Biomedical subjects

John P Klein

Publications and source records attributed to John P Klein.

At least 19 recordsLinked to original sources

PubMed2007

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.

Biometry↗

PubMed2006

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.

Adult↗

PubMed2006

Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation.

We previously compared outcomes after allogeneic peripheral-blood stem cell (PBSC) and bone marrow (BM) transplantation in 706 patients with leukemia. We obtained long-term follow up on 413 of 491 patients who were alive at the time of the initial report: 141 PBSC and 272 BM recipients. Chronic graft-versus-host disease (GVHD) was more frequent after PBSC compared to BM transplantation (RR 1.65, P < .001) yet relapse rates were similar in both groups. Leukemia-free survival rates were higher after PBSC than BM transplantation for patients with advanced chronic myeloid leukemia (33% versus 25%) but lower for those in first chronic phase (41% versus 61%) due to higher rates of late transplant-related mortality. Leukemia-free survival was similar after PBSC and BM transplantation for acute leukemia. These data represent the early experience with PBSC grafts. Long-term outcomes in recipients of more recent transplants are required to better evaluate the role of PBSC grafts relative to BM transplantation.

Bone Marrow Transplantation↗

PubMed2006

Modelling competing risks in cancer studies.

Competing risks arise commonly in the analysis of cancer studies. Most common are the competing risks of relapse and death in remission. These two risks are the primary reason that patients fail treatment. In most medical papers the effects of covariates on the three outcomes (relapse, death in remission and treatment failure) are model by distinct proportional hazards regression models. Since the hazards of relapse and death in remission must add to that of treatment failure, we argue that this model leads to internal inconsistencies. We argue that additive models for either the hazard rates or the cumulative incidence functions are more natural and that these models properly partition the effect of a covariate on treatment failure into its component parts. We illustrate the use and interpretation of additive models for the hazard rate or for the cumulative incidence function using data from a study of the efficacy of two preparative regimes for hematopoietic stem cell transplantation.

Adult↗

PubMed2006

Regression models for hazard rates versus cumulative incidence probabilities in hematopoietic cell transplantation data.

In this article, we consider methods of regression modeling in the competing risks setting commonly encountered in analyzing stem cell transplantation data. We clarify the distinction between modeling the cause-specific hazard rate and modeling the cumulative incidence probability or function, and we review regression techniques for both types of quantities. We apply them to 2 examples: 1 comparing engraftment and 1 examining relapse. These examples illustrate that different conclusions may result depending on the type of regression model used for comparing treatments. Finally, we show how these discrepancies occur because 2 different characteristics of the time-to-event distribution are being modeled.

Graft Rejection↗

PubMed2006

Clinical and hemodynamic comparison of 15:2 and 30:2 compression-to-ventilation ratios for cardiopulmonary resuscitation.

OBJECTIVE: To compare cardiopulmonary resuscitation (CPR) with a compression to ventilation (C:V) ratio of 15:2 vs. 30:2, with and without use of an impedance threshold device (ITD). DESIGN: Prospective randomized animal and manikin study. SETTING: Animal laboratory and emergency medical technician training facilities. SUBJECTS: Twenty female pigs and 20 Basic Life Support (BLS)-certified rescuers. INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS ANIMALS: Acid-base status, cerebral, and cardiovascular hemodynamics were evaluated in 18 pigs in cardiac arrest randomized to a C:V ratio of 15:2 or 30:2. After 6 mins of cardiac arrest and 6 mins of CPR, an ITD was added. Compared to 15:2, 30:2 significantly increased diastolic blood pressure (20 +/- 1 to 26 +/- 1; p < .01); coronary perfusion pressure (18 +/- 1 to 25 +/- 2; p = .04); cerebral perfusion pressure (16 +/- 3 to 18 +/- 3; p = .07); common carotid blood flow (48 +/- 5 to 82 +/- 5 mL/min; p < .001); end-tidal CO2 (7.7 +/- 0.9 to 15.7 +/- 2.4; p < .0001); and mixed venous oxygen saturation (26 +/- 5 to 36 +/- 5, p < .05). Hemodynamics improved further with the ITD. Oxygenation and arterial pH were similar. Only one of nine pigs had return of spontaneous circulation with 15:2, vs. six of nine with 30:2 (p < 0.03). HUMANS: Fatigue and quality of CPR performance were evaluated in 20 BLS-certified rescuers randomized to perform CPR for 5 mins at 15:2 or 30:2 on a recording CPR manikin. There were no significant differences in the quality of CPR performance or measurement of fatigue. Significantly more compressions per minute were delivered with 30:2 in both the animal and human studies. CONCLUSIONS: These data strongly support the contention that a ratio of 30:2 is superior to 15:2 during manual CPR and that the ITD further enhances circulation with both C:V ratios.

