bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding prognostic benefits of exercise and antidepressant therapy for persons with depression and heart disease: the UPBEAT study — rationale, design, and methodological issues
Authors: Blumenthal James A , Sherwood Andrew , Rogers Sharon D. , Babyak Michael A. , Murali Doraiswamy P. , Watkins Lana , Hoffman Benson M. , O'Connell Cara , Johnson Julie J. , Patidar Seema M. , Waugh Robert , Hinderliter Alan 
Published: October 2007

Background Depression is relatively common in patients with coronary heart disease (CHD) and is associated with worse prognosis. Recently there has been interest in evaluating the impact of treating depression on clinical outcomes. Anti-depressant medications have been shown to be safe and efficacious for many patients; exercise also may be effective for treating depression and may also improve cardiopulmonary functioning. However, methodological limitations of previous studies have raised questions about the value of exercise, and no study has compared the effects of exercise with standard anti-depressant medication in depressed cardiac patients. Purpose UPBEAT is a randomized clinical trial (RCT) funded by NHLBI to evaluate the effects of sertraline or exercise compared to placebo on depression and biomarkers of cardiovascular risk in patients with CHD and elevated depressive symptoms. Methods The UPBEAT study includes 200 stable CHD patients with scores on the Beck Depression Inventory (BDI) ≥9 randomized to 4 months of treatment with aerobic exercise, sertraline, or placebo. The primary outcomes include depressive symptoms determined by clinical ratings on the Hamilton Rating Scale for Depression (HAM-D) and measures of heart rate variability (HRV), baroreflex control (BRC), vascular function (i.e., flow-mediated dilation (FMD)), and measures of inflammation and platelet aggregation. Results This article reviews the rationale and design of UPBEAT and addresses several key methodologic issues that were carefully considered in the development of this protocol: the use of a placebo control condition in depressed cardiac patients, study design, and selection of intermediate endpoints or biomarkers of cardiovascular risk. Limitations This study is not powered to assess treatment group differences in CHD morbidity and mortality. Intermediate endpoints are not equivalent to `hard' clinical events and further studies are needed to determine the clinical significance of these biomarkers. Conclusions The UPBEAT study is designed to assess the efficacy of exercise in treating depression in cardiac patients and evaluates the impact of treating depression on important biomarkers of cardiovascular risk. Clinical Trials 2007; 4: 548—559. http://ctj.sagepub.com
Predicting event times in clinical trials when randomization is masked and blocked
Authors: Donovan J. Mark , Elliott Michael R. , Heitjan Daniel F. 
Published: October 2007

Background Timing for interim or final analysis of data in an event-based trial is often determined by the accrual of events during the study. Existing Bayesian methods may be used to predict the date of the landmark event using observed enrollment, event, and loss times when treatment arm information is masked. Purpose For event-based trials with a blocked randomization, knowledge of blocks in which patients are enrolled can provide additional information to improve predictions versus models that only assume a known treatment allocation proportion. We therefore propose to incorporate blocking information into existing methods for prediction. Methods We derive a latent variable (LV) extension of a mixture model used in Donovan JM, Elliott MR, Heitjan DF. Predicting Event Times in Clinical Trials When Treatment Arm is Masked. J Biopharmaceut Stat 2006; 16:343—56 to incorporate block randomization (constrained LV) for predicting the landmark event and compare this model with (a) methods where blocking information is ignored (unconstrained LV), and (b) methods assuming a single population (SP). Results Comparison of the constrained and unconstrained LV models in our application shows that the constrained LV model has narrower prediction intervals. Simulation studies show that the constrained LV model can have better coverage probabilities for the prediction intervals than SP models if a treatment effect is present, and prediction intervals from the constrained LV model are narrower than those for the unconstrained LV model. These differences varied by block size and prediction time. Limitations We have limited focus to the exponential model for events. Coverage for the LV models may be somewhat reduced if no treatment effect is present. Conclusions Extra information provided by knowledge of blocking can be used to decrease prediction interval width versus the unconstrained LV model, while providing better coverage properties than the SP model if a treatment effect is present. Clinical Trials 2007; 4: 481—490. http://ctj.sagepub.com
The intermediate endpoint effect in logistic and probit regression
Authors: MacKinnon D.P. , Lockwood C.M. , Brown C.H. , Wang W. , Hoffman J.M. 
Published: October 2007

