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1.  Update on Cardiovascular Outcomes at 30 Years of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):39-43.
OBJECTIVE
To describe the beneficial long-term effects of an average of 6.5 years of intensive diabetes therapy (INT) in type 1 diabetes on measures of atherosclerosis, cardiac structure and function, and clinical cardiovascular events observed in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
RESEARCH DESIGN AND METHODS
The DCCT was a randomized clinical trial of 1,441 participants assigned to receive INT or conventional therapy (CON). It was conducted between 1983–1993 with an average follow-up of 6.5 years. EDIC (1994–present) is an observational follow-up of the DCCT cohort. Cardiovascular events have been recorded throughout. During EDIC common carotid intima-media thickness (IMT) was measured with ultrasound, coronary artery calcification with computed tomography, and cardiac structure and function with cardiac magnetic resonance imaging.
RESULTS
DCCT INT and lower levels of HbA1c during DCCT/EDIC were associated with thinner carotid IMT, less coronary calcification, and a lower incidence of clinical cardiovascular events including myocardial infarction, stroke, and cardiac death. While there were no significant differences in cardiac structure and function between the former INT and CON groups, they were significantly associated with higher HbA1c during DCCT/EDIC.
CONCLUSIONS
DCCT INT and the attendant 6.5 years of lower HbA1c had long-term salutary effects on the development and progression of atherosclerosis and cardiovascular disease during the subsequent follow-up during EDIC.
doi:10.2337/dc13-2116
PMCID: PMC3868002  PMID: 24356596
2.  Applications of the Wei-Lachin Multivariate One-Sided Test for Multiple Outcomes on Possibly Different Scales 
PLoS ONE  2014;9(10):e108784.
Many studies aim to assess whether a therapy has a beneficial effect on multiple outcomes simultaneously relative to a control. Often the joint null hypothesis of no difference for the set of outcomes is tested using separate tests with a correction for multiple tests, or using a multivariate T2-like MANOVA or global test. However, a more powerful test in this case is a multivariate one-sided or one-directional test directed at detecting a simultaneous beneficial treatment effect on each outcome, though not necessarily of the same magnitude. The Wei-Lachin test is a simple 1 df test obtained from a simple sum of the component statistics that was originally described in the context of a multivariate rank analysis. Under mild conditions this test provides a maximin efficient test of the null hypothesis of no difference between treatment groups for all outcomes versus the alternative hypothesis that the experimental treatment is better than control for some or all of the component outcomes, and not worse for any. Herein applications are described to a simultaneous test for multiple differences in means, proportions or life-times, and combinations thereof, all on potentially different scales. The evaluation of sample size and power for such analyses is also described. For a test of means of two outcomes with a common unit variance and correlation 0.5, the sample size needed to provide 90% power for two separate one-sided tests at the 0.025 level is 64% greater than that needed for the single Wei-Lachin multivariate one-directional test at the 0.05 level. Thus, a Wei-Lachin test with these operating characteristics is 39% more efficient than two separate tests. Likewise, compared to a T2-like omnibus test on 2 df, the Wei-Lachin test is 32% more efficient. An example is provided in which the Wei-Lachin test of multiple components has superior power to a test of a composite outcome.
doi:10.1371/journal.pone.0108784
PMCID: PMC4201485  PMID: 25329662
3.  Association between seven years of intensive treatment of type 1 diabetes and long term mortality 
JAMA  2015;313(1):45-53.
Importance
Whether mortality in type 1 diabetes mellitus is affected following intensive glycemic therapy has not been established.
Objective
To determine whether mortality differed between the original intensive and conventional treatment groups in the long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort.
Design, Setting, and Participants
After the DCCT (1983–1993) ended, participants were followed up in a multisite (27 US and Canadian academic clinical centers) observational study (Epidemiology of Diabetes Control and Complications [EDIC]) until December 31, 2012. Participants were 1441 healthy volunteers with diabetes mellitus who, at baseline, were 13 to 39 years of age with 1 to 15 years of diabetes duration and no or early microvascular complications, and without hypertension, preexisting cardiovascular disease, or other potentially life-threatening disease.
Intervention/Exposure
During the clinical trial, participants were randomly assigned to receive intensive therapy (n = 711) aimed at achieving glycemia as close to the nondiabetic range as safely possible, or conventional therapy (n = 730) with the goal of avoiding symptomatic hypoglycemia and hyperglycemia. At the end of the DCCT, after a mean of 6.5 years, intensive therapy was taught and recommended to all participants and diabetes care was returned to personal physicians.