Adult↗

PubMed2006

Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research.

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.

Acute Disease↗

PubMed2005

A note on testing in Aalen's additive hazards regression models.

Aalen's additive hazards regression model is a useful alternative to the proportional hazards model for censored data regression. When used to compare treatments this approach leads to weighted comparisons of the crude estimate of the hazard rate of each group as compared to a baseline group. This is contrasted to the weighted log rank test from the proportional hazards model which compares each treatment's rate to the pooled rate. We show in this brief note that Aalen's suggestion for weights in this test leads to inconsistent tests in the sense that the test statistic depends on which group we pick for a baseline group. We show that 'consistent' tests are obtained by using common weight functions for all comparisons and we make some suggestions.

Humans↗

PubMed2005

Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study.

The most commonly used grading system for acute graft-versus-host disease (aGVHD) was introduced 30 years ago by Glucksberg; a revised system was developed by the International Bone Marrow Transplant Registry (IBMTR) in 1997. To prospectively compare the 2 classifications and to evaluate the effect of duration and severity of aGVHD on survival, we conducted a multicenter study of 607 patients receiving T-cell-replete allografts, scored weekly for aGVHD in 18 transplantation centers. Sixty-nine percent of donors were HLA-identical siblings and 28% were unrelated donors. The conditioning regimen included total body irradiation in 442 (73%) patients. The 2 classifications performed similarly in explaining variability in survival by aGVHD grade, although the Glucksberg classification predicted early survival better. There was less physician bias or error in assigning grades with the IBMTR scoring system. With either system, only the maximum observed grade had prognostic significance for survival; neither time of onset nor progression from an initially lower grade of aGVHD was associated with survival once maximum grade was considered. Regardless of scoring system, aGVHD severity accounted for only a small percentage of observed variation in survival. Validity of these results in populations receiving peripheral blood transplants or nonmyeloablative conditioning regimens remains to be tested.

Acute Disease↗

PubMed2005

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.

Algorithms↗

PubMed2005

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.

Bone Marrow Transplantation↗

PubMed2005

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.

Adult↗

PubMed2005

Effects of the toe-only rocker on gait kinematics and kinetics in able-bodied persons.

Rocker sole shoes are commonly prescribed to diabetic patients with insensate feet. Recent passage of the therapeutic shoe bill has drawn an increased focus on prescription of rehabilitative footwear. The purpose of this work is to investigate the dynamics of lower extremity joints (hip, knee, and ankle) with the application of a toe-only rocker sole shoe under controlled laboratory conditions. Forty (40) normal adults volunteered for gait analysis using controlled baseline and prescription toe-only rocker sole shoes. Three-dimensional motion analysis techniques were used to acquire kinematic and kinetic data using a six camera Vicon 370 motion system and two AMTI force plates. While significant changes from baseline to toe-only rocker were noted in cadence (increased) and stride length (decreased), no significant change in walking speed was observed. The most significant kinematic changes with the application of the toe-only shoe occurred at the ankle and knee in the sagittal plane during stance. The most significant kinetic effects were observed in the hip and knee during swing phase. Changes in power were noted at all joints, mostly in terminal stance. These kinematic and kinetic changes, along with previously studied effects of pressure relief at the metatarsal heads, should aid medical professionals in prescribing prophylactic footwear.

Adult↗

PubMed2005

Regression modeling of competing risks data based on pseudovalues of the cumulative incidence function.

Typically, regression models for competing risks outcomes are based on proportional hazards models for the crude hazard rates. These estimates often do not agree with impressions drawn from plots of cumulative incidence functions for each level of a risk factor. We present a technique which models the cumulative incidence functions directly. The method is based on the pseudovalues from a jackknife statistic constructed from the cumulative incidence curve. These pseudovalues are used in a generalized estimating equation to obtain estimates of model parameters. We study the properties of this estimator and apply the technique to a study of the effect of alternative donors on relapse for patients given a bone marrow transplant for leukemia.

Biometry↗

PubMed2005

Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia.