Background An intermediate endpoint is hypothesized to be in the middle of the causal sequence relating an independent variable to a dependent variable. The intermediate variable is also called a surrogate or mediating variable and the corresponding effect is called the mediated, surrogate endpoint, or intermediate endpoint effect. Clinical studies are often designed to change an intermediate or surrogate endpoint and through this intermediate change influence the ultimate endpoint. In many intermediate endpoint clinical studies the dependent variable is binary, and logistic or probit regression is used. Purpose The purpose of this study is to describe a limitation of a widely used approach to assessing intermediate endpoint effects and to propose an alternative method, based on products of coefficients, that yields more accurate results. Methods The intermediate endpoint model for a binary outcome is described for a true binary outcome and for a dichotomization of a latent continuous outcome. Plots of true values and a simulation study are used to evaluate the different methods. Results Distorted estimates of the intermediate endpoint effect and incorrect conclusions can result from the application of widely used methods to assess the intermediate endpoint effect. The same problem occurs for the proportion of an effect explained by an intermediate endpoint, which has been suggested as a useful measure for identifying intermediate endpoints. A solution to this problem is given based on the relationship between latent variable modeling and logistic or probit regression. Limitations More complicated intermediate variable models are not addressed in the study, although the methods described in the article can be extended to these more complicated models. Conclusions Researchers are encouraged to use an intermediate endpoint method based on the product of regression coefficients. A common method based on difference in coefficient methods can lead to distorted conclusions regarding the intermediate effect. Clinical Trials 2007; 4: 499—513. http://ctj.sagepub.com
Meta-analysis of longitudinal studies
Authors: Ishak K. Jack , Platt Robert W. , Joseph Lawrence , Hanley James A. , Caro J. Jaime 
Published: October 2007

Background Longitudinal studies typically report estimates of the effect of a treatment or exposure at various times during the course of follow-up. Meta-analyses of these studies must account for correlations between effect estimates from the same study. Purpose To describe and contrast alternative approaches to handling correlations inherent to longitudinal effect estimates in meta-analyses. Methods. Linear mixed-effects models can account for correlations in a number of ways. We considered three alternatives: including study-specific random-effects, correlated time-specific random-effects or a general multivariate specification that also allows correlated within-study residuals. Data from a review of studies of the effect of deep-brain stimulation (DBS) in patients with Parkinson's disease are used to illustrate the application of these models. Results are contrasted with those from a naïve meta-analysis in which the correlations are ignored. Results The data included 46 studies that yielded 82 estimates of the effect of DBS measured at 3, 6, 12 months or later after implantation of the stimulator. Models that accounted for correlations, particularly the full multivariate specification, provided better fit (lower AIC) and yielded slightly more precise effect estimates. This was in part due to a relatively extreme observation from a study that provided similar estimates at other times, which in the naïve approach exerts greater influence since it is treated as an independent observation. Limitations Since the true values of the parameters are not known, it is impossible to confirm that estimates from the multivariate approach are necessarily more accurate. Conclusion Standard meta-analytic models can be readily extended to account for correlations between effects in longitudinal studies. These models may provide better fit and possibly more precise summary effect estimates. Clinical Trials 2007; 4: 525—539. http://ctj.sagepub.com
Hormonal regulators of muscle and metabolism in aging (HORMA): design and conduct of a complex, double masked multicenter trial
Authors: Schroeder E. Todd , Castaneda-Sceppa Carmen , Ying Wang  , Binder Ellen F. , Kawakubo Miwa , Stewart Yolanda , Storer Thomas , Roubenoff Ronenn , Bhasin Shalender , Yarasheski Kevin E. , Sattler Fred R. , Azen Stanley P. 
Published: October 2007

Background Older persons often lose muscle mass, strength, and physical function. This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging. Methods HORMA is a multicenter, randomized double masked study of 65—90-year-old community dwelling men with testosterone levels of 150—550 ng/dL and IGF-1 < 167 ng/dL. Subjects were randomized to transdermal testosterone (5 or 10 g/day) and rhGH (0, 3, or 5 μg/kg/day) for 16 weeks. Outcome measures included body composition by DEXA, MRI, and 2H2O dilution; muscle performance (strength, power, and fatigability), VO2peak, measures of physical function, synthesis/breakdown of myofibrillar proteins, other measures of metabolism, and quality of life. Results Major challenges included delay in startup caused by need for 7 institutional contracts, creating a 142-page manual of operations, orientation and training, creating a 121-page CRF; enrollment inefficiencies; scheduling 16 evaluations/ subject; overnight admissions for invasive procedures and isotope infusions; large data and image management and transfer; quality control at multiples sites; staff turnover; and replacement of a clinical testing site. Impediments were largely solved by implementation of a web-based data entry and eligibility verification; electronic scheduling for multiple study visits; availability of research team members to educate and reassure subjects; more frequent site visits to validate all source documents and reliability of data entry; and intensifying quality control in testing and imaging. The study exceeded the target goal of 108 (n = 112) completely evaluable cases. Two interim DSMB meetings confirmed the lack of excessive adverse events, lack of center effects, comparability of subjects, and that distribution of subjects and enrollment will not jeopardize outcomes or generalizability of results. Conclusions Flexibility and rapidly solving evolving problems is critical when conducting highly complex multicenter metabolic studies. Clinical Trials 2007; 4: 560—570. http://ctj.sagepub.com
Bias reduction with an adjustment for participants' intent to dropout of a randomized controlled clinical trial
Authors: Leon Andrew C. , Demirtas Hakan , Hedeker Donald 
Published: October 2007

