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J Whitehead

Publications and source records attributed to J Whitehead.

At least 37 records · Page 2Linked to original sources
PubMed1999

A novel Bayesian decision procedure for early-phase dose-finding studies.

Phase I first-in-man studies in normal, healthy volunteers are performed to define a maximum safe dose and to identify a range of acceptable doses for later drug development studies in patients. Analysis of pharmacokinetic and pharmacodynamic data using mixed-effects modeling can be used to fit an overall dose-response relationship. By expressing prior information as pseudodata, the same methodology can be used to perform a Bayesian analysis and to determine posterior modal estimates for the model parameters. Decision theory can then be applied to maximize a chosen gain function, utilizing real-time data capture for choosing safe doses in a way that will provide more informative responses, thus accelerating study completion. The methodology is introduced elsewhere (1). The purpose of this paper is to describe software currently in development and to illustrate the method using an example from a recent study.

Area Under Curve↗
PubMed1999

Decision theoretic designs for phase II clinical trials with multiple outcomes.

In many phase II clinical trials, it is essential to assess both efficacy and safety. Although several phase II designs that accommodate multiple outcomes have been proposed recently, none are derived using decision theory. This paper describes a Bayesian decision theoretic strategy for constructing phase II designs based on both efficacy and adverse events. The gain function includes utilities assigned to patient outcomes, a reward for declaring the new treatment promising, and costs associated with the conduct of the phase II trial and future phase III testing. A method for eliciting gain function parameters from medical collaborators and for evaluating the design's frequentist operating characteristics is described. The strategy is illustrated by application to a clinical trial of peripheral blood stem cell transplantation for multiple myeloma.

Bayes Theorem↗
PubMed1998

Sample size review in a head injury trial with ordered categorical responses.

Between 1993 and 1996, a total of 452 patients were entered into a randomized trial evaluating eliprodil (a non-competitive NMDA receptor antagonist) in patients suffering from severe head injury. The primary efficacy analysis concerned the Glasgow Outcome Score (GOS), six months after randomization. This outcome was classified into three ordered categories: good recovery; moderate disability, and the worst category made up by combining severe disability, vegetative state and dead. A sample size calculation was performed prior to the commencement of the study, using a formula which depends on the anticipated proportions of patients in the three different outcome categories, the proportional odds assumption and on the relationship between outcome and prognostic factors such as Glasgow Coma Score at entry. Owing to uncertainty about the influence of prognostic factors, and about the proportion of patients in the three GOS categories, a blinded sample size review was planned. This review was performed on the basis of the first 93 patients to respond, and this led to an increase in the sample size from 400 to 450. In this paper the pre-trial simulations showing that the type I error rate would be influenced and the power would be preserved will be presented, and the implementation of the procedure will be described.

Craniocerebral Trauma↗
PubMed1998

The interpretation of clinical trials of immediate versus delayed therapy.

Prospective, randomised clinical comparisons with a control group are the ideal way to evaluate the effectiveness of a new therapy. However if the new therapy is already available, then it may be unethical to refuse patients this treatment indefinitely. In some trials, patients randomised to the control group receive placebo until their condition deteriorates, and are then switched to the new therapy. Patients randomised to the experimental group receive the new treatment immediately. An analysis following the intention-to-treat principle will be a valid comparison of the two treatment policies actually used. However, such an analysis will underestimate the effect of immediate therapy relative to completely untreated controls, and in particular a negative conclusion should not be interpreted to mean that the therapy is ineffective. In this paper we introduce a parametric approach, which models the dependence between the survival time and the time of switching to the new treatment. This is used first to illustrate the lack of power of the intention-to-treat analysis for evaluating the therapy relative to a pure control. More speculatively, an alternative method of analysis based on our model is presented. We illustrate the issues with data from a prospective randomised study, in which one group of HIV-positive patients received zidovudine immediately after randomisation while control patients were switched to zidovudine only when their condition deteriorated.

Anti-HIV Agents↗
PubMed1998

Bayesian decision procedures based on logistic regression models for dose-finding studies.

Early-phase clinical trials, conducted to determine the appropriate dose of an experimental drug to take forward to later trials, are considered. The objective is to find the dose associated with some low probability of an adverse event. A Bayesian model is presented, and a decision-theoretic procedure for finding the optimal doses for each of a series of cohorts of subjects is derived. The procedure is flexible and can easily be conducted using standard statistical software. The results of simulations investigating the properties of the procedure are presented.

Bayes Theorem↗
PubMed1998

A method for sequential analysis of survival data with nonproportional hazards.