STUDY OBJECTIVES: Reported risk factors for bronchiolitis obliterans (BO) in allogeneic hematopoietic stem-cell transplant recipients come from modest-sized studies and are limited to experiences of single institutions. We sought to identify risk factors for BO using data from the International Bone Marrow Transplant Registry. METHODS: Registry data on 6,275 adult patients with leukemia who received human leukocyte antigen-identical sibling transplants from 1989 to 1997 and survived at least 100 days after transplantation were evaluated for the study. Risk factors for BO were analyzed using proportional hazards regression. RESULTS: Seventy-six patients were found to have BO, with an incidence rate of 1.7% at 2 years after transplantation. The Kaplan-Meier estimate of median time to onset of BO was 431 days. Histologic evaluation was performed in 36 patients (47%). In 28 patients (37%), diagnosis was based on pulmonary function tests, CT scans of the chest, or a combination of both. On multivariate analysis, the factors that were associated with an increased risk for BO included the following: peripheral blood-derived stem cell, a busulfan-based conditioning regimen, interval from diagnosis to transplant > or = 14 months, female donor to male recipient sex match, prior interstitial pneumonitis, and an episode of moderate-to-severe acute graft-vs-host disease (GVHD). CONCLUSION: In addition to corroborating previously reported risk factors, such as acute GVHD and a busulfan-based conditioning regimen, we found that peripheral blood stem-cell transplantation, long duration to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are associated with an increased risk for BO.

Adolescent↗

PubMed2004

Association of transplant center and physician factors on mortality after hematopoietic stem cell transplantation in the United States.

The effect of the organization and delivery of health care at medical centers, referred to as "center effects," with clinical outcomes after hematopoietic stem cell transplantation (HSCT) is not clear. We examined the association between center and treatment provider factors and mortality after HSCT. We surveyed 163 (87% response rate) United States transplantation centers that performed HLA-identical sibling HSCT for leukemia or autologous HSCT for lymphoma between 1998 and 2000 among patients at least 18 years old. One hundred thirteen (69%) centers performed HLA-identical sibling transplantations, whereas 162 (99%) performed autologous transplantations. Factors associated with decreased 100-day mortality in the allogeneic setting include a higher patient-per-physician ratio (P = .003) and centers where physicians answer calls after office hours (P = .03). Medical school affiliation was not associated with increased 100-day mortality except in centers where students/residents are present without fellows (P = .02). Center effects were weaker in autologous HSCT at 1 year. Differences in 100-day mortality in patients receiving transplants in centers with favorable versus unfavorable factors were greater in allogeneic than autologous HSCT. Greater physician involvement in patient care is important in producing favorable outcomes after HSCT. To more clearly establish the role of the factors we identified, further studies are recommended.

Academic Medical Centers↗

PubMed2004

Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry.

PURPOSE: Peripheral-blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Despite lack of data on PBSC transplantation in children, there has been a change in clinical practice, with increasing numbers of children receiving PBSC allografts. PATIENTS AND METHODS: We compared the results of 143 PBSC and 630 BM transplants from human leukocyte antigen-identical sibling donors in children aged 8 to 20 years with acute leukemia. PBSC transplant recipients were older, and were more likely to have advanced leukemia, receive growth factors post-transplantation, and have undergone transplantation more recently. Risks of acute and chronic graft-versus-host disease (GVHD), treatment-related mortality, relapse, treatment failure (relapse or death), and overall mortality were compared using Cox proportional hazards regression to adjust for potentially confounding factors. RESULTS: Hematopoietic recovery was faster after PBSC transplantation. Risks of grade 2 to 4 acute GVHD were similar, but chronic GVHD risk was higher after PBSC transplantation (relative risk [RR], 1.85; 95% CI, 1.28 to 2.66; P = .001). In contrast to reports in adults, treatment-related mortality (RR, 1.89; 95% CI, 1.28 to 2.80; P = .001), treatment failure (RR, 1.31; 95% CI, 1.03 to 1.68; P = .03), and mortality (RR, 1.38; 95% CI, 1.07 to 1.79; P = .01) were higher after PBSC transplantation. Risks of relapse were similar. CONCLUSION: These data suggest poorer outcomes after PBSC compared with BM transplantation in children after adjusting for relevant risk factors. Given the trend toward increased use of PBSC allografts in children, prospective clinical trials are required to determine their appropriate role in this group of patients.

Acute Disease↗

PubMed2004

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.

Adolescent↗