Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale.

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

Effect of Incorporating 1 Avocado Per Day Versus Habitual Diet on Visceral Adiposity: A Randomized Trial.

Background Excess visceral adiposity is associated with increased risk of cardiometabolic disorders. Short-term well-controlled clinical trials suggest that regular avocado consumption favorably affects body weight, visceral adiposity, and satiety. Methods and Results The HAT Trial (Habitual Diet and Avocado Trial) was a multicenter, randomized, controlled parallel-arm trial designed to test whether consuming 1 large avocado per day for 6 months in a diverse group of free-living individuals (N=1008) with an elevated waist circumference compared with a habitual diet would decrease visceral adiposity as measured by magnetic resonance imaging. Secondary and additional end points related to risk factors associated with cardiometabolic disorders were assessed. The primary outcome, change in visceral adipose tissue volume during the intervention period, was not significantly different between the Avocado Supplemented and Habitual Diet Groups (estimated mean difference (0.017 L [-0.024 L, 0.058 L], P=0.405). No significant group differences were observed for the secondary outcomes of hepatic fat fraction, hsCRP (high-sensitivity C-reactive protein), and components of the metabolic syndrome. Of the additional outcome measures, modest but nominally significant reductions in total and low-density lipoprotein cholesterol were observed in the Avocado Supplemented compared with the Habitual Diet Group. Changes in the other additional and post hoc measures (body weight, body mass index, insulin, very low-density lipoprotein concentrations, and total cholesterol:high-density lipoprotein cholesterol ratio) were similar between the 2 groups. Conclusions Addition of 1 avocado per day to the habitual diet for 6 months in free-living individuals with elevated waist circumference did not reduce visceral adipose tissue volume and had minimal effect on risk factors associated with cardiometabolic disorders. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT03528031.

Changes in Cardiovascular Risk Factors Over 6 Years in Young Adults in a Randomized Trial of Weight Gain Prevention.

OBJECTIVE: This study aimed to determine the impact of weight gain prevention interventions on changes in cardiovascular risk factors over 6 years. METHODS: The Study of Novel Approaches to Weight Gain Prevention (SNAP) randomized 599 participants (ages 18-35; 46% with BMI 21-25; 54% with BMI 25-30) to Large Changes (produce buffer by losing 5-10 pounds initially), Small Changes (daily small changes in intake and activity) or Control and followed 355 participants with ongoing intervention and assessments through 6 years. RESULTS: There were no significant differences among interventions for changes in weight or cardiovascular disease (CVD) risk factors from baseline to 6 years. However, 44% of participants gained ≥5%, and only 14% lost ≥5% over 6 years. Weight changes, from baseline to year 6, were significantly associated with changes in risk factors, especially insulin and high-density lipoprotein cholesterol. Earlier weight changes (e.g., weight cycling) had no beneficial or adverse effect on changes in CVD risk factors at 6 years, independent of 6-year weight changes. CONCLUSIONS: Despite participation in a weight gain prevention trial, almost half of these young adults gained ≥5% or more over 6 years, with significant worsening in CVD risk factors. Greater attention to long-term weight gain prevention in young adults is needed.

Examining Heterogeneity of Outcomes in a Weight Gain Prevention Program for Young Adults.

OBJECTIVE: This study aimed to characterize young adults who experienced significant weight gains (> 10%) over 3 years in a weight gain prevention program. METHODS: Secondary data analysis from the Study of Novel Approaches to Weight Gain Prevention (SNAP), a randomized trial comparing two self-regulation interventions and a control arm in young adults (18-35 years; BMI 21-30.9 kg/m2 ), was used. Large Gainers (≥ 10% of their body weight; n = 48), Small Gainers (2.6%-9.9%; n = 149), and Weight Stable participants (± 2.5%; n = 143) were compared on dimensions affecting weight gain. RESULTS: Differences in weight gain among the three groups were significant by year 1 and subsequently increased. Those who became Large Gainers were heavier at baseline and further below their highest weight, and they reported more weight cycling than Weight Stable, with Small Gainers intermediate. Neither study arm nor pregnancy explained weight change differences among the three groups. Large Gainers reported more depressive symptoms than Weight Stable at years 1 and 2. Large Gainers were less likely to weigh themselves at least weekly at 4 months, before differences in weight gain emerged, and at years 1 and 2. CONCLUSIONS: Large Gainers (representing almost 10% of participants) could be identified early by greater weight issues at baseline and lower use of weight gain prevention strategies.

