Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions.

Bone marrow (BM) is the preferred graft source for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) compared with mobilized peripheral blood stem cells (PBSCs). We hypothesized that this recommendation may not apply to those regions where patients present later in their disease course, with heavier transfusion load and with higher graft failure rates. Patients with SAA who received HSCT from an HLA-matched sibling donor from 1995 to 2009 and reported to the Center for International Blood and Marrow Transplant Research or the Japan Society for Hematopoietic Cell Transplantation were analyzed. The study population was categorized by gross national income per capita and region/countries into 4 groups. Groups analyzed were high-income countries (HIC), which were further divided into United States-Canada (n = 486) and other HIC (n = 1264); upper middle income (UMIC) (n = 482); and combined lower-middle, low-income countries (LM-LIC) (n = 142). In multivariate analysis, overall survival (OS) was highest with BM as graft source in HIC compared with PBSCs in all countries or BM in UMIC or LM-LIC (P < .001). There was no significant difference in OS between BM and PBSCs in UMIC (P = .32) or LM-LIC (P = .23). In LM-LIC the 28-day neutrophil engraftment was higher with PBSCs compared with BM (97% versus 77%, P = .002). Chronic graft-versus-host disease was significantly higher with PBSCs in all groups. Whereas BM should definitely be the preferred graft source for HLA-matched sibling HSCT in SAA, PBSCs may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infective complications.

Comparison of statistics in association tests of genetic markers for survival outcomes.

Computationally efficient statistical tests are needed in association testing of large scale genetic markers for survival outcomes. In this study, we explore several test statistics based on the Cox proportional hazards model for survival data. First, we consider the classical partial likelihood-based Wald and score tests. A revised way to compute the score statistics is explored to improve the computational efficiency. Next, we propose a Cox-Snell residual-based score test, which allows us to handle the controlling variables more conveniently. We also illustrated the incorporation of these three tests into a permutation procedure to adjust for the multiple testing. In addition, we examine a simulation-based approach proposed by Lin (2005) to adjust for multiple testing. We presented the comparison of these four statistics in terms of type I error, power, family-wise error rate, and computational efficiency under various scenarios via extensive simulation.

Race and socioeconomic status influence outcomes of unrelated donor hematopoietic cell transplantation.

Success of hematopoietic cell transplantation (HCT) can vary by race, but the impact of socioeconomic status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative (MA) HCT recipients transplanted between 1995 and 2004 for acute or chronic leukemia or myelodysplastic syndrome (MDS). Patients were reported by transplant center to be White (n = 5253), African American (n = 368), Asian/Pacific-Islander (n = 141), or Hispanic (n = 445). Patient income was estimated from residential zip code at time of HCT. Cox regression analysis adjusting for other significant factors showed that African American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47; 95% confidence interval [CI] 1.29-1.68, P < .001) compared to Whites. Treatment-related mortality (TRM) was higher in African Americans (RR 1.56; 95% CI 1.34-1.83, P < .001) and in Hispanics (RR 1.30; 95% CI 1.11-1.51, P = .001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15; 95% CI 1.04-1.26, P = .005) and higher risks of TRM (RR 1.21; 1.07-1.36, P = .002). Inferior outcomes among African Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that have an impact on drug metabolism or unmeasured comorbidities, socioeconomic factors, and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes.

Inference for current leukemia free survival.

Donor lymphocyte infusion (DLI) for patients who relapse following an allogeneic stem cell transplant has proved remarkably durable. Because of the potential for second remissions with DLI, the current leukemia free survival (CLFS), which is the probability that a patient has not failed the entire course of the treatment, is becoming of interest to clinical investigators. Based on either a multistate Markov model or a linear combination of Kaplan-Meier estimators, we explore regression models for the CLFS. We focus on the two sample problem and we develop confidence bands for the CLFS or for differences in CLFS as well as a Kolmogorov type hypothesis test using a re-sampling technique. We also examine the use of pseudo-values to make inference on the direct effects of covariates on the CLFS function and we develop a score test for the equality of two CLFS. We illustrate these inference methods on a bone marrow transplant dataset.

Analyzing survival curves at a fixed point in time.

A common problem encountered in many medical applications is the comparison of survival curves. Often, rather than comparison of the entire survival curves, interest is focused on the comparison at a fixed point in time. In most cases, the naive test based on a difference in the estimates of survival is used for this comparison. In this note, we examine the performance of alternatives to the naive test. These include tests based on a number of transformations of the survival function and a test based on a generalized linear model for pseudo-observations. The type I errors and power of these tests for a variety of sample sizes are compared by a Monte Carlo study. We also discuss how these tests may be extended to situations where the data are stratified. The pseudo-value approach is also applicable in more detailed regression analysis of the survival probability at a fixed point in time. The methods are illustrated on a study comparing survival for autologous and allogeneic bone marrow transplants.

Asymptotic theory for the Cox semi-Markov illness-death model.

