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Background: Patients with type 2 diabetes (T2D) are at high risk of cardiovascular (CV) morbidity/mortality. The ACCORD trial (NCT00000620) tested intensive glycemic, lipid and blood pressure interventions on major CV events in 10,251 T2D patients with baseline HbA1c concentration >7.5%. Despite its landmark findings, a data-driven systematic evaluation of predictors for major cardiovascular events among hundreds of ACCORD variables has not been conducted. Methods: Random Survival Forest (RSF), a machine-learning method for survival analysis, identified important predictors for total mortality (TM), CV death (CVd), hospitalization/death due to heart failure (hdHF), fatal/non-fatal stroke (CVA), non-fatal myocardial infarction (MI) and MACE (composite of CVd, MI and CVA). Among 378 risk factors, including some highly correlated features, the top-ranked predictors (collected at baseline or derived from repeated measures prior to events) were selected, resulting in a hierarchy of predictive variables. Effects of RSF-selected predictors were then evaluated by multivariate Cox Proportional Hazards Models. Results: Table 1 presented the top ten predictors for six major events. Variables associated with changes in renal function predicted TM, CVd, and hdHF with ~90% accuracy. Insulin use was an important predictor along with predefined composite renal microvascular events for MI, CVA and MACE (74-79% accuracy). The Cox regression models based on RSF variable selection yielded similar findings for these important predictors of events. Conclusions: RSF approach revealed that insulin use and overt renal microvascular events were predictors for the occurrence of MI, stroke, and MACE in T2D patients. Moreover, dynamic changes in urinary renal function biomarkers had additional predictive values for fatal events. These results provide important clinical insights for reducing CV events in Type 2 diabetes patients.

Introduction: An objective of the Meta-AnalyTical Interagency Group (MATIG) is to conduct patient-level meta-analyses of cardiovascular outcomes using data from publicly available repositories. We describe challenges with data re-use from a seminal trial, provide a systematic approach to identify and curate data elements for hypothesis generation, and establish stackable trials to support these analyses. Methods: We used data from the ACCORD trial to assess risk factors and their gender specific differences for the event of hospitalization or death due to heart failure (hdHF), in patients with type 2 diabetes*. We identified the data elements needed to answer the research questions, reviewed the trial protocol to verify definitions, extracted patient-level data, performed quality assessment and statistical analysis. The results showed a gender difference in the effect of intensive vs. standard glucose-lowering therapy on hdHF. To validate the findings, we sought additional trials in BioLINCC to develop a compendium for meta-analysis, and repeated these steps for each trial. Results: Challenges for reusing the ACCORD trial included access to complete patient-level data and metadata. The compendium, developed to evaluate the stackability** of data across trials, identified differences in trial designs, patient populations, study interventions, and data elements that may impact the feasibility and interpretation of meta-analysis. An example of compendium components is shown in Table 1. Conclusion: High-quality metadata facilitate re-use of trial repository data. This compendium standardizes common data elements for gender, racial and age-group specific outcome assessment in major clinical trials. It provides the framework to assess the fitness of trials for patient-level meta-analyses. Efforts are underway by MATIG to expand the compendium to include risk factors and major cardiovascular outcomes across multiple large trials for meta-analysis.

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial was designed to test whether raising HDL levels with niacin reduces cardiovascular risk given that LDL levels are controlled with a statin. We sought to identify

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) was a randomized, double-blind, placebo-controlled designed to test whether treatment with spironolactone reduces hospitalization due to heart failure (hHF), cardiovascular mortality, or aborted cardiac

Coronary artery disease is the leading cause of death in Type 2 diabetes patients (T2D) with lipid abnormalities. Fibrates have emerged as second-line agents to reduce circulating triglycerides and elevate HDL-C. The ACCORD Lipid study, a subset of the ACCORD trial([NCT00000620][1]), investigated

Background: Patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) often exhibit myocardial insulin resistance, potentially contributing to morbidity and mortality. In a prior secondary analysis of publicly available ACCORD data, we noted increased hospitalization or death due to heart