Weight Gain Over 6 Years in Young Adults: The Study of Novel Approaches to Weight Gain Prevention Randomized Trial.

OBJECTIVE: The study objective was to determine whether two self-regulation interventions that reduced 3-year weight gain in young adults remain effective at 6 years. METHODS: A randomized trial was conducted in two academic settings in 599 young adults, aged 18 to 35 years, with normal weight or overweight; 504 (84%) reconsented for a 6-year extension (Study of Novel Approaches to Weight Gain Prevention-Extended [SNAP-E]) with ongoing intervention and assessments. Weight gain over 6 years was compared for all assigned to Control, Large Changes (LC; lose 5-10 pounds initially), and Small Changes (SC; make small daily changes in intake and activity). RESULTS: Weight change from baseline to 6 years did not differ significantly among the three groups (Control = 3.9 kg, SC = 4.1 kg, and LC = 2.8 kg). However, there was a significant age-by-treatment interaction (P = 0.002). Among those < 25 years old, weight gain from baseline to 6 years averaged 7.3 kg in the Control group and was reduced by almost 50% in LC and SC. LC also significantly reduced mean weight gain (area under the curve) over 6 years compared with Control or SC. CONCLUSIONS: Although the interventions did not reduce weight gain at 6 years for the full cohort, they were effective in those < 25 years old. Future efforts should focus on young adults aged 18 to 24.9 and test more intensive interventions with more diverse participants.

Innovative Self-Regulation Strategies to Reduce Weight Gain in Young Adults: The Study of Novel Approaches to Weight Gain Prevention (SNAP) Randomized Clinical Trial.

IMPORTANCE: Weight gain occurs commonly in young adults and has adverse effects on health. OBJECTIVE: To compare 2 self-regulation interventions vs control in reducing weight gain in young adults over a mean follow-up of 3 years. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial in 2 academic settings of 599 participants aged 18 to 35 years with body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 21.0 to 30.0, recruited via mailings and emails from August 2010 to February 2012. Data were analyzed from January 2015 to January 2016. INTERVENTIONS: Participants were randomized to control, self-regulation plus small changes, or self-regulation plus large changes. Both interventions focused on frequent self-weighing to cue behavior changes. "Small changes" taught participants to reduce intake and increase activity, both by approximately 100 calories per day. "Large changes" focused on losing 2.3 to 4.5 kg initially to buffer against expected weight gain. MAIN OUTCOMES AND MEASURES: Changes in weight from baseline over mean follow-up of 3 years. Secondary outcomes included proportion gaining at least 0.45 kg from baseline, proportion developing obesity (BMI, ≥30.0), and weight change baseline to 2 years. RESULTS: Among the 599 participants (22% men; 27% minority; mean [SD] age, 27.7 [4.4] years; mean [SD] BMI, 25.4 [2.6]), mean (SE) weight changes over a mean follow-up of 3 years were 0.26 (0.22), -0.56 (0.22), and -2.37 (0.22) kg in the control, small-changes, and large-changes groups, respectively (P < .001). Differences among all 3 groups were significant (large changes vs control, P < .001; small changes vs control, P = .02; large changes vs small changes, P < .001). On secondary outcomes, both interventions significantly reduced incidence of obesity relative to control (mean [SE], 8.6% [2.0%], 7.9% [2.0%], and 16.9% [2.7%] in the large-changes, small-changes, and control groups, respectively; P = .02 for large changes vs control and P = .002 for small changes vs control); a smaller percentage of participants in the large-changes group gained 0.45 kg or more (mean [SE], 23.6% [2.8%], 32.5% [3.8%], and 40.8% [4.4%], respectively; P < .001 vs control and P = .02 vs small changes) and weight change from baseline to 2 years was greater in control than in small or large changes (mean [SE], 0.54 [0.33], -0.77 [0.33], and -1.50 [0.34] kg, respectively; P = .02 vs small changes and P < .001 vs large changes). CONCLUSIONS AND RELEVANCE: Self-regulation with large or small changes both reduced weight gain in young adults over 3 years relative to control, but the large-changes intervention was more effective. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01183689.