Irreversible illness-death models are used to model disease processes and in cancer studies to model disease recovery. In most applications, a Markov model is assumed for the multistate model. When there are covariates, a Cox (1972, J Roy Stat Soc Ser B 34:187-220) model is used to model the effect of covariates on each transition intensity. Andersen et al. (2000, Stat Med 19:587-599) proposed a Cox semi-Markov model for this problem. In this paper, we study the large sample theory for that model and provide the asymptotic variances of various probabilities of interest. A Monte Carlo study is conducted to investigate the robustness and efficiency of Markov/Semi-Markov estimators. A real data example from the PROVA (1991, Hepatology 14:1016-1024) trial is used to illustrate the theory.

Incomplete chest wall decompression: a clinical evaluation of CPR performance by trained laypersons and an assessment of alternative manual chest compression-decompression techniques.

BACKGROUND: Complete chest wall recoil improves hemodynamics during CPR by generating relatively negative intrathoracic pressure, which draws venous blood back to the heart, providing cardiac preload prior to the next chest compression. OBJECTIVE: This study was designed to assess the quality of CPR delivered by trained laypersons and to determine if a change in CPR technique or hand position would improve complete chest wall recoil, while maintaining adequate duty cycle, compression depth, and proper hand position placement. Standard manual CPR and three alternative manual CPR approaches were assessed. METHODS: This randomized prospective trial was performed on an electronic test manikin. Thirty laypersons (mean age of 40.6 years (range 28-55)), who were trained in CPR within the last 24 months, signed an informed consent and participated in the trial. Subjects performed 3 min of CPR on a Laerdal Skill Reportertrade mark CPR manikin using the Standard Hand Position followed by 3 min of CPR (in random order) using three alternative CPR techniques: (1) Two-Finger Fulcrum Technique - lifting the heel of the hand slightly but completely off the chest during the decompression phase of CPR using the thumb and little finger as a fulcrum; (2) Five-Finger Fulcrum Technique - lifting the heel of the hand slightly but completely off the chest during the decompression phase of CPR using all five fingers as a fulcrum; (3) Hands-Off Technique - lifting the heel and all fingers of the hand slightly but completely off the chest during the decompression phase of CPR. The participants did not know the purpose of the study prior to, or during this investigation. RESULTS: Adequate compression depth was poor for all hand positions tested and ranged only from 18.6 to 35.7% of all compressions. When compared with the Standard Hand Position, the Hands-Off Technique decreased the mean compression duty cycle from 39.0 +/- 1.0 to 33.5 +/- 1.0%, (P < 0.0001) but achieved the highest rate of complete chest wall recoil (92.5% versus 24.1%, P < 0.0001) and was 46.3 times more likely to provide complete chest wall recoil (OR: 46.3; CI: 16.4-130.3). There were no significant differences in accuracy of hand placement, adequate depth of compression, or perceived discomfort with its use compared with the Standard Hand Position. CONCLUSIONS: The Hands-Off Technique decreased compression duty cycle but was 46.3 times more likely to provide complete chest wall recoil (OR: 46.3; CI: 16.4-130.3) compared to the Standard Hand Position without differences in accuracy of hand placement, adequate depth of compression, or perceived discomfort with its use. All forms of manual CPR tested (including the Standard Hand Position) in trained laypersons produced an inadequate depth of compression for two-thirds of the time. These data support development and testing of more effective layperson CPR training programmes and more effective means to deliver manual as well as mechanical CPR.

A random effects model for multistate survival analysis with application to bone marrow transplants.

We present an extension of the non-homogeneous Markov model for a bone marrow transplant recovery process which allows for possible associations between the transition intensities. The associations between intensities are modeled by a correlated gamma frailty model. Based on a parametric model for the conditional transition intensities, we obtain estimates of the model parameters. We use these estimates to make predictions of patient's eventual prognosis given the current medical history of the patient. Estimates of the uncertainty in our predictions are obtained by a modified bootstrap technique.

Incomplete chest wall decompression: a clinical evaluation of CPR performance by EMS personnel and assessment of alternative manual chest compression-decompression techniques.