Main Outcomes
Total and cause-specific mortality was assessed through annual contact with family and friends and through records over 27 years mean follow-up.
Results
Vital status was ascertained for 1429 (99.2%) participants. There were 107 deaths, 64 in the conventional and 43 in the intensive group. The absolute risk difference was −109 per 100 000 patient-years (95%CI, −218 to −1), with lower all-cause mortality risk in the intensive therapy group (hazard ratio [HR] = 0.67 [95%CI, 0.46–0.99]; P = .045). Primary causes of death were cardiovascular disease (24 deaths; 22.4%), cancer (21 deaths; 19.6%), acute diabetes complications (19 deaths; 17.8%), and accidents or suicide (18 deaths; 16.8%). Higher levels of glycated hemoglobin (HbA1c) were associated with all-cause mortality (HR = 1.56 [95%CI, 1.35–1.81 per 10% relative increase in HbA1c]; P < .001), as well as the development of albuminuria (HR = 2.20 [95%CI, 1.46–3.31]; P < .001).
Conclusions and Relevance
After a mean of 27 years’ follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a modestly lower all-cause mortality compared with conventional therapy.
doi:10.1001/jama.2014.16107
PMCID: PMC4306335  PMID: 25562265
4.  Relationship of Glycated Albumin to Blood Glucose and HbA1c Values and to Retinopathy, Nephropathy, and Cardiovascular Outcomes in the DCCT/EDIC Study 
Diabetes  2013;63(1):282-290.
The association of chronic glycemia, measured by HbA1c, with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease (CVD) is less clear. In order to examine the interrelationships among long-term, intermediate-term, and acute measures of glucose and its daily variability, we compared HbA1c, glycated albumin (GA), and seven-point glucose profile concentrations measured longitudinally in a case-cohort subpopulation of the DCCT. HbA1c and GA were closely correlated with each other and with the mean blood glucose (MBG) calculated from the seven-point profile. The associations of glucose variability and postprandial concentrations with HbA1c and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA1c and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA1c was significantly associated with CVD. The demonstrated interrelationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes.
doi:10.2337/db13-0782
PMCID: PMC3868040  PMID: 23990364
5.  Identifying Change Points in a Covariate Effect on Time-to-Event Analysis with Reduced Isotonic Regression 
PLoS ONE  2014;9(12):e113948.
Isotonic regression is a useful tool to investigate the relationship between a quantitative covariate and a time-to-event outcome. The resulting non-parametric model is a monotonic step function of a covariate X and the steps can be viewed as change points in the underlying hazard function. However, when there are too many steps, over-fitting can occur and further reduction is desirable. We propose a reduced isotonic regression approach to allow combination of small neighboring steps that are not statistically significantly different. In this approach, a second stage, the reduction stage, is integrated into the usual monotonic step building algorithm by comparing the adjacent steps using appropriate statistical testing. This is achieved through a modified dynamic programming algorithm. We implemented the approach with the simple exponential distribution and then its extension, the Weibull distribution. Simulation studies are used to investigate the properties of the resulting isotonic functions. We apply this methodology to the Diabetes Control and Complication Trial (DCCT) data set to identify potential change points in the association between HbA1c and the risk of severe hypoglycemia.
doi:10.1371/journal.pone.0113948
PMCID: PMC4256386  PMID: 25473827
6.  Validity of Self Report in Type 1 Diabetic Subjects for Laser Treatment of Retinopathy 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.06.002.
Purpose
This study sought to determine the validity of self report of prior pan-retinal photocoagulation (PRP) and focal photocoagulation (FP) compared to fundus photography.
Design
Prospective cohort study.
Participants
1363 type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, a subset of the 1441 subjects originally enrolled in the multi-center Diabetes Control and Complications Trial.
Methods
At each annual visit, subjects were asked by EDIC staff whether they had PRP and/or FP since the last completed annual clinic visit. Fundus photographs were collected in one quarter of the cohort each year and in the whole cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.
Main Outcome Measures
Kappa, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.
Results
For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. Sensitivities for PRP and FP were 90.4 and 74.0%; specificities, 96.0 and 98.8%; positive predictive values, 75.9 and 80.3%; negative predictive values, 98.9 and 98.4%; and kappa 0.80 and 0.76. Risk factors associated with misreporting include prior laser for diabetic retinopathy and prior ocular surgery (each p <0.04).