Recruitment strategies and challenges in a large intervention trial: Systolic Blood Pressure Intervention Trial.

BACKGROUND: The Systolic Blood Pressure Intervention Trial is a multicenter, randomized clinical trial of 9361 participants with hypertension who are ≥50 years old. The trial is designed to evaluate the effect of intensive systolic blood pressure control (systolic blood pressure goal <120 mm Hg) compared to standard control (systolic blood pressure goal <140 mm Hg) on cardiovascular events using commonly prescribed antihypertensive medications and lifestyle modification. OBJECTIVE: To describe the recruitment strategies and lessons learned during recruitment of the Systolic Blood Pressure Intervention Trial cohort and five targeted participant subgroups: pre-existing cardiovascular disease, pre-existing chronic kidney disease, age ≥75 years, women, and minorities. METHODS: In collaboration with the National Institutes of Health Project Office and Systolic Blood Pressure Intervention Trial Coordinating Center, five Clinical Center Networks oversaw clinical site selection, recruitment, and trial activities. Recruitment began on 8 November 2010 and ended on 15 March 2013 (about 28 months). Various recruitment strategies were used, including mass mailing, brochures, referrals from healthcare providers or friends, posters, newspaper ads, radio ads, and electronic medical record searches. RESULTS: Recruitment was scheduled to last 24 months to enroll a target of 9250 participants; in just over 28 months, the trial enrolled 9361 participants. The trial screened 14,692 volunteers, with 33% of initial screens originating from the use of mass mailing lists. Screening results show that participants also responded to recruitment efforts through referral by Systolic Blood Pressure Intervention Trial staff, healthcare providers, or friends (45%); brochures or posters placed in clinic waiting areas (15%); and television, radio, newspaper, Internet ads, or toll-free numbers (8%). The overall recruitment yield (number randomized/number screened) was 64% (9361 randomized/14,692 screened), 77% for those with cardiovascular disease, 79% for those with chronic kidney disease, 70% for those aged ≥75 years, 55% for women, and 61% for minorities. As recruitment was observed to lag behind expectations, additional clinics were included and inclusion criteria were broadened, keeping event rates and trial power in mind. As overall recruitment improved, a greater focus on subgroup recruitment was implemented. CONCLUSION: Systolic Blood Pressure Intervention Trial met its overall projected recruitment goal using diverse, locally adapted enrollment strategies to specifically target persons with cardiovascular disease, chronic kidney disease, ≥75 years old, women, and minority subgroups. The trial exceeded its recruitment goal for minorities but found it a challenge to meet the competing demands of the targeted goals for recruiting into the remaining four subgroups. Important lessons include the imperative to monitor the recruitment process carefully, decide early to add new clinics or modify inclusion and exclusion criteria if recruitment lags, and consider limiting enrollment to subgroups only. We found benefit in using multiple recruitment sources simultaneously; mass mailing produced the largest number of participants, but referrals resulted in the greater randomization yield.

The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study.

