A summarization approach for Affymetrix GeneChip data using a reference training set from a large, biologically diverse database

BACKGROUND: Many of the most popular pre-processing methods for Affymetrix expression arrays, such as RMA, gcRMA, and PLIER, simultaneously analyze data across a set of predetermined arrays to improve precision of the final measures of expression. One problem associated with these algorithms is that expression measurements for a particular sample are highly dependent on the set of samples used for normalization and results obtained by normalization with a different set may not be comparable. A related problem is that an organization producing and/or storing large amounts of data in a sequential fashion will need to either re-run the pre-processing algorithm every time an array is added or store them in batches that are pre-processed together. Furthermore, pre-processing of large numbers of arrays requires loading all the feature-level data into memory which is a difficult task even with modern computers. We utilize a scheme that produces all the information necessary for pre-processing using a very large training set that can be used for summarization of samples outside of the training set. All subsequent pre-processing tasks can be done on an individual array basis. We demonstrate the utility of this approach by defining a new version of the Robust Multi-chip Averaging (RMA) algorithm which we refer to as refRMA. RESULTS: We assess performance based on multiple sets of samples processed over HG U133A Affymetrix GeneChip(® )arrays. We show that the refRMA workflow, when used in conjunction with a large, biologically diverse training set, results in the same general characteristics as that of RMA in its classic form when comparing overall data structure, sample-to-sample correlation, and variation. Further, we demonstrate that the refRMA workflow and reference set can be robustly applied to naïve organ types and to benchmark data where its performance indicates respectable results. CONCLUSION: Our results indicate that a biologically diverse reference database can be used to train a model for estimating probe set intensities of exclusive test sets, while retaining the overall characteristics of the base algorithm. Although the results we present are specific for RMA, similar versions of other multi-array normalization and summarization schemes can be developed

Towards a consensus-based classification of childhood arterial ischemic stroke.

Background and purposeThe implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS.MethodsUsing a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic.ResultsIn Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]).ConclusionsA new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible

Insulin Resistance in African-American and Caucasian Women: Differences in Lipotoxicity, Adipokines, and Gene Expression in Adipose Tissue and Muscle

Objectives: We tested whether African-American (AA) women are different from Caucasian women in regard to lipotoxicity, adipokines, and gene expression in adipose tissue and muscle

Pre-impaired fasting glucose state is a risk factor for endothelial dysfunction: Flow-mediated Dilation Japan (FMD-J) study

Introduction Diabetes mellitus is associated with endothelial dysfunction. However, there is little information on the relationships of fasting blood glucose (FBG), including high normal blood glucose and impaired fasting glucose (IFG) with endothelial function. The purpose of this study was to evaluate the relationship between FBG level and flow-mediated vasodilation (FMD) using a large sample size.Research design and methods This study was a cross-sectional study. We measured FMD in 7265 subjects at 31 general hospitals. The subjects were divided into four groups based on FBG levels: <100, 100–109, 110–125, and ≥126 mg/dL or known diabetes. The subjects were also divided into six groups based on FBG levels: <90, 90–94, 95–99, 100–109, 110–125, and ≥126 mg/dL or known diabetes.Results FMD decreased in relation to increase in FBG level. There was a significant difference in FMD between the FBG of <100 mg/dL group and the other three groups (6.7±3.1% vs 5.9±2.8%, 5.7±3.1%, and 5.1±2.6%, respectively; p<0.001). After adjustment for confounding factors, the odds of having the lowest quartile of FMD were significantly higher in the FBG of 95–99, 100–104, 105–109, 110–125, and ≥126 mg/dL or known diabetes groups than in the FBG of the <90 mg/dL group.Conclusions These findings suggest that FBG of 100–109 mg/dL and FBG of 110–125 mg/dL are similarly associated with endothelial dysfunction and that a pre-IFG state (FBG of 95–99 mg/dL) is also a risk for endothelial dysfunction compared with FBG of <90 mg/dL.Trial registration number UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Long-term metformin adherence in the Diabetes Prevention Program Outcomes Study