Conclusions
For subjects with type 1 diabetes, in the absence of a clinical exam or fundus photographs, subject self report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.
doi:10.1016/j.ophtha.2013.06.002
PMCID: PMC3818390  PMID: 23890420
8.  Sample Size and Power for a Logrank Test and Cox Proportional Hazards Model with Multiple Groups and Strata, or a Quantitative Covariate with Multiple Strata 
Statistics in medicine  2013;32(25):4413-4425.
Summary
General expressions are described for the evaluation of sample size and power for the K group Mantel-logrank test or the Cox PH model score test. Under an exponential model, the method of Lachin and Foulkes [1] for the 2 group case is extended to the K ≥ 2 group case using the non-centrality parameter of the K – 1 df chi-square test. Similar results are also shown to apply to the K group score test in a Cox PH model. Lachin and Foulkes [1] employed a truncated exponential distribution to provide for a non-linear rate of enrollment. Expressions for the mean time of enrollment and the expected follow-up time in the presence of exponential losses-to-follow-up are presented. When used with the expression for the non-centrality parameter for the test, equations are derived for the evaluation of sample size and power under specific designs with R years of recruitment and T years total duration.
Sample size and power are also described for a stratified-adjusted K group test and for the assessment of a group by stratum interaction. Similarly computations are described for a stratified-adjusted analysis of a quantitative covariate and a test of a stratum by covariate interaction in the Cox PH model.
doi:10.1002/sim.5839
PMCID: PMC3775959  PMID: 23670965
Sample size; power; logrank test; Cox Proportional Hazards Model; multiple groups; exponential survival; stratified analysis; interactions
9.  Effects of Prior Intensive Versus Conventional Therapy and History of Glycemia on Cardiac Function in Type 1 Diabetes in the DCCT/EDIC 
Diabetes  2013;62(10):3561-3569.
Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis and the risk of cardiovascular disease (CVD) events in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared with conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years of additional follow-up in EDIC, left ventricular (LV) indices were measured by cardiac magnetic resonance (CMR) imaging in 1,017 of the 1,371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume (EDV), end systolic volume, stroke volume (SV), cardiac output (CO), LV mass, ejection fraction, LV mass/EDV, or aortic distensibility (AD). Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LV mass, LV mass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.
doi:10.2337/db12-0546
PMCID: PMC3781466  PMID: 23520132
10.  Haptoglobin Genotype and the Rate of Renal Function Decline in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes  2013;62(9):3218-3223.
Many patients with type 1 diabetes develop renal disease despite moderately good metabolic control, suggesting other risk factors may play a role. Recent evidence suggests that the haptoglobin (HP) 2-2 genotype, which codes for a protein with reduced antioxidant activity, may predict renal function decline in type 1 diabetes. We examined this hypothesis in 1,303 Caucasian participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. HP genotype was determined by polyacrylamide gel electrophoresis. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and albumin excretion based on timed urine samples. Participants were followed up for a mean of 22 years. HP genotype was significantly associated with the development of sustained estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 and with end-stage renal disease (ESRD), with HP 2-2 having greater risk than HP 2-1 and 1-1. No association was seen with albuminuria. Although there was no treatment group interaction, the associations were only significant in the conventional treatment group, where events rates were much higher. We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study.
doi:10.2337/db13-0256
PMCID: PMC3749329  PMID: 23761102
11.  Aortic Distensibility in Type 1 Diabetes 
Diabetes Care  2013;36(8):2380-2387.
OBJECTIVE
To evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes.
RESEARCH DESIGN AND METHODS
Eight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models.
RESULTS
The mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA1c measured over an average of 22 years (−26.3% per 10 years, −11.0% per 10 mmHg SBP, −1.8% per 10 mg/dL of LDL, and −9.3% per unit mean HbA1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (−3.4% per 0.1 g/mL; P < 0.0001).
CONCLUSIONS
Our findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort.
doi:10.2337/dc12-0393
PMCID: PMC3714531  PMID: 23474588
12.  Circulating Vitamin D Metabolites and Subclinical Atherosclerosis in Type 1 Diabetes 
Diabetes Care  2013;36(8):2423-2429.
OBJECTIVE
People with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study.