PURPOSE: To report additional ocular outcomes of intensive treatment of hyperglycemia, blood pressure, and dyslipidemia in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. DESIGN: Double 2×2 factorial, multicenter, randomized clinical trials in people with type 2 diabetes who had cardiovascular disease or cardiovascular risk factors. In the glycemia trial, targets of intensive and standard treatment were: hemoglobin A1c <6.0% and 7.0% to 7.9%, respectively, and in the blood pressure trial: systolic blood pressures of <120 and <140 mmHg, respectively. The dyslipidemia trial compared fenofibrate plus simvastatin with placebo plus simvastatin. PARTICIPANTS: Of the 3472 ACCORD Eye Study participants enrolled, 2856 had 4-year data (85% of survivors). METHODS: Eye examinations and fundus photographs were taken at baseline and year 4. Photographs were graded centrally for retinopathy severity and macular edema using the Early Treatment Diabetic Retinopathy Study (ETDRS) methods. MAIN OUTCOME MEASURES: Three or more steps of progression on the ETDRS person scale or treatment of retinopathy with photocoagulation or vitrectomy. RESULTS: As previously reported, there were significant reductions in the primary outcome in the glycemia and dyslipidemia trials, but no significant effect in the blood pressure trial. Results were similar for retinopathy progression by 1, 2, and 4 or more steps on the person scale and for ≥ 2 steps on the eye scale. In the subgroup of patients with mild retinopathy at baseline, effect estimates were large (odds ratios, ∼0.30; P < 0.001), but did not reach nominal significance for participants with no retinopathy or for those with moderate to severe retinopathy at baseline. CONCLUSIONS: Slowing of progression of retinopathy by intensive treatment of glycemia was observed in ACCORD participants, whose average age and diabetes duration were 62 and 10 years, respectively, and who had cardiovascular disease or cardiovascular risk factors. The effect seemed stronger in patients with mild retinopathy. Similar slowing of progression was observed in patients treated with fenofibrate, with no effect observed with intensive blood pressure treatment. This is the second study to confirm the benefits of fenofibrate in reducing diabetic retinopathy progression, and fenofibrate should be considered for treatment of diabetic retinopathy.

Comparison of standardized clinical classification with fundus photograph grading for the assessment of diabetic retinopathy and diabetic macular edema severity.

PURPOSE: To compare evaluation by clinical examination with image grading at a reading center for the classification of diabetic retinopathy and diabetic macular edema. METHODS: Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Family Investigations of Nephropathy in Diabetes (FIND) had similar methods of clinical and fundus photograph evaluation. For analysis purposes, the photographic grading scales were condensed to correspond to the clinical scales, and agreement between clinicians and reading center classification were compared. RESULTS: Six thousand nine hundred and two eyes of ACCORD participants and 3,638 eyes of FIND participants were analyzed for agreement (percent, kappa) on diabetic retinopathy on a 5-level scale. Exact agreement between clinicians and reading center on diabetic retinopathy severity category was 69% in ACCORD and 74% in FIND (kappa 0.42 and 0.65). Sensitivities of the clinical grading to identify the presence of mild nonproliferative retinopathy or worse were 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. Diabetic macular edema agreement in 6,649 eyes of ACCORD participants and 3,366 eyes of FIND participants was similar (kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify diabetic macular edema were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively. CONCLUSION: The results support the use of clinical information for defining broad severity categories but not for documenting small-to-moderate changes in diabetic retinopathy over time.

Design of the value of imaging in enhancing the wellness of your heart (VIEW) trial and the impact of uncertainty on power.

