Asymptotic Results for Simultaneous Group Sequential Analysis of Rank-Based and Weighted Kaplan-Meier Tests with Paired Survival Data in the Presence of Censoring. Technical report

This research sequentially monitors paired survival differences using a new class of non-parametric tests based on functionals of standardized paired weighted log-rank (PWLR) and standardized paired weighted Kaplan-Meier (PWKM) tests. During a trial these tests may alternately assume the role of the more extreme statistic. By monitoring PEMAX, the maximum between the absolute values of the standardized PWLR and PWKM, one combines advantages of rank-based and non rank-based paired testing paradigms. Simulations show that monitoring treatment differences using PEMAX maintains type I error and is nearly as powerful as using the more advantageous of the two tests, in proportional hazards (PH) as well as non-PH situations. Hence, PEMAX preserves power more robustly than individually monitored PWLR and PWKM, while maintaining a reasonably simple approach to design and analysis of results. An example from the Early Treatment Diabetic Retinopathy Study (ETDRS) is given

Estimating the Quality-of-Life-Adjusted Gap Time Distribution of Successive Events Subject to Censoring

When treatment effects are studied in the context of successive or recurrent life events, separate analyses of the quality-of-life scores and of the inter-event, gap, times might lead to possibly contradictory conclusions. In an attempt to reconcile this, we propose a unitary and more comprehensive nonparametric analysis that combines the two separate analyses by introducing the quality-of-life-adjusted gap time concept. Inverse probability of censoring estimators of the quality-of-life-adjusted gap time joint and conditional distributions are proposed and are shown to be consistent and asymptotically normal. Simulations performed in a variety of scenarios indicate that the joint and conditional quality-of-life-adjusted gap time distribution estimators are virtually unbiased, with properly estimated standard errors and asymptotic normality features. An example from the International Breast Cancer Study Group Trial V illustrates the use of the proposed estimators.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91896/1/Adi's Biometrika paper.pd

Regression Models for the Mean of the Quality-of-Life-Adjusted Restricted Survival Time Using Pseudo-Observations

In this research we develop generalized linear regression models for the mean of a quality-of-life-adjusted restricted survival time. Parameter and standard error estimates could be obtained from generalized estimating equations applied to pseudo-observations. Simulation studies with moderate sample sizes are conducted and an example from the International Breast Cancer Study Group Ludwig Trial V is used to illustrate the newly developed methodology.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66346/1/j.1541-0420.2006.00723.x.pd

Simultaneous Group Sequential Analysis of Rank-Based and Weighted Kaplan–Meier Tests for Paired Censored Survival Data

This research sequentially monitors paired survival differences using a new class of nonparametric tests based on functionals of standardized paired weighted log-rank (PWLR) and standardized paired weighted Kaplan–Meier (PWKM) tests. During a trial, these tests may alternately assume the role of the more extreme statistic. By monitoring PEMAX, the maximum between the absolute values of the standardized PWLR and PWKM, one combines advantages of rank-based (RB) and non-RB paired testing paradigms. Simulations show that monitoring treatment differences using PEMAX maintains type I error and is nearly as powerful as using the more advantageous of the two tests in proportional hazards (PH) as well as non-PH situations. Hence, PEMAX preserves power more robustly than individually monitored PWLR and PWKM, while maintaining a reasonably simple approach to design and analysis of results. An example from the Early Treatment Diabetic Retinopathy Study (ETDRS) is given.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65557/1/j.1541-0420.2005.00337.x.pd

The Perioperative Effect of Increased Body Mass Index on Peripheral Nerve Blockade: an Analysis of 528 Ultrasound Guided Interscalene Blocks

SummaryBackground and objectivesObese patients can pose a unique perioperative anesthetic challenge, making regional anesthetic techniques an intriguing means of providing analgesia for this population. Ultrasound guidance has been touted recently as being beneficial for this population in which surface landmarks can become obscured. In this study, the effect of increased Body Mass Index (BMI) on ultrasound guided interscalene peripheral nerve blockade is investigated.Material and methodsThis study is a retrospective review of 528 consecutive patients who received preoperative ultrasound-guided interscalene nerve blocks at the University of Wisconsin Hospital and Clinics. We examined the association between BMI and the following parameters: time required for block placement; presence of Postoperative Nausea and Vomiting (PONV); postoperative Post Anesthesia Care Unit (PACU) pain scores; volume of local anesthetic injected; acute complications; and opioid administration preoperatively, intraoperatively, and postoperatively. Univariate and multivariate least squares and logistic regression models were used.ResultsAn elevated BMI was associated with an increased: time required for block placement (p-value=0.025), intraoperative fentanyl administration (p-value<0.001), peak PACU pain scores (p-value<0.001), PACU opioid administration (p-value<0.001), PACU oral opioid administration (p-value<0.001), total PACU opioid administration (p-value<0.001) and incidence of PACU nausea (p-value=0.025)ConclusionsUltrasound guided interscalene nerve blocks for perioperative analgesia can be safely and effectively performed in the obese patient but they may be more difficult to perform and analgesia may not be as complete

Idiopathic pulmonary fibrosis: Prognostic value of changes in physiology and six minute hallwalk.

