1·03-1·68, p=0·0304) and lower chance of normal glucose regulation (OR 0·59, 95% CI 0·42-0·82, p=0·0014) than did the placebo group in DPPOS.nnnINTERPRETATIONnWe conclude that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention. Reversion to normal glucose regulation, even if transient, is associated with a significantly reduced risk of future diabetes independent of previous treatment group.nnnFUNDINGnUS National Institutes of Health.

Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program

OBJECTIVE We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss–inducing interventions (lifestyle and metformin) versus placebo. RESEARCH DESIGN AND METHODS Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end). RESULTS Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (−0.63 and −0.93 kg/allele, P ≤ 0.005, respectively). Gene–treatment interactions were observed for short-term (LYPLAL1 rs2605100, Plifestyle*SNP = 0.032; GNPDA2 rs10938397, Plifestyle*SNP = 0.016; MTCH2 rs10838738, Plifestyle*SNP = 0.022) and long-term (NEGR1 rs2815752, Pmetformin*SNP = 0.028; FTO rs9939609, Plifestyle*SNP = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (Plifestyle*SNP < 0.05). CONCLUSIONS Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.

Impact of lifestyle intervention and metformin on health-related quality of life: the diabetes prevention program randomized trial.

ABSTRACTBACKGROUNDAdults at high risk for diabetes may have reduced health-related quality of life (HRQoL).OBJECTIVETo assess changes in HRQoL after interventions aimed at diabetes risk reduction.DESIGN, SETTING, AND PARTICIPANTSA randomized clinical trial, the Diabetes Prevention Program, was conducted in 27 centers in the United States, in 3,234 non-diabetic persons with elevated fasting and post-load plasma glucose, mean age 51xa0years, mean BMI 34 Kg/m²; 68 % women, and 45 % members of minority groups.INTERVENTIONSIntensive lifestyle (ILS) program with the goals of at least 7 % weight loss and 150 min of physical activity per week, metformin (MET) 850xa0mg twice daily, or placebo (PLB).MEASUREMENTSHRQoL using the 36-Item Short-Form (SF-36) health survey to evaluate health utility index (SF-6D), physical component summaries (PCS) and mental component summaries (MCS). A minimally important difference (MID) was met when the mean of HRQoL scores between groups differed by at least 3xa0%.RESULTSAfter a mean follow-up of 3.2xa0years, there were significant improvements in the SF-6D (+0.008, pu2009=u20090.04) and PCS (+1.57, pu2009<u20090.0001) scores in ILS but not in MET participants (+0.002 and +0.15, respectively, pu2009=u20090.6) compared to the PLB group. ILS participants showed improvements in general health (+3.2, pu2009<u20090.001), physical function (+3.6, pu2009<u20090.001), bodily pain (+1.9, pu2009=u20090.01), and vitality (+2.1, pu2009=u20090.01) domain scores. Treatment effects remained significant after adjusting sequentially for baseline demographic factors, and for medical and psychological comorbidities. Increased physical activity and weight reduction mediated these ILS treatment effects. Participants who experienced weight gain had significant worsening on the same HRQoL specific domains when compared to those that had treatment-related (ILS or MET) weight loss. No benefits with ILS or MET were observed in the MCS score.CONCLUSIONOverweight/obese adults at high risk for diabetes show small improvement in most physical HRQoL and vitality scores through the weight loss and increased physical activity achieved with an ILS intervention.

Effects of Weight Loss, Weight Cycling, and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program

OBJECTIVE This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors. RESEARCH DESIGN AND METHODS This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years. RESULTS Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = −0.57 mg/dL per kg, 95% CI −0.66, −0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0–6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits. CONCLUSIONS Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.

Impact of diagnosis of diabetes on health-related quality of life among high risk individuals: the Diabetes Prevention Program outcomes study

PurposeThe purpose of this study is to assess if diagnosis of type 2 diabetes affected health-related quality of life (HRQoL) among participants in the Diabetes Prevention Program/Diabetes Prevention Program Outcome Study and changes with treatment or diabetes duration.Methods3,210 participants with pre-diabetes were randomized to metformin (MET), intensive lifestyle intervention (ILS), or placebo (PLB). HRQoL was assessed using the SF-36 including: (1) 8 SF-36 subscales; (2) the physical component (PCS) and mental component summary (MCS) scores; and (3) the SF-6D. The sample was categorized by diabetes free versus diagnosed. For diagnosed subgroup, mean scores in the diabetes-free period, at 6xa0months, 2, 4 and 6xa0years post-diagnosis, were compared.ResultsPCS and SF-6D scores declined in all participants in all treatment arms (Pxa0<xa0.001). MCS scores did not change significantly in any treatment arm regardless of diagnosis. ILS participants reported a greater decrease in PCS scores at 6xa0months post-diagnosis (Pxa0<xa0.001) and a more rapid decline immediately post-diagnosis in SF-6D scores (Pxa0=xa0.003) than the MET or PLB arms. ILS participants reported a significant decrease in the social functioning subscale at 6xa0months (Pxa0<xa0.001) and two years (Pxa0<xa0.001) post-diagnosis.ConclusionsParticipants reported a decline in measures of overall health state (SF-6D) and overall physical HRQoL, whether or not they were diagnosed with diabetes during the study. There was no change in overall mental HRQoL. Participants in the ILS arm with diabetes reported a more significant decline in some HRQoL measures than those in the MET and PLB arms that developed diabetes.

Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials

Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2–4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10−3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10−4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.

Mastectomy and Contralateral Prophylactic Mastectomy Rates: An Institutional Review

BackgroundBreast conservation surgery (BCS) followed by radiation is as effective as mastectomy for long-term survival and is considered standard of care for early-stage breast cancer. An increasing number of patients are opting for cancer-side mastectomies (CM) and often contralateral prophylactic mastectomies (CPM). Our study investigates if there are increasing trends in our patient population toward CM and CPM and identifies common factors associated with those electing to have more extensive surgery.MethodsA retrospective analysis was performed on 812 breast cancer surgeries between January 2001 and December 2009 at The George Washington University Breast Care Center. BCS-eligible patients who elected to have BCS were compared with those who chose CM. Patients who underwent CM were compared with patients undergoing CM and CPM.ResultsA personal or family history of breast cancer and larger tumor size were positively associated with choosing CM in BCS-eligible patients. A nonstatistically significant trend toward CM was seen in younger patients. Age, family history, fewer children, Caucasian race, and reconstructive surgery were positively associated with choosing CPM.ConclusionMastectomy rates at this institution have not shown the recent sharp increase observed by some authors. The association of age, race, family history, and parity with CPM has been corroborated in multiple studies. However, there is disagreement between statistically significant findings among investigators evaluating factors associated with CPM, and there is limited data in the literature characterizing BCS-eligible patients who chose CM. Larger prospective studies are necessary to further evaluate CM and CPM rates.

Efficient Utilization of the Expanded Criteria Donor (ECD) Deceased Donor Kidney Pool: An Analysis of the Effect of Labeling

We investigated the effect of the expanded criteria donor (ECD) label on (i) recovery of kidneys and (ii) acceptance for transplantation given recovery. An ECD is age ≥ 60, or age 50–59 with ≥ 2 of 3 specified comorbidities. Using data from the Scientific Registry of Transplant Recipients from 1999 to 2005, we modeled recovery rates through linear regression and transplantation probabilities via logistic regression, focusing on organs from donors just‐younger versus just‐older than the ECD age thresholds. We split the sample at July 1, 2002 to determine how decisions changed at the approximate time of implementation of the ECD definition. Before July 2002, the number of recovered kidneys with 0–1 comorbidities dropped at age 60, but transplantation probabilities given recovery did not. After July 2002, the number of recovered kidneys with 0–1 comorbidities rose at age 60, but transplantation probabilities contingent on recovery declined. No similar trends were observed at donor age 50 among donors with ≥ 2 comorbidities. Overall, implementation of the ECD definition coincided with a reversal of an apparent reluctance to recover kidneys from donors over age 59, but increased selectiveness on the part of surgeons/centers with respect to these kidneys.

Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program.

To assess associations and genotype × treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity‐related traits.

Evaluating bias correction in weighted proportional hazards regression

Often in observational studies of time to an event, the study population is a biased (i.e., unrepresentative) sample of the target population. In the presence of biased samples, it is common to weight subjects by the inverse of their respective selection probabilities. Pan and Schaubel (Can J Stat 36:111–127, 2008) recently proposed inference procedures for an inverse selection probability weighted (ISPW) Cox model, applicable when selection probabilities are not treated as fixed but estimated empirically. The proposed weighting procedure requires auxiliary data to estimate the weights and is computationally more intense than unweighted estimation. The ignorability of sample selection process in terms of parameter estimators and predictions is often of interest, from several perspectives: e.g., to determine if weighting makes a significant difference to the analysis at hand, which would in turn address whether the collection of auxiliary data is required in future studies; to evaluate previous studies which did not correct for selection bias. In this article, we propose methods to quantify the degree of bias corrected by the weighting procedure in the partial likelihood and Breslow-Aalen estimators. Asymptotic properties of the proposed test statistics are derived. The finite-sample significance level and power are evaluated through simulation. The proposed methods are then applied to data from a national organ failure registry to evaluate the bias in a post-kidney transplant survival model.