BACKGROUND: Although observational evidence has suggested that the measurement of coronary artery calcium (CAC) may improve risk stratification for cardiovascular events and thus help guide the use of lipid-lowering therapy, this contention has not been evaluated within the context of a randomized trial. The Value of Imaging in Enhancing the Wellness of Your Heart (VIEW) trial is proposed as a randomized study in participants at low intermediate risk of future coronary heart disease (CHD) events to evaluate whether CAC testing leads to improved patient outcomes. PURPOSE: To describe the challenges encountered in designing a prototypical screening trial and to examine the impact of uncertainty on power. METHODS: The VIEW trial was designed as an effectiveness clinical trial to examine the benefit of CAC testing to guide therapy on a primary outcome consisting of a composite of nonfatal myocardial infarction, probable or definite angina with revascularization, resuscitated cardiac arrest, nonfatal stroke (not transient ischemic attack (TIA)), CHD death, stroke death, other atherosclerotic death, or other cardiovascular disease (CVD) death. Many critical choices were faced in designing the trial, including (1) the choice of primary outcome, (2) the choice of therapy, (3) the target population with corresponding ethical issues, (4) specifications of assumptions for sample size calculations, and (5) impact of uncertainty in these assumptions on power/sample size determination. RESULTS: We have proposed a sample size of 30,000 (800 events), which provides 92.7% power. Alternatively, sample sizes of 20,228 (539 events), 23,138 (617 events), and 27,078 (722 events) provide 80%, 85%, and 90% power. We have also allowed for uncertainty in our assumptions by computing average power integrated over specified prior distributions. This relaxation of specificity indicates a reduction in power, dropping to 89.9% (95% confidence interval (CI): 89.8-89.9) for a sample size of 30,000. Samples sizes of 20,228, 23,138, and 27,078 provide power of 78.0% (77.9-78.0), 82.5% (82.5-82.6), and 87.2% (87.2-87.3), respectively. LIMITATIONS: These power estimates are dependent on form and parameters of the prior distributions. CONCLUSIONS: Despite the pressing need for a randomized trial to evaluate the utility of CAC testing, conduct of such a trial requires recruiting a large patient population, making efficiency of critical importance. The large sample size is primarily due to targeting a study population at relatively low risk of a CVD event. Our calculations also illustrate the importance of formally considering uncertainty in power calculations of large trials as standard power calculations may tend to overestimate power.

Biobanking, consent, and commercialization in international genetics research: the Type 1 Diabetes Genetics Consortium.

BACKGROUND: and PURPOSE: This article describes several ethical, legal, and social issues typical of international genetics biobanking, as encountered in the Type 1 Diabetes Genetics Consortium (T1DGC). METHODS: By studying the examples set and lessons learned from other international biobanking studies and by devoting considerable time and resources to identifying, addressing, and continually monitoring ethical and regulatory concerns, T1DGC was able to minimize the problems reported by some earlier studies. CONCLUSIONS: Several important conclusions can be drawn based on the experience in this study: (1) Basic international standards for research ethics review and informed consent are broadly consistent across developed countries. (2) When consent forms are adapted locally and translated into different languages, discrepancies are inevitable and therefore require prompt central review and resolution before research is initiated. (3) Providing separate 'check-box' consent for different elements of a study creates confusion and may not be essential. (4) Creating immortalized cell lines to aid future research is broadly acceptable, both in the US and internationally. (5) Imposing some limits on the use of stored samples aids in obtaining ethics approvals worldwide. (6) Allowing potential commercial uses of donated samples is controversial in some Asian countries. (7) Obtaining government approvals can be labor-intensive and time-consuming, and can require legal and diplomatic skills.

Measurement of islet cell antibodies in the Type 1 Diabetes Genetics Consortium: efforts to harmonize procedures among the laboratories.

