Biomedical subjects
Publications and source records attributed to Peter A Lachenbruch.
This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; 'Confirmatory clinical trials with an adaptive design' by Armin Koch; and 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill.
This is a discussion of the paper' Sample size recalculation in internal pilot study designs' by Tim Friede and Meinhard Kieser, appearing in this special issue on adaptive designs.
Biology-based markers that can be used to confirm the diagnosis of chronic graft-versus-host disease (GVHD) or monitor progression of the disease could help in the evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biologic or pathogenic process, a pharmacologic response to a therapeutic intervention, or a surrogate end point intended to substitute for a clinical end point. The following applications of biomarkers could be useful in chronic GVHD clinical trials or management: (1) predicting response to therapy; (2) measuring disease activity and distinguishing irreversible damage from continued disease activity; (3) predicting the risk of developing chronic GVHD; (4) diagnosing chronic GVHD: (5) predicting the prognosis of chronic GVHD; (6) evaluating the balance between GVHD and graft-versus-leukemia effects (graft-versus-leukemia or GVT); and (7) serving as a surrogate end point for therapeutic response. Such biomarkers can be identified by either hypothesis-driven testing or by high-throughput discovery-based methods. To date, no validated biomarkers have been established for chronic GVHD, although several candidate biomarkers have been identified from limited hypothesis-driven studies. Both approaches have merit and should be pursued. The consistent treatment and standardized documentation needed to support biomarker studies are most likely to be satisfied in prospective clinical trials.
The lack of standardized criteria for quantitative measurement of therapeutic response in clinical trials poses a major obstacle for the development of new agents in chronic graft-versus-host disease (GVHD). This consensus document was developed to address several objectives for response criteria to be used in chronic GVHD-related clinical trials. The proposed measures should be practical for use both by transplantation and nontransplantation medical providers, adaptable for use in adults and in children, and focused on the most important chronic GVHD manifestations. The measures should also give preference to quantitative, rather than semiquantitative, measures; capture information regarding signs, symptoms, and function separately from each other; and use validated scales whenever possible to demonstrate improved patient outcomes and meet requirements for regulatory approval of novel agents. Based on these criteria, we propose a set of measures to be considered for use in clinical trials, and forms for data collection are provided (). Measures should be made at 3-month intervals and whenever major changes are made in treatment. Provisional definitions of complete response, partial response, and progression are proposed for each organ and for overall outcomes. The proposed response criteria are based on current expert consensus opinion and are intended to improve consistency in the conduct and reporting of chronic GVHD trials, but their use remains to be demonstrated in practice.
BACKGROUND: Hepatitis B virus (HBV) infections are still a major health issue, with approximately 350 million people chronically infected with HBV worldwide. Information about the minimum copy number of HBV genomes required for infection would be useful as a reference for drug and vaccine development; for monitoring HBV patients during treatment; for screening of blood, organ, and tissue donors; and for regulating nucleic acid amplification assays for HBV. STUDY DESIGN AND METHODS: Serum samples from chronic carriers (hepatitis B surface antigen-positive and antibody to HBV core antigen-positive) of the three most common subtypes of HBV were studied; their infectivity titers had been evaluated previously in chimpanzees. The genotypes of the HBV samples were determined by DNA sequences and type-specific amino acids of the S gene of HBV. Copy numbers of HBV DNA were quantified by real-time TaqMan polymerase chain reaction (PCR) and by nested PCR applied to limiting dilutions. The copy number determined for each inoculum was compared with previously defined chimpanzee infectivity titers. RESULTS: The genotypes of the HBV adw, ayw, and adr inocula were A, D, and C, respectively. The concentration of HBV DNA was determined to be 5.4 x 10(9), 2.5 x 10(9), and 3.1 x 10(8) genome equivalents (geq) per mL for serum samples containing the adw, ayw, and adr, respectively. The chimpanzee infectivity titers per milliliter of these initial HBV-containing serum samples were previously determined to be 10(7.5) for adw, 10(7.5) for ayw (MS-2 strain), and 10(8) for adr. CONCLUSION: The minimal copy number of HBV DNA in chronic carriers of HBV that can infect the chimpanzee model was estimated to be from 3 to 169 geq based upon the three well-characterized inocula.
There are minimal standards for the processing of whole blood components, and to apply those standards requires a system of quality assurances. Excessive indications of failures in compliance trigger inspections and other remedial actions, but the demarcation of what is excessive is a critical issue. Issues of low volume in some production facilities, low expected frequency of nonconformance, multiple nonindependent statistical tests, and controlling both the false-positive and false-negative rates all complicate quality assurance procedures. The scan statistic is a statistic that computes the number of events in a moving window throughout the period of risk. Monitoring plans based on scan statistics are developed to estimate the probability that a process that is under control.
This paper discusses the US Food and Drug Administration's approach to evaluation of vaccines in general, and vaccines against diseases of bioterrorism in particular. We summarize the scientific bases for development and approval of vaccines and then discuss specific issues regarding vaccines against disease organisms that could potentially be used as weapons of bioterrorism.