Background Attrition, which is virtually ubiquitous in randomized controlled clinical trials, introduces problems of increased bias and reduced statistical power. Although likelihood-based statistical models such as mixed-effects models can accommodate incomplete data, the assumption of ignorable attrition is usually required for valid inferences. Purpose In an effort to make the ignorability assumption more plausible, we consider the value of one readily obtained covariate that has been recommended by others, asking participants to rate their Intent to Attend the next assessment session. Methods Here we present a simulation study that compares the bias and coverage in mixed-effects outcome analyses that do and do not include Intent to Attend as a covariate. Results For the simulation specifications that we examined, the results are promising in the sense of reduced bias and greater precision. Specifically, if the time-varying Intent to Attend variable is associated with attrition, outcome and treatment group, bias is substantially reduced by including it in the outcome analyses. Limitations Analyses that are adjusted in this way will only yield unbiased estimates of efficacy if attrition is ignorable based on the self-rated intentions. Conclusions Accounting for participants' Intent to Attend the next assessment session will reduce attrition bias under conditions examined here. The item adds little burden and can be used both for data analyses and to identify participants at risk of attrition. Clinical Trials 2007; 4: 540—547. http://ctj.sagepub.com
Balanced two-stage designs for phase II clinical trials
Authors: Fei Ye  , Shyr Yu 
Published: October 2007

Background Oncology phase II clinical trials are often designed using Simon's two-stage designs (optimal and `minimax') for independent observations. Simon's designs do not include the use of correlated observations, and do not balance the sample sizes of the two stages. In these designs, the sample sizes of the two stages can be highly unequal. In certain circumstances, an alternative design option that balances the sample sizes is desirable. Purpose To develop a two-stage phase II design that balances the sample sizes of the first and the second stages, while controlling for type I and type II error rates. Methods We simulated designs based on response rates under various null and alternative hypotheses, type I and type II error constraints, and the degree of correlation in the case of correlated data. For correlated data, Sargent's method is adopted to account for the loss of information due to intra-person correlation. Results Design characteristics for different parameter settings were generated using balanced design method, separately for independent and correlated data. Results were evaluated and compared to the optimal and minimax design. Limitations For correlated data, designs were produced only for trials with half of the participants having one observation and the other half having two. Also, the degree of intra-person correlation was fixed at three levels. Conclusion The balanced design provides an additional choice for two-stage phase II trials when the investigators would like to monitor the trial near a study's halfway point. Meanwhile, its total sample sizes are comparable with Simon's designs. Clinical Trials 2007; 4: 514—524. http://ctj.sagepub.com
Treatment and prevention of pain due to vaso-occlusive crises in adults with sickle cell disease: an educational void
Authors: Solomon Lawrence R. 
Published: October 2007

Abstract
Pain due to vaso-occlusive crisis is the major cause of hospital use in sickle cell disease. Although available guidelines provide recommendations for opioid administration in this setting, only 4 (21%) of 19 medical textbooks present treatment regimens that are consistent with them. Moreover, only 7 texts (37%) note that addiction is infrequent in this population, while 11 (92%) of 12 texts provide such reassurance for cancer-related pain (P < .005). Finally, hydroxyurea use to decrease the frequency of vaso-occlusive crises is completely defined only in 2 textbooks. Thus, most medical texts provide neither adequate information for the treatment or prevention of pain due to vaso-occlusive crisis in sickle cell disease nor reassurance of the unlikelihood of addiction in this population. In contrast, treatment recommendations for less common hematologic disorders are consistent with current standards in 53% to 84% of appropriate texts (P < .05). Limited knowledge regarding the principles and appropriateness of opioid therapy; a lack of evidence-based research on pain control; and misconceptions and prejudices about drug abuse and addiction contribute to this educational void. Thus, research and training on pain control in sickle cell disease are needed to parallel studies of environmental and genetic factors contributing to the known clinical heterogeneity of this disorder.
Cbfβ-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B-cell development
Authors: Kuo Ya-Huei , Gerstein Rachel M. , Castilla Lucio H. 
Published: October 2007