RESEARCH DESIGN AND METHODS
We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT.
RESULTS
At the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower—not higher—with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68–0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT.
CONCLUSIONS
We did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes.
doi:10.2337/dc12-2020
PMCID: PMC3714470  PMID: 23530012
13.  Rationale and Design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) 
Diabetes Care  2013;36(8):2254-2261.
OBJECTIVE
The epidemic of type 2 diabetes (T2DM) threatens to become the major public health problem of this century. However, a comprehensive comparison of the long-term effects of medications to treat T2DM has not been conducted. GRADE, a pragmatic, unmasked clinical trial, aims to compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.
RESEARCH DESIGN AND METHODS
GRADE was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The consensus protocol was approved by NIDDK and the GRADE Research Group. Eligibility criteria for the 5,000 metformin-treated subjects include <5 years' diabetes duration, ≥30 years of age at time of diagnosis, and baseline hemoglobin A1c (A1C) of 6.8–8.5% (51–69 mmol/mol). Medications representing four classes (sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and insulin) will be randomly assigned and added to metformin (minimum–maximum 1,000–2,000 mg/day). The primary metabolic outcome is the time to primary failure defined as an A1C ≥7% (53 mmol/mol), subsequently confirmed, over an anticipated mean observation period of 4.8 years (range 4–7 years). Other long-term metabolic outcomes include the need for the addition of basal insulin after a confirmed A1C >7.5% (58 mmol/mol) and, ultimately, the need to implement an intensive basal/bolus insulin regimen. The four drugs will also be compared with respect to selected microvascular complications, cardiovascular disease risk factors, adverse effects, tolerability, quality of life, and cost-effectiveness.
CONCLUSIONS
GRADE will compare the long-term effectiveness of major glycemia-lowering medications and provide guidance to clinicians about the most appropriate medications to treat T2DM. GRADE begins recruitment at 37 centers in the U.S. in 2013.
doi:10.2337/dc13-0356
PMCID: PMC3714493  PMID: 23690531
14.  Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™) 
Background
Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.
Methods
Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.
Results
Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015.
Discussion
EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.
Trial registration
Clinicaltrials.gov NCT01131676
doi:10.1186/1475-2840-13-102
PMCID: PMC4072621  PMID: 24943000
Blood pressure; Body weight; Empagliflozin; Glycemic control; Macrovascular; Microvascular; SGLT2 inhibitor; Type 2 diabetes
15.  The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes 
PURPOSE
We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT).
METHODS
From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine(FL) using isotope dilution method.
RESULTS
GSPNE and MG-H1 correlated with age and diabetes duration (p<0.02), while GSPNE and FL correlated with the history of glycemia expressed as mean A1c(p≤0.003). Age and duration-adjusted GSPNE and FL levels were lower in intensive (INT) vs. conventional (CONV) treatment subjects in the primary prevention DCCT cohort (p < 0.0001), and FL lower in INT in the secondary intervention cohort (p < 0.0001). GSPNE was associated with increased incidence of retinopathy progression (odds ratio (OR)/unit increase in GSPNE: 2.5 for 3 step progression on the ETDRS scale, p=0.003) and sustained ≥ 3 microaneurysms (MA) (OR=4.8, p<0.0001) from DCCT baseline up to the time of the biopsy, and prevalence of microalbuminuria or AER>40 mg/24 hr (OR=5.3, P<0.0001), and confirmed clinical neuropathy (OR=3.4, p=0.015) at the time of the biopsy. GSPNE adjusted for mean A1c remained significant for ≥ 3 MA (p=0.0252) and AER (p=0.0006). The strong association of complications with A1c was reduced or eliminated when adjusted for GSPNE.
CONCLUSIONS
Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications.
doi:10.1016/j.jdiacomp.2012.10.004
PMCID: PMC3577949  PMID: 23153673
Glycemia; retinopathy; nephropathy; collagen; methylglyoxal; advanced glycation endproducts (AGEs)
16.  Power of the Mantel-Haenszel and Other Tests for Discrete or Grouped Time-to-event Data Under a Chained Binomial Model 
Statistics in medicine  2012;32(2):220-229.
Summary
Power for time-to-event analyses is usually assessed under continuous time models. Often, however, times are discrete or grouped, as when the event is only observed when a procedure is performed. Wallenstein and Wittes (Biometrics, 1993) describe the power of the Mantel-Haenszel test for discrete life-tables under their chained binomial model for specified vectors of event probabilities over intervals of time. Herein the expressions for these probabilities are derived under a piecewise exponential model allowing for staggered entry and losses to follow-up.