OBJECTIVE: To document and evaluate the scores that normal, healthy children achieve when performing 9 maneuvers of the Childhood Myositis Assessment Scale (CMAS). METHODS: A total of 303 healthy children, 4-9 years of age, were scored as they performed 9 CMAS maneuvers. The data were then evaluated to determine whether normal scores for some maneuvers are age and sex dependent. RESULTS: All children were able to achieve maximum possible scores for the supine to prone, supine to sit, floor sit, floor rise, and chair rise maneuvers. All but 2 4-year-olds achieved a maximum possible score for the arm raise/duration maneuver. Performance of the head lift and sit-up maneuvers varied significantly, depending primarily on age. Children in all age groups had less difficulty performing the leg lift than the head lift or sit-up. CONCLUSION: The normative data generated by this study are of value for interpreting the serial CMAS scores of children with idiopathic inflammatory myopathies.
OBJECTIVE: To examine the measurement characteristics of the Childhood Myositis Assessment Scale (CMAS) in children with juvenile idiopathic inflammatory myopathy (juvenile IIM), and to obtain preliminary data on the clinical significance of CMAS scores. METHODS: One hundred eight children with juvenile IIM were evaluated on 2 occasions, 7-9 months apart, using various measures of physical function, strength, and disease activity. Interrater reliability, construct validity, and responsiveness of the CMAS were examined. The minimum clinically important difference (MID) and CMAS scores corresponding to various degrees of physical disability were estimated. RESULTS: The intraclass correlation coefficient for 26 patients assessed by 2 examiners was 0.89, indicating very good interrater reliability. The CMAS score correlated highly with the Childhood Health Assessment Questionnaire (C-HAQ) score and with findings on manual muscle testing (MMT) (r(s) = -0.73 and 0.73, respectively) and moderately with physician-assessed global disease activity and skin activity, parent-assessed global disease severity, and muscle magnetic resonance imaging (r(s) = -0.44 to -0.61), thereby demonstrating good construct validity. The standardized response mean was 0.81 (95% confidence interval 0.53, 1.09) in patients with at least 0.8 cm improvement on a 10-cm visual analog scale for physician-assessed global disease activity, indicating strong responsiveness. In bivariate regression models predicting physician-assessed global disease activity, MMT remained significant in models containing the CMAS (P = 0.03) while the C-HAQ did not (P = 0.4). Estimates of the MID ranged from 1.5 to 3.0 points on a 0-52-point scale. CMAS scores corresponding to no, mild, mild-to-moderate, and moderate physical disability, respectively, were 48, 45, 39, and 30. CONCLUSION: The CMAS exhibits good reliability, construct validity, and responsiveness, and is therefore a valid instrument for the assessment of physical function, muscle strength, and endurance in children with juvenile IIM. Preliminary data on MID and corresponding levels of disability should aid in the clinical interpretation of CMAS scores when assessing patients with juvenile IIM.
OBJECTIVE: To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials. METHODS: Twenty-nine experts in the assessment of myositis achieved consensus on 102 adult and 102 juvenile paper patient profiles as clinically improved or not improved. Two hundred twenty-seven candidate definitions of improvement were developed using the experts' consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set of measures. Seventeen additional candidate definitions of improvement were developed from classification and regression tree analysis, a data-mining decision tree tool analysis. Six candidate definitions specifying percentage change or raw change in the core set of measures were developed using logistic regression analysis. Adult and pediatric working groups ranked the 13 top-performing candidate definitions for face validity, clinical sensibility, and ease of use, in which the sensitivity and specificity were >/=75% in adult, pediatric, and combined data sets. Nominal group technique was used to facilitate consensus formation. RESULTS: The definition of improvement (common to the adult and pediatric working groups) that ranked highest was 3 of any 6 of the core set measures improved by >/=20%, with no more than 2 worse by >/=25% (which could not include manual muscle testing to assess strength). Five and 4 additional preliminary definitions of improvement for adult and juvenile myositis, respectively, were also developed, with several definitions common to both groups. Participants also agreed to prospectively test 6 logistic regression definitions of improvement in clinical trials. CONCLUSION: Consensus preliminary definitions of improvement were developed for adult and juvenile myositis, and these incorporate clinically meaningful change in all myositis core set measures in a composite end point. These definitions require prospective validation, but they are now proposed for use as end points in all myositis trials.