BACKGROUND: and PURPOSE: Three network laboratories measured antibodies to islet autoantigens. Antibodies to glutamic acid decarboxylase (GAD65 [GADA]) and the intracellular portion of protein tyrosine phosphatase (IA-2(ic) [IA-2A]) were measured by similar, but not identical, methods in samples from participants in the Type 1 Diabetes Genetics Consortium (T1DGC). METHODS: All laboratories used radiobinding assays to detect antibodies to in vitro transcribed and translated antigen, but with different local standards, calibrated against the World Health Organization (WHO) reference reagent. Using a common method to calculate WHO units/mL, we compared results reported on samples included in the Diabetes Autoantibody Standardization Program (DASP), and developed standard methods for reporting in WHO units/mL. We evaluated intra-assay and inter-assay coefficient of variation (CV) in blind duplicate samples and assay comparability in four DASP workshops. RESULTS: Values were linearly related in the three laboratories for both GADA and IA-2A, and intra-assay technical errors for values within the standard curve were below 13% for GADA and below 8.5% for IA-2A. Correlations in samples tested 1-2 years apart were >97%. Over the course of the study, internal CVs were 10-20% with one exception, and the laboratories concordantly called samples GADA or IA-2A positive or negative in 96.7% and 99.6% of duplicates within the standard curve. Despite acceptable CVs and general concordance in ranking samples, the laboratories differed markedly in absolute values for GADA and IA-2A reported in WHO units/mL in DASP over a large range of values. LIMITATIONS: With three laboratories using different assay methods (including calibrators), consistent values among them could not be attained. CONCLUSIONS: Modifications in the assays are needed to improve comparability of results expressed as WHO units/mL across laboratories. It will be essential to retain high intra- and inter-assay precision, sensitivity and specificity and to confirm the accuracy of harmonized methods.

Effects of medical therapies on retinopathy progression in type 2 diabetes.

BACKGROUND: We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS: In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS: At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

HLA genotyping in the international Type 1 Diabetes Genetics Consortium.

BACKGROUND: Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers. PURPOSE: In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years. METHODS: Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences. RESULTS: A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances. LIMITATIONS: The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required. CONCLUSIONS: High-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies.

Collection and processing of whole blood for transformation of peripheral blood mononuclear cells and extraction of DNA: the Type 1 Diabetes Genetics Consortium.

BACKGROUND: and PURPOSE: To yield large amounts of DNA for many genotype analyses and to provide a renewable source of DNA, the Type 1 Diabetes Genetics Consortium (T1DGC) harvested DNA and peripheral blood mononuclear cells (PBMCs) from individuals with type 1 diabetes and their family members in several regions of the world. METHODS: DNA repositories were established in Asia-Pacific, Europe, North America, and the United Kingdom. To address region-specific needs, different methods and sample processing techniques were used among the laboratories to extract and to quantify DNA and to establish Epstein-Barr virus transformed cell lines. RESULTS: More than 98% of the samples of PBMCs were successfully transformed. Approximately 20-25 microg of DNA were extracted per mL of whole blood. Extraction of DNA from the cell pack ranged from 92 to 165 microg per cell pack. In addition, the extracted DNA from whole blood or transformed cells was successfully utilized in each regional human leukocyte antigen genotyping laboratory and by several additional laboratories performing consortium-wide genotyping projects. LIMITATIONS: Although the isolation of PBMCs was consistent among sites, the measurement of DNA was difficult to harmonize. CONCLUSIONS: DNA repositories can be established in different regions of the world and produce similar amounts of high-quality DNA for a variety of high-throughput genotyping techniques. Furthermore, even with the distances and time necessary for transportation, highly efficient transformation of PBMCs is possible. For future studies/trials involving several laboratories in different locations, the T1DGC experience includes examples of protocols that may be applicable. In summary, T1DGC has developed protocols that would be of interest to any scientific organization attempting to overcome the logistical problems associated with studies/trials spanning multiple research facilities, located in different regions of the world.

Quality control of phenotypic forms data in the Type 1 Diabetes Genetics Consortium.

BACKGROUND: When collecting phenotypic data in clinics across the globe, the Type 1 Diabetes Genetics Consortium (T1DGC) used several techniques that ensured consistency, completeness, and accuracy of the data. PURPOSE: The aim of this article is to describe the procedures used for collection, entry, processing, and management of the phenotypic data in this international study. METHODS: The T1DGC ensured the collection of high quality data using the following procedures throughout the entire study period. The T1DGC used centralized and localized training, required a pilot study, certified all data entry personnel, created standardized data collection forms, reviewed a sample of form sets quarterly throughout the duration of the study, and used a data entry system that provided immediate feedback to those entering the data. RESULTS: Due to the intensive procedures in developing the forms, the study was able to uphold consistency among all clinics and minimal changes were required after implementation of the forms. The train-the-trainer model was efficient and only a small number of clinics had to repeat a pilot study. The study was able to maintain a low percentage of missing data (<0.001%) and low duplicate data entry error rate (0.10%). CONCLUSIONS: It is critical to provide immediate follow-up in order to reinforce training and ensure the quality of the data collected and entered.