Radhakrishna (Biometrics, 1965) showed that the Mantel-Haenszel test is maximally efficient under the alternative of a constant odds ratio and derived the optimal weighted test under other alternatives. Lachin (Biostatistical Methods: The Assessment of Relative Risks, 2011) describes the power function of this family of weighted Mantel-Haenszel tests. Prentice and Gloeckler (Biometrics, 1978) describe a generalization of the proportional hazards model for grouped time data, and the corresponding maximally efficient score test. Their test is also shown to be a weighted Mantel-Haenszel test and its power function is likewise obtained.
There is trivial loss in power under the discrete chained binomial model relative to the continuous-time case provided that there is a modest number of periodic evaluations. Relative to the case of homogeneity of odds ratios, there can be substantial loss in power when there is substantial heterogeneity of odds ratios, especially when heterogeneity occurs early in a study when most subjects are at risk, but little loss in power when there is heterogeneity late in a study.
doi:10.1002/sim.5480
PMCID: PMC3634579  PMID: 22807191
Sample size; power; Mantel-Haenszel test; chained binomial model; Cox Proportional Hazards Model; Prentice-Gloeckler discrete Proportional Hazards Model
17.  The effect of excess weight gain with intensive diabetes treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study 
Circulation  2012;127(2):10.1161/CIRCULATIONAHA.111.077487.
Rationale
Intensive diabetes therapy of type 1 diabetes (T1DM) reduces diabetes complications but can be associated with excess weight gain, central obesity, and dyslipidemia.
Objective
The purpose of this study was to determine if excessive weight gain with diabetes therapy of T1DM is prospectively associated with atherosclerotic disease.
Methods and Results
Subjects with T1DM (97% Caucasian, 45% female, mean age 35 years) randomly assigned to intensive (INT) or conventional (CONV) diabetes treatment during the Diabetes Control and Complications Trial (DCCT) underwent intima-media thickness (IMT) (n=1015) and coronary artery calcium (CAC) score (n=925) measurements during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. INT subjects were classified by quartile of BMI change during the DCCT. Excess gainers (4th quartile, including CONV subjects meeting this threshold) maintained greater BMI and waist circumference (WC), needed more insulin, had greater IMT (+5%, P<0.001 EDIC year 1, P=0.003 EDIC year 6), and trended towards greater CAC scores (OR 1.55, CI 0.97 – 2.49, P=0.07) than minimal gainers. DCCT subjects meeting metabolic syndrome criteria for WC and blood pressure had greater IMT in both EDIC years (P =0.02 to <0.001); those meeting HDL criteria had greater CAC scores (OR 1.6 and CI 1.1 – 2.4, P=0.01) during follow-up. Increasing frequency of a family history of diabetes, hypertension, and hyperlipidemia was associated with greater IMT thickness with INT but not CONV.
Conclusions
Excess weight gain in DCCT is associated with sustained increases in central obesity, insulin resistance, dyslipidemia and blood pressure, as well as more extensive atherosclerosis during EDIC.
doi:10.1161/CIRCULATIONAHA.111.077487
PMCID: PMC3819101  PMID: 23212717
diabetes mellitus; carotid intima media thickness; coronary artery calcium; imaging; obesity
18.  Relationship between Carotid Intima-Media Thickness and Left Ventricular Mass in Type 1 Diabetes: results from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study 
The American journal of cardiology  2012;110(10):1534-1540.
Introduction
Type 1 diabetes mellitus is associated with early atherosclerosis and enhanced cardiovascular mortality. The relationship between carotid IMT (cIMT), a marker of subclinical atherosclerosis and left ventricular (LV) mass, an independent predictor of cardiovascular morbidity has not been previously studied in type 1 diabetics.
Methods
The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter observational study designed to follow up the Diabetes Control and Complications Trial (DCCT) cohort. LV mass was measured with cardiac MRI at EDIC year 15 and common cIMT was assessed using B-mode ultrasound at EDIC year 12. Multivariable linear regression models were used to assess the relationship between cIMT at year 12 and LV mass at year 15.