This article includes a retrospective review of fatalities caused by transfusion-related acute lung injury (TRALI) over a 5-year period (from 1997 to 2002) that were reported to the Center for Biologics Evaluation and Research involving 58 recipient deaths and the corresponding 63 blood component donors. Descriptive statistics are presented. Recipient characteristics include age, sex, and admitting diagnosis. Cardiovascular disease, pulmonary disorders, and cancer were the most frequent diagnoses of transfusion recipients. Reported deaths did not appear to be associated with age, sex, reason for transfusion, or transfusion component. Implicated blood component(s) and clinical symptoms at the time of reaction were recorded. Fresh frozen plasma was implicated in one half of the cases, whereas red blood cells played a role in approximately one third. The clinical characteristics described most often in TRALI reports included shortness of breath, frothy sputum, pulmonary infiltrates, and hypoxia. Donor variables included age, sex, parity, and laboratory tests for antibodies to HLA and/or antigranulocyte antibodies. Laboratory tests showed HLA antibodies and/or antigranulocyte antibodies were positive in the majority of donors tested. More data are needed to better describe the role of antibodies in these reactions. Greater awareness is crucial for the practitioner to be alert for signs and symptoms of TRALI and to be aware of the necessary steps in treatment.
Of major importance in clinical trials is the ability to predict individual patient outcome or endpoints using biomarkers, also known as variables or predictors, in as safe, efficient, and accurate a manner as possible. This review addresses the concepts and possible strategies for use of predictor and surrogate biomarkers in the design of clinical trials in renal transplantation. The statistical concepts apply equally well to other organ grafts.
A simulation study was performed to study the effects of non-normality and to examine procedures to ameliorate possible loss of power when data are incorrectly assumed to be normally distributed. It was found that only distributions with high asymmetry or heavy tails seriously affect the t-test. The Box-Cox likelihood ratio test appears to have some advantages over the others, but this must be offset by the greater complexity in making the results understandable to non-statisticians. The variability in outcomes with the different procedures demonstrates the importance of specifying such procedures a priori.
The lack of consensus regarding outcome measures and trial design issues in the idiopathic inflammatory myopathies (IIM) is inhibiting the conduct and interpretation of clinical trials. To begin to address these problems, a multispecialty group of over 70 adult and pediatric neurologists, rheumatologists, rehabilitation medicine physicians, statisticians, and patient support group leaders, called the International Myositis Outcome Assessment Collaborative Study Group (IMACS), is engaged in developing consensus on the assessment of disease activity and damage for myositis clinical trials. As part of this ongoing international effort, members of this group met in November 2001 at a work-shop entitled "Defining Clinical Improvement in Adult and Juvenile Myositis." A goal of the work-shop was to review current data on the validity and responsiveness of the recently published proposed preliminary core set measures for disease outcome assessment in clinical trials for myositis and to define the degree of change in each core set measure that is clinically meaningful. Despite differences in the clinical presentations, natural history and responses to therapy between adult onset and juvenile onset myositis, expert specialists in these diseases came to a consensus that the amount of improvement that is clinically meaningful in each core measure is the same for adult and juvenile myositis. For the domains of muscle strength and physical function, a minimum of 15% improvement is clinically significant, whereas for the physician and patient global assessments, as well as the extramuscular assessment, a minimum of 20% improvement is considered clinically meaningful, and for serum levels of muscle associated enzymes, at least 30% improvement is needed to be clinically important. This workshop is the first of several planned to develop multidisciplinary, international consensus on the conduct and reporting of IIM clinical trials.
This paper is an introduction to a set of papers on two-part models that were presented at the 2000 Joint Statistical Meetings of American Statistical Association, International Biometric Society (ENAR), International Biometric Society (WNAR), Institute of Mathematical Statistics, and Statistical Society of Canada. The second part of the paper summarizes results of a study of the size and power of two-part models. It proposes that two-part models are a useful alternative to the t-test and the Wilcoxon test.
OBJECTIVE: We evaluated the utility of neopterin and quinolinic acid (QUIN) as surrogate measures of disease activity in juvenile idiopathic inflammatory myopathies (IIMs). METHODS: Plasma and first morning void urine samples were measured for neopterin and QUIN using commercial ELISA, HPLC, or gas chromatography-mass spectrometry in 45 juvenile IIM patients and 79 healthy controls. Myositis disease activity assessments were obtained. RESULTS: Plasma and urine neopterin and QUIN concentrations were increased in juvenile IIM patients compared with healthy controls (P <0.017). Urine neopterin and QUIN highly correlated with each other (r(s) = 0.73; P <0.0001). Urine neopterin and QUIN correlated moderately with myositis disease activity assessments, including physician and parent global activity assessments, muscle strength testing, functional assessments (Childhood Myositis Assessment Scale, Childhood Health Assessment Questionnaire), skin global activity, and edema on magnetic resonance imaging (r(s) = 0.42-0.62; P <0.05), but generally not with muscle-associated enzymes in serum. Urine neopterin or QUIN, in combination with either serum lactate dehydrogenase (LD) or aspartate aminotransferase (AST), significantly predicted global disease activity (R(2) =0.40-0.56; P <0.002), and both were more sensitive to change than these serum enzymes (standardized response means, -0.41 to -0.48). CONCLUSIONS: Urinary neopterin and QUIN are candidate measures of disease activity in juvenile IIM patients and add significantly to the prediction of global disease activity in combination with serum LD or AST values. Measurement of these markers in first morning void urine specimens appears to be as good as, or possibly better than, measurements of their concentrations in plasma.