Ethnicity is an important factor known to impact the biology and outcome of many cancers. In pancreatic cancer, African Americans are thought to have a higher incidence and poorer prognosis than Whites.A total 645 pancreatic cancer patients were identified in the database, of which, 530 patients were eligible for this study and retained for the statistical analysis. Of the 530 patients, 137 (25.8%) were Blacks, 393 (74.2%) were Whites, 275 (51.9%) were males and 255 (48.1) were females. Ages ranged from 21 to 93 years with values of 62.3+/-13.3 years, 64.2+/-11.6 years, 63.1+/-10.9 and 64.3+/-13.3 (mean+/-SD) for Blacks, Whites, males, and females, respectively. Overall, 132 patients out of 415 (31.8%) were seen in stage I, 61 (14.7%) in stage II, 105 (25.3%) in stage III, 117 (28.2%) in stage IV, while 115 patients (21.7%) had missing stage.There were no significant differences between Blacks and Whites with respect to distributions across stages (P=0.422). Adenocarcinoma was the most common histology in both ethnicities with poor differentiation in 47.4% of Blacks and 57.0% of Whites. Overall, 125 (23.6%) received surgery alone, 54 (10.2%) surgery with chemotherapy, 5 (0.9%) surgery with external radiation therapy, 10 (1.9%) external radiation therapy alone, 68 (12.8%) chemotherapy alone, 58 (10.9%) chemo-external radiation therapy, and 210 (39.6%) no therapy. Overall, only 22 patients survived at 5-yr (4.2%). Median survival was 8.0 months for Blacks (95% CI: 6.4-10.2) and 8.1 months for Whites (95% CI: 7.1-9.7) and there was no significant difference in survival between Blacks and Whites (P=0.971). There were more survivors in females (43/255, 16.9%) than in males (25/275, 9.1%; P=0.009), and females had significantly greater survival times as compared to males (P=0.022).Pancreatic cancer is a disease of both ethnicities with a slight male predominance among Whites and female predominance among Blacks. We did not find any significant difference in the treatment specific outcome and survival between Blacks and Whites.

Ovarian carcinoma has a high mortality rate, because most ovarian carcinomas are detected at a late stage. Traditional therapies, such as surgical debulking and chemotherapy, have not been successful in improving the long-term survival of these patients. Alternative therapies targeting various biomarkers, such as carcinoembryonic antigen (CEA), Tag-72, and Lewis-Y antigen, have been developed to treat patients with advanced ovarian cancers. To ensure that therapies targeting these biomarkers are effective, it is imperative to determine whether there is any differential expression of these targeted biomarkers between primary and metastatic ovarian carcinomas. In the present study, primary and metastatic lesions from 68 and 58 patients, respectively, including primary and matched metastatic lesions from 31 patients, were evaluated for cytoplasmic and membranous expression of CEA (clone Col-1), Tag-72 (clone CC-49), and Lewis-Y antigen (clone BR-96) by immunohistochemistry. No significant differences were observed with cytoplasmic and membranous expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) in the primary and metastatic, matched and unmatched lesions (Wilcoxon signed-rank test). Although there was no statistically significant difference in the scores of CEA (Col-1) between primary and metastatic lesions, 5 of 11 (45%) cases with positive staining with CEA (Col-1) demonstrated discordant results between primary and metastatic lesions. There was a moderate positive correlation of the cytoplasmic and membranous expression of Tag-72 (CC-49), as well as cytoplasmic expression of BR-96 between primary and metastatic ovarian carcinomas. There was a weak negative correlation between the membranous expression of CEA (Col-1) and that of Lewis-Y antigen (BR-96); however, the difference was not statistically significant. No correlation was observed with other combinations of biomarkers. Our findings suggest that samples from either primary or metastatic ovarian carcinomas can be used for the evaluation of the expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) to identify targets for novel therapies in patients with disseminated ovarian carcinomas. CEA (Col-1), due to its low expression and variation in phenotypic expression between primary and metastatic lesions, should be evaluated carefully in metastatic lesions before targeting the CEA antigen with CEA (Col-1)-like antibodies.