Results
A total of 889 participants had both cardiac MRI and cIMT measures available for these analyses. At EDIC year 15, the mean age of the participants was 49 (±7) years; mean diabetes duration was 28 (±5) years and 52% were males. Spearman correlation coefficient (r) between LV mass and cIMT was 0.33 (p<0.0001). After adjusting for basic covariates (machine, reader, age and gender), a significant association between LV mass and cIMT (estimate 2.0 g/m2 per 0.1 mm cIMT increment, p < 0.0001) was observed. This association was diminished by the addition of systolic blood pressure in particular 1.15 g/m2 per 0.1 mm cIMT increment, p<0.0001) and to a lessor extent other cardiovascular disease (CVD) risk factors. The relationship observed between LV mass and cIMT was stronger (HOW MUCH) in patients with shorter diabetes duration.
Conclusion
In a well characterized population with type 1 diabetes, cIMT was an independent predictor of higher LV mass. These findings suggest a common pathway, possibly mediated by blood pressure dependent mechanisms, for vascular and myocardial structural change in T1DM.
doi:10.1016/j.amjcard.2012.07.014
PMCID: PMC3488435  PMID: 22884107
19.  Fall in C-Peptide During First 2 Years From Diagnosis 
Diabetes  2012;61(8):2066-2073.
Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was −0.0245 pmol/mL/month (95% CI −0.0271 to −0.0215) through the first 12 months and −0.0079 (−0.0113 to −0.0050) from 12 to 24 months (P < 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials.
doi:10.2337/db11-1538
PMCID: PMC3402330  PMID: 22688329
20.  Effect of rituximab on human in vivo antibody immune responses 
Background
B-lymphocyte depletion with rituximab has been shown to benefit patients with various autoimmune diseases. We have previously demonstrated that this benefit is also apparent in patients with newly diagnosed type 1 diabetes.
Objectives
The effect of rituximab on in vivo antibody responses, particularly during the period of B-lymphocyte depletion, is incompletely determined. This study was designed to assess this knowledge void.
Methods
In patients with recent-onset type 1 diabetes treated with rituximab (n = 46) or placebo (n = 29), antibody responses to neoantigen phiX174 during B-lymphocyte depletion and with hepatitis A (as a second neoantigen) and tetanus/diphtheria (as recall antigens) after B-lymphocyte recovery were studied. Anti- tetanus, diphtheria, mumps, measles, and rubella titers were measured before and after treatment by means of ELISA. Antibody titers and percentage IgM versus percentage IgG to phiX174 were measured by means of phage neutralization. B-lymphocyte subsets were determined by means of flow cytometry.
Results
No change occurred in preexisting antibody titers. Tetanus/diphtheria and hepatitis A immunization responses were protective in the rituximab-treated subjects, although significantly blunted compared with those seen in the controls subjects, when immunized at the time of B-lymphocyte recovery. Anti-phiX174 responses were severely reduced during the period of B-lymphocyte depletion, but with B-lymphocyte recovery, anti-phiX174 responses were within the normal range.
Conclusions
During the time of B-lymphocyte depletion, rituximab recipients had a decreased antibody response to neoantigens and significantly lower titers after recall immunization with diphtheria and tetanus toxoid. With recovery, immune responses return toward normal. Immunization during the time of B-lymphocyte depletion, although ineffective, does not preclude a subsequent response to the antigen.
doi:10.1016/j.jaci.2011.08.008
PMCID: PMC3659395  PMID: 21908031
B lymphocytes; human; diabetes; antibodies; immunization; CD20
21.  Point: Intensive Glycemic Control and Mortality in ACCORD—A Chance Finding? 
Diabetes Care  2010;33(12):2719-2721.
doi:10.2337/dc10-1506
PMCID: PMC2992220  PMID: 21115777
22.  Sample Size Evaluation for a Multiply Matched Case-Control Study Using the Score Test From a Conditional Logistic (Discrete Cox PH) Regression Model 
Statistics in medicine  2008;27(14):2509-2523.