Designing and implementing sample and data collection for an international genetics study: the Type 1 Diabetes Genetics Consortium (T1DGC).

BACKGROUND AND PURPOSE: The Type 1 Diabetes Genetics Consortium (T1DGC) is an international project whose primary aims are to: (a) discover genes that modify type 1 diabetes risk; and (b) expand upon the existing genetic resources for type 1 diabetes research. The initial goal was to collect 2500 affected sibling pair (ASP) families worldwide. METHODS: T1DGC was organized into four regional networks (Asia-Pacific, Europe, North America, and the United Kingdom) and a Coordinating Center. A Steering Committee, with representatives from each network, the Coordinating Center, and the funding organizations, was responsible for T1DGC operations. The Coordinating Center, with regional network representatives, developed study documents and data systems. Each network established laboratories for: DNA extraction and cell line production; human leukocyte antigen genotyping; and autoantibody measurement. Samples were tracked from the point of collection, processed at network laboratories and stored for deposit at National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repositories. Phenotypic data were collected and entered into the study database maintained by the Coordinating Center. RESULTS: T1DGC achieved its original ASP recruitment goal. In response to research design changes, the T1DGC infrastructure also recruited trios, cases, and controls. Results of genetic analyses have identified many novel regions that affect susceptibility to type 1 diabetes. T1DGC created a resource of data and samples that is accessible to the research community. LIMITATIONS: Participation in T1DGC was declined by some countries due to study requirements for the processing of samples at network laboratories and/or final deposition of samples in NIDDK Central Repositories. Re-contact of participants was not included in informed consent templates, preventing collection of additional samples for functional studies. CONCLUSIONS: T1DGC implemented a distributed, regional network structure to reach ASP recruitment targets. The infrastructure proved robust and flexible enough to accommodate additional recruitment. T1DGC has established significant resources that provide a basis for future discovery in the study of type 1 diabetes genetics.

Lack of association between thiazolidinediones and macular edema in type 2 diabetes: the ACCORD eye substudy.

OBJECTIVE: To assess the cross-sectional association of thiazolidinediones with diabetic macular edema (DME). METHODS: The cross-sectional association of DME and visual acuity with thiazolidinediones was examined by means of baseline fundus photographs and visual acuity measurements from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Visual acuity was assessed in 9690 participants in the ACCORD trial, and 3473 of these participants had fundus photographs that were centrally read in a standardized fashion by masked graders to assess DME and retinopathy from October 23, 2003, to March 10, 2006. RESULTS: Among the subsample, 695 (20.0%) people had used thiazolidinediones, whereas 217 (6.2%) people had DME. Thiazolidinedione use was not associated with DME in unadjusted (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.71-1.44; P = .95) and adjusted (OR, 0.97; 95% CI, 0.67-1.40; P = .86) analyses. Significant associations with DME were found for retinopathy severity (P < .001) and age (OR, 0.97; 95% CI, 0.952-0.997; P = .03) but not for hemoglobin A(1c) (P = .06), duration of diabetes (P = .65), sex (P = .72), and ethnicity (P = .20). Thiazolidinedione use was associated with slightly greater visual acuity (0.79 letter; 95% CI, 0.20-1.38; P = .009) of uncertain clinical significance. CONCLUSIONS: In a cross-sectional analysis of data from the largest study to date, no association was observed between thiazolidinedione exposure and DME in patients with type 2 diabetes; however, we cannot exclude a modest protective or harmful association. Trial Registration clinicaltrials.gov Identifier: NCT00542178.