BACKGROUND: Complete chest wall recoil improves hemodynamics during cardiopulmonary resuscitation (CPR) by generating relatively negative intrathoracic pressure and thus draws venous blood back to the heart, providing cardiac preload prior to the next chest compression phase. OBJECTIVE: Phase I was an observational case series to evaluate the quality of chest wall recoil during CPR performed by emergency medical services (EMS) personnel on patients with an out-of-hospital cardiac arrest. Phase II was designed to assess the quality of CPR delivered by EMS personnel using an electronic test manikin. The goal was to determine if a change in CPR technique or hand position would improve complete chest wall recoil, while maintaining adequate duty cycle, compression depth, and correct hand position placement. Standard manual CPR and three alternative manual CPR approaches were assessed. METHODS AND RESULTS: Phase I--The clinical observational study was performed by an independent observer noting incomplete chest wall decompression and correlating that observation with electronically measured airway pressures during CPR in adult patients with out-of-hospital cardiac arrest. Rescuers were observed to maintain some residual and continuous pressure on the chest wall during the decompression phase of CPR, preventing full chest wall recoil, at some time during resuscitative efforts in 6 (46%) of 13 consecutive adults (average +/- S.D. age 63 +/-5.8 years). Airway pressures were consistently positive during the decompression phase (>0 mmHg) during those observations. Phase II: This randomized prospective trial was performed on an electronic test manikin. Thirty EMS providers (14 EMT-Basics, 5 EMT-Intermediates, and 11 EMT-Paramedics), with an average age +/- S.D. of 32 +/- 8 years and 6.5 +/- 4.2 years of EMS experience, performed 3 min of CPR on a Laerdal Skill Reporter CPR manikin using the Standard Hand Position followed by 3 min of CPR (in random order) using three alternative CPR techniques: (1) Two-Finger Fulcrum Technique--lifting the heel of the hand slightly but completely off the chest during the decompression phase of CPR using the thumb and little finger as a fulcrum; (2) Five-Finger Fulcrum Technique--lifting the heel of the hand slightly but completely off the chest during the decompression phase of CPR using all five fingers as a fulcrum; and (3) Hands-Off Technique--lifting the heel and all fingers of the hand slightly but completely off the chest during the decompression phase of CPR. These EMS personnel did not know the purpose of the studies prior to or during this investigation. Adequate compression depth was poor for all hand positions tested and ranged only from 29.9 to 48.5% of all compressions. When compared with the Standard Hand Position, the Hands-Off Technique decreased mean compression duty cycle from 46.9 +/- 6.4% to 33.3 +/- 4.6%, (P < 0.0001) but achieved the highest rate of complete chest wall recoil (95.0% versus 16.3%, P < 0.0001) and was 129 times more likely to provide complete chest wall recoil (OR: 129.0; CI: 43.4-382.0). There were no significant differences in accuracy of hand placement, depth of compression, or reported increase in fatigue or discomfort with its use compared with the Standard Hand Position. CONCLUSIONS: Incomplete chest wall decompression was observed at some time during resuscitative efforts in 6 (46%) of 13 consecutive adult out-of-hospital cardiac arrests. The Hands-Off Technique decreased compression duty cycle but was 129 times more likely to provide complete chest wall recoil (OR: 129.0; CI: 43.4-382.0) compared to the Standard Hand Position without differences in accuracy of hand placement, depth of compression, or reported increase in fatigue or discomfort with its use. All forms of manual CPR tested (including the Standard Hand Position) in professional EMS rescuers using a recording manikin produced an inadequate depth of compression more than half the time. These data support development and testing of more effective means to deliver manual as well as mechanical CPR.

A class of goodness of fit tests for a copula based on bivariate right-censored data.

The copula of a bivariate distribution, constructed by making marginal transformations of each component, captures all the information in the bivariate distribution about the dependence between two variables. For frailty models for bivariate data the choice of a family of distributions for the random frailty corresponds to the choice of a parametric family for the copula. A class of tests of the hypothesis that the copula is in a given parametric family, with unspecified association parameter, based on bivariate right censored data is proposed. These tests are based on first making marginal Kaplan-Meier transformations of the data and then comparing a non-parametric estimate of the copula to an estimate based on the assumed family of models. A number of options are available for choosing the scale and the distance measure for this comparison. Significance levels of the test are found by a modified bootstrap procedure. The procedure is used to check the appropriateness of a gamma or a positive stable frailty model in a set of survival data on Danish twins.

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

Regression analysis of restricted mean survival time based on pseudo-observations.

Regression models for survival data are often specified from the hazard function while classical regression analysis of quantitative outcomes focuses on the mean value (possibly after suitable transformations). Methods for regression analysis of mean survival time and the related quantity, the restricted mean survival time, are reviewed and compared to a method based on pseudo-observations. Both Monte Carlo simulations and two real data sets are studied. It is concluded that while existing methods may be superior for analysis of the mean, pseudo-observations seem well suited when the restricted mean is studied.

Multi-state models for bone marrow transplantation studies.

High-dose chemotherapy followed by stem cell recovery, more commonly called a bone marrow transplant, is a common treatment for a number of diseases. This article examines four problems commonly encountered when dealing with bone marrow transplant studies. First, we look at the problem of competing causes of failure and at methods based on a multi-state model to estimate meaningful probabilities for these risks. Second, we examine methods for estimating the prevalence of an intermediate condition, here the prevalence of chronic GVHD. Third, we look at the problem of modeling the post transplant recovery process and we provide two examples of how these estimates can be used to assess dynamically a patient's prognosis or how these probabilities can be used to design trials of new therapy. Finally, we present an estimate of a new measure of treatment efficiency, the current leukemia free survival function, which is derived from a multi-state model approach.