Summary
The conditional logistic regression model (Breslow NE. Covariance adjustment of relative-risk estimates in matched studies. Biometrics, 1982; 38:661-672) provides a convenient method for the assessment of qualitative or quantitative covariate effects on risk in a study with matched sets, each containing a possibly different numbers of cases and controls. The conditional logistic likelihood is identical to the stratified Cox proportional hazards model likelihood with an adjustment for ties (Regression models and life-tables (with discussion). J. Roy. Statist. Soc., B, 1972; 34:187-220). This likelihood also applies to a nested case control study with multiply matched cases and controls selected from those at risk at selected event times. Herein the distribution of the score test for the effect of a covariate in the model is used to derive simple equations to describe the power of the test to detect a coefficient θ (log odds ratio or log hazard ratio), or the number of cases (or matched sets) and controls required to provide a desired level of power. Additional expressions are derived for a quantitative covariate as a function of the difference in the assumed mean covariate values among cases and controls, and for a qualitative covariate in terms of the difference in the probabilities of exposure for cases and controls. Examples are presented for a nested case-control study and a multiply matched case-control study.
doi:10.1002/sim.3057
PMCID: PMC3626499  PMID: 17886235
Sample size; power; conditional logistic model; Cox Proportional Hazards Model; multiple matching; case-control study; nested case-control study
23.  DCCT and EDIC Studies in Type 1 Diabetes: Lessons for Diabetic Neuropathy Regarding Metabolic Memory and Natural History 
Current diabetes reports  2010;10(4):276-282.
The DCCT/EDIC (Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications) provides a comprehensive characterization of the natural history of diabetic neuropathy in patients with type 1 diabetes and provides insight into the impact of intensive insulin therapy in disease progression. The lessons learned about the natural history of distal symmetrical polyneuropathy and cardiovascular autonomic neuropathy and the impact of glycemic control on neuropathy are discussed in this review.
doi:10.1007/s11892-010-0120-8
PMCID: PMC3608672  PMID: 20464532
Distal symmetrical polyneuropathy; Cardiovascular autonomic neuropathy; Nerve conduction studies; Heart rate variability studies; Glycemic control
24.  Myocardial Structure, Function and Scar in Patients with Type 1 Diabetes 
Circulation  2011;124(16):1737-1746.
BACKGROUND
We report relationships of cardiovascular disease (CVD) risk factors with myocardial structure, function and scar in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.
METHODS and RESULTS
Cardiac magnetic resonance (CMR) was obtained in 1017 patients with type 1 diabetes. Gadolinium CMR was also obtained in 741 patients. The mean age was 49 ± 7 years, 52% were men, and mean diabetes duration was 28± 5 years. Associations of CVD risk factors with CMR parameters were examined using linear and logistic regression models. History of macroalbuminuria was positively associated with LV mass (by +14.8 g) leading to a significantly higher LV mass/EDV ratio (by 8%). Mean hemoglobin A1c (HbA1c) levels over the preceding 22 years were inversely associated with end-diastolic volume (−3.0 ml per unit mean HbA1c %) and stroke volume (−2.3 ml per unit mean HbA1c %) and positively related to elevated LV mass/EDV ratio (0.02 g/ml per unit). The overall prevalence of myocardial scar was 4.3% by CMR and 1.4% by clinical adjudication of myocardial infarction. Both mean HbA1c (Odds ratio (O.R.) 1.5 [1.0–2.2] per unit) and macroalbuminuria (OR 3.5 [1.2–9.9]) were significantly associated with myocardial scar as well as traditional CVD risk factors.
CONCLUSIONS
In addition to traditional CVD risk factors, elevated mean HbA1c and macroalbuminuria were significantly associated with alterations in LV structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function.
doi:10.1161/CIRCULATIONAHA.111.022327
PMCID: PMC3215589  PMID: 21947298
Myocardial function; myocardial scar; type 1 diabetes; delayed enhancement; CMR
25.  Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in Type 1 diabetes 
Type 1 diabetes mellitus (T1DM) is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte antibody can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease- associated target antigens, and C-peptide levels of participants that did (responders) or did not (non-responders) show signs of β-cell preservation one year after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after 4 weekly doses of mAb. T cell proliferative responses to diabetes –associated antigens were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 months (58%), the proliferative responses to diabetes associated total (p=0.032), islet-specific (p=0.048), and neuronal auto-antigens (p=0.005) increased over the 12 month observation period. This relationship was not seen in placebo treated patients. We conclude that in patients with T1DM, anti-B cell mAb causes increased proliferative responses to diabetes antigens and attenuated β cell loss. The way in which these responses affect the disease course remains unknown.
doi:10.4049/jimmunol.1100539
PMCID: PMC3150302  PMID: 21775681
type 1 diabetes; biomarker; B lymphocyte; cellular immunology; T lymphocyte

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