Rationale and Hypothesis: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide. Methods: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation 88% during a baseline 6MWT. For patients with a baseline saturation 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients. Conclusion: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91940/1/2006 AJRCCM Idiopathic pulmonary fibrosis - Prognostic value of changes in physiology and six minute hallwalk.pd

Anxiety is associated with diminished exercise performance and quality of life in severe emphysema: a cross-sectional study

Background: Anxiety in patients with chronic obstructive pulmonary disease (COPD) is associated with selfreported disability. The purpose of this study is to determine whether there is an association between anxiety and functional measures, quality of life and dyspnea. Methods: Data from 1828 patients with moderate to severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), collected prior to rehabilitation and randomization, were used in linear regression models to test the association between anxiety symptoms, measured by the Spielberger State Trait Anxiety Inventory (STAI) and: (a) six-minute walk distance test (6 MWD), (b) cycle ergometry peak workload, (c) St. Georges Respiratory Questionnaire (SRGQ), and (d) UCSD Shortness of Breath Questionnaire (SOBQ), after controlling for potential confounders including age, gender, FEV1 (% predicted), DLCO (% predicted), and the Beck Depression Inventory (BDI). Results: Anxiety was significantly associated with worse functional capacity [6 MWD (B = -0.944, p < .001), ergometry peak workload (B = -.087, p = .04)], quality of life (B = .172, p < .001) and shortness of breath (B = .180, p < .001). Regression coefficients show that a 10 point increase in anxiety score is associated with a mean decrease in 6 MWD of 9 meters, a 1 Watt decrease in peak exercise workload, and an increase of almost 2 points on both the SGRQ and SOBQ. Conclusion: In clinically stable patients with moderate to severe emphysema, anxiety is associated with worse exercise performance, quality of life and shortness of breath, after accounting for the influence of demographic and physiologic factors known to affect these outcomes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91944/1/2010 RR Anxiety is associated with diminished exercise performance and quality of life in severe emphysema.pd

Longitudinal change in the BODE index predicts mortality in severe emphysema

Rationale: The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients. Objectives: To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival. Methods: Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components. Measurements and Main Results: The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91943/1/2008 AJRCCM Longitudinal change in the BODE index predicts mortality in severe emphysema.pd

Idiopathic interstitial pneumonia: Do community and academic physicians agree on diagnosis?

Rationale: Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult. Objectives: Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers. Methods: Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days. Measurements and Main Results: Each observer’s diagnosis was coded into one of eight categories. A statistic allowing formultiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (Kappa= 0.55–0.71) than within community centers (Kappa=0.32–0.44). Clinically significant disagreement was present between academic and communitybased physicians (Kappa=0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians. Conclusions: Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91941/1/2007 AJRCCM Idiopathic interstitial pneumonia - Do community and academic physicians agree on diagnosis.pd

Nonparametric and semiparametric censored survival analysis of correlated times to event and their sequelae.

The main goal of this dissertation is to construct nonparametric or semiparametric methods for analyzing correlated failure times. Landmark events such as cancer occurrence, time to severe vision loss or HIV infection are intimately tied to patient quality-of-life (QOL) and they are both of capital scientific interest in this dissertation. In Chapter II we develop testing methods for the group sequential monitoring of paired censored survival data, as in the Early Treatment Diabetic Retinopathy Study. With independent groups, the log-rank is most powerful under proportional hazards (PH), while the Pepe-Fleming test might be more powered in non-PH situations. However, the paired versions of the weighted log-rank (PWLR) and the weighted Pepe-Fleming (PWKM) tests are not known to be optimal, under general standard assumptions. We propose monitoring methods based on PEMAX, the largest, in absolute value, of PWLR and PWKM. With correlation properly accounted for in the asymptotic variance of PEMAX, type I error is properly maintained and power robustness is observed in PH and non-PH scenarios, under stochastic ordering. Methods for correlated QOL-adjusted successive failure times are developed in Chapter III. Attempting to reconcile the quantitative and the qualitative aspects of individual survival during successive life events, we propose the concept of QOL-adjusted gap time (QAGT), in anticipation of a scenario when deteriorating QOL accompanies a series of successive adverse events. We develop estimators of joint and conditional distributions of QAGTs, prove consistency and characterize their asymptotic distributional properties. Applications to the International Breast Cancer Study Group (IBCSG) Trial V are presented. In Chapter IV, we develop methods for incorporating prognostic covariates via generalized linear regression models on pseudo-values for the restricted mean of the quality-of-life-adjusted survival time (RMQAST). Existing methods model QOL-adjusted lifetime through Cox models for the QOL-adjusted hazard function. The coefficient estimates thus obtained do not have clinically meaningful interpretations. By modeling covariate effects on RMQAST directly, we facilitate the interpretability of the regression coefficients. At the modeling stage, which involves the pseudo-observations, generalized estimating equations (GEE) are used. We present applications to the IBCSG Trial V. Comments and interesting directions for future research conclude this dissertation.Ph.D.Biological SciencesBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125009/2/3186564.pd