Introduction To investigate long-term metformin adherence in the Diabetes Prevention Program Outcomes Study (DPPOS) by examining: (1) predictors of long-term adherence to study metformin and (2) whether metformin adherence was associated with incident type 2 diabetes.Research design and methods DPPOS was an open-label continuation of the randomized clinical trial (Diabetes Prevention Program (DPP)) in which eligible participants randomized to the metformin group were offered study metformin and followed over 11 years. A brief structured adherence interview was administered semiannually. Metformin adherence was assessed by pill counts. Predictors of metformin adherence were examined in multivariate regression models. Incident diabetes associated with metformin adherence and other variables was assessed in Cox proportional hazards models.Results Of 868 participants eligible to continue taking study metformin, 664 (76%) took at least some metformin over 11 years, with 478 of them reporting problems with adherence. DPPOS cumulative adherence showed significant associations of higher adherence (≥80%) with early adherence at 3 months in DPP (p<0.001) and lower depression scores during DPPOS (p<0.001); significant differences were also seen by race/ethnicity (p<0.004). Predicting adherence by multivariate modeling showed odds of adherence significantly lower for Black participants and for participants reporting more than one barrier. Odds for adherence were significantly higher for those adherent early in DPP and those reporting at least one planned strategy to improve adherence. Higher metformin adherence was significantly associated with a lower diabetes risk (p=0.04), even after adjustment for demographic variables, depression, and anxiety scores.Conclusions In this long-term diabetes prevention study, early metformin adherence and planned strategies to promote adherence improved long-term adherence over 11 years; higher adherence to metformin was related to lower diabetes incidence. Incorporating strategies to promote adherence when initially prescribing metformin and counseling to support adherence over time are warranted

Towards a consensus-based classification of childhood arterial ischemic stroke.

Background and purposeThe implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS.MethodsUsing a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic.ResultsIn Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]).ConclusionsA new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible

Comparative effects of randomized second-line therapy for type 2 diabetes on a composite outcome incorporating glycemic control, body weight, and hypoglycemia: An analysis of the Glycemia Reduction Approaches in Type 2 Diabetes - A Comparative Effectiveness (GRADE) Study

Background: The GRADE Study (5047 participants, mean follow-up 5.0 years) demonstrated differences in glycemic control over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. Methods: The composite outcome was time to first occurrence of any of: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent non-severe hypoglycemia. Secondary analyses examined individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated using the Kaplan-Meier estimator. Cox proportional hazards models assessed pairwise group differences in risk of an outcome. Results: Risk of reaching the composite outcome (events per 100 participant-treatment years, PTYs) was lowest with liraglutide (19/100 PTYs) followed by sitagliptin (26/100 PTYs), glargine (29/100 PTYs), and glimepiride (40/100 PTYs); all pairwise comparisons were statistically significant. Risk of weight gain and hypoglycemia had the same order, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across pre-specified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. Conclusions: Among common second-line drug classes for type 2 diabetes, liraglutide had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy.</p

Impact of Glucose-Lowering Medications on Health-Related Quality of Life in the Glycemia Reduction Approaches in Diabetes (GRADE) Study: A Comparative Effectiveness Randomized Clinical Trial

Objective: Diabetes is associated with reduced health-related quality of life (HRQoL). Information on the relationship between HRQoL and glucose-lowering medications in recently diagnosed type 2 diabetes (T2D) is limited. We assessed changes in HRQoL in participants with T2D receiving metformin plus one of four glucose-lowering medications in the GRADE study.Research Design and Methods: 5047 participants with baseline mean age of 57 years, Results: None of the medications worsened HRQoL. There were no differences in QWB-SA or MCS by treatment group at any time point. PCS scores improved with liraglutide versus other groups at Y1 only. Greater weight loss during Y1 explained half the improvement in PCS scores with liraglutide versus glargine and glimepiride. Liraglutide participants in the upper tertile of baseline body mass index showed the greatest improvement in PCS scores at Y1. Conclusion: Adding liraglutide to metformin in participants within 10 years of T2D diagnosis showed improvement in the SF-36 PCS compared with the other medications at 1 year, which was no longer significant at Y2 and Y3. Improvement was related to weight loss and baseline BMI.</p