AbstractThe core-binding factor (CBF)–associated leukemia fusion protein CBFβ-SMMHC impairs myeloid and lymphoid differentiation. By inhibiting RUNX function, the fusion oncoprotein predisposes specifically to acute myeloid leukemia in both patients and mouse models. We have shown that Cbfβ-SMMHC expression leads to a sustained reduction of circulating B lymphocytes in the mouse. In this study, we demonstrate that the activation of Cbfβ-SMMHC reduces pre–pro-B cells approximately 3-fold and pre-B cells more than 10-fold and that this differentiation block is cell-autonomous. The reduction of pre–pro-B cells coincided with an increase in apoptosis in this population. The number of common lymphoid progenitors (CLPs) were not affected; however, the expression of critical early B-cell factors Ebf1, Tcfe2a, and Pax5 was significantly reduced. In addition, Cbfβ-SMMHC reduced Rag1 and Rag2 expression and impaired V(D)J recombination in the CLPs. Furthermore, CLPs expressing Cbfβ-SMMHC also show inhibition of B cell–specific genes Cd79a, Igll1, VpreB1, and Blk. These results demonstrate that CBF/RUNX function is essential for the function of CLPs, the survival of pre–pro-B cells, and the establishment of a B lineage–specific transcriptional program. This study also provides a mechanistic basis for the myeloid-lineage bias of CBFβ-SMMHC–associated leukemia.
FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications
Authors: Whitman Susan P. , Ruppert Amy S. , Radmacher Michael D. , Mrózek Krzysztof , Paschka Peter , Langer Christian , Baldus Claudia D. , Wen Jing , Racke Frederick , Powell Bayard L. , Kolitz Jonathan E. , Larson Richard A. , Caligiuri Michael A. , Marcucci Guido , Bloomfield Clara D. 
Published: October 2007

AbstractThe prognostic relevance of FLT3 D835/I836 mutations (FLT3-TKD) in cytogenetically normal acute myeloid leukemia (CN-AML) remains to be established. After excluding patients with FLT3 internal tandem duplications, we compared treatment outcome of 16 de novo CN-AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 (FLT3-WT), less than 60 years of age and similarly treated on Cancer and Leukemia Group B protocols. All FLT3-TKD+ patients and 85% of FLT3-WT patients achieved a complete remission (P = .13). Disease-free survival (DFS) of FLT3-TKD+ patients was worse than DFS of FLT3-WT patients (P = .01; estimated 3-year DFS rates, 31% vs 60%, respectively). In a multivariable analysis, FLT3-TKD was associated with worse DFS (P = .02) independent of NPM1 status and percentage of bone marrow blasts. To gain further biologic insights, a gene-expression signature differentiating FLT3-TKD+ from FLT3-WT patients was identified. The signature (333 probe sets) included overexpression of VNN1, C3AR1, PTPN6, and multiple other genes involved in monocarboxylate transport activity, and underexpression of genes involved in signal transduction regulation. These associations with outcome, other prognostic markers, and the elucidated expression signature enhance our understanding of FLT3-TKD–associated biology and may lead to development of novel therapies that improve clinical outcome of CN-AML patients with FLT3-TKD.
Large scale clustering of protein sequences with FORCE -A layout based heuristic for weighted cluster editing
Authors: Wittkop Tobias , Baumbach Jan , Lobo Francisco P , Rahmann Sven 
Published: October 2007

Abstract

Background
Detecting groups of functionally related proteins from their amino acid sequence alone has been a long-standing challenge in computational genome research. Several clustering approaches, following different strategies, have been published to attack this problem. Today, new sequencing technologies provide huge amounts of sequence data that has to be efficiently clustered with constant or increased accuracy, at increased speed.

Results
We advocate that the model of weighted cluster editing, also known as transitive graph projection is well-suited to protein clustering. We present the FORCE heuristic that is based on transitive graph projection and clusters arbitrary sets of objects, given pairwise similarity measures. In particular, we apply FORCE to the problem of protein clustering and show that it outperforms the most popular existing clustering tools (Spectral clustering, TribeMCL, GeneRAGE, Hierarchical clustering, and Affinity Propagation). Furthermore, we show that FORCE is able to handle huge datasets by calculating clusters for all 192 187 prokaryotic protein sequences (66 organisms) obtained from the COG database. Finally, FORCE is integrated into the corynebacterial reference database CoryneRegNet.

Conclusion
FORCE is an applicable alternative to existing clustering algorithms. Its theoretical foundation, weighted cluster editing, can outperform other clustering paradigms on protein homology clustering. FORCE is open source and implemented in Java. The software, including the source code, the clustering results for COG and CoryneRegNet, and all evaluation datasets are available at http://gi.cebitec.uni-bielefeld.de/comet/force/.