Two tests are proposed for comparing the survival curves of patients randomised between an experimental treatment and a control treatment when it is anticipated that the two survival curves may not satisfy the assumption of proportional hazards. The tests are particularly useful for the situation in which the survival curves are coincident or cross over early in the follow-up period and then diverge. The tests compare the probabilities of survival for longer than some fixed time since randomisation for the two groups of patients. Both methods take account of the right-censored observations, and both are associated with methods for estimating and setting confidence limits for treatment differences. The first method is a mathematically direct approach based on the derivation of the efficient score statistic and Fisher's information. The second method is simpler, being based on Kaplan-Meier estimates and their variances. Conventional methods of sample size determination require the assumption of proportional hazards. Here a sequential approach is used, as it is difficult to set the sample size in advance without strong assumptions about the relationship between the two survival curves. Simulation results giving information on the size and power of the proposed tests are provided and the tests are applied to data from a clinical trial in breast cancer.

Biometry↗
PubMed1997

Investigation of the variation in orientation and crystallinity in poly(ethylene terephthalate) containers using microfocus X-ray diffraction.

The microfocus X-ray beamline at the European Synchrotron Radiation Facility has been used to investigate the variation in molecular orientation and crystallinity in the wall of a container fabricated from poly(ethylene terephthalate). Two-dimensional wide-angle X-ray scattering patterns were recorded and displayed in real time as the specimen was tracked across the incident X-ray beam enabling the measurement of textural changes to be made with a spatial resolution of ~2 mum.

Journal Article↗
PubMed1997

Cautionary tales of survival analysis: conflicting analyses from a clinical trial in breast cancer.

Data from a completed randomized trial in breast cancer are used to demonstrate and quantify the variation in estimated survival curves and log-rank statistics at different times throughout a trial. False 'plateaux' are common, as are wide fluctuations in chi2 values obtained from the log-rank test when there are few events. We show how analyses conducted at different times can demonstrate different effects. Long follow-up is often necessary to allow correct interpretation of results. We discuss the assumption of proportional hazards and the consequences of making that assumption inappropriately. We show how checking whether hazards are proportional can help in avoiding erroneous conclusions.

Breast Neoplasms↗
PubMed1997

A sequential trial of pain killers in arthritis: issues of multiple comparisons with control and of interval-censored survival data.

A large clinical comparison of pain killers used in the treatment of arthritis was conducted using a sequential design. The trial presented two major challenges: there were three treatments to be compared, and patients were assessed annually for up to 7 years. Treatment comparisons were made by selecting appropriate pairwise comparisons, to which standard theory could be applied. Rules concerning actions to take in the event of each stopping criterion being reached were evaluated by simulation. The annual assessments were used to create an interval-censored survival time: the year during which "disease progression" first occurred.

Analgesics↗
PubMed1997

Relative importance of success in sport and schoolwork.

Cross-domain studies of achievement-related cognitions have been gaining attention in the United States. This study provides comparative data from a United Kingdom upper school. 390 subjects age 13 (n = 218) or 15 (n = 172) years rated the importance of success in sport and schoolwork. Academic success was more important than sport success, and sport success was more important to boys (n = 203) than girls (n = 187). Academic success was less important to older subjects, and sport success was less important to older girls. Predictions, from importance and perceived ability, of free time spent in each domain were stronger for sport than for schoolwork indicating that the model held better for voluntary activity.

Achievement↗
PubMed1997

Patterns of geographic mobility of persons with AIDS in Canada from time of AIDS index diagnosis to death.

OBJECTIVE: To characterize migration patterns of persons with AIDS in Canada during the period from AIDS diagnosis to death. DESIGN: Descriptive, population-based study. SETTING: Canada. PATIENTS: Canada's AIDS Case Reporting Surveillance System (ACRSS) was linked to deaths in the Canadian Mortality Data Base (CMDB). Probabilistic linkage was based on initials, date of birth, date of death, birthplace, and location at diagnosis and at death. Analysis was restricted to AIDS cases reported from Jan. 1, 1982, to Sept. 30, 1994, and to deaths reported from Jan. 1, 1982, to Dec. 31, 1992. MAIN OUTCOME MEASURES: Change in usual place of residence; migration rates by region and community size. RESULTS: A total of 5755 AIDS cases recorded in the ACRSS were linked to deaths in the CMDB. Of these linked cases, 5366 (93%) included information on province or territory of usual residence or community size. A total of 160 (3.0%) persons with AIDS changed their province or territory of residence between the time of their AIDS diagnosis and death. Multivariate analysis indicated that those who changed residences between AIDS index diagnosis and death were more likely than other persons with AIDS to live in provinces other than British Columbia, Ontario and Quebec (p < 0.001), to be diagnosed earlier (p = 0.004), to be younger (p < 0.001) and to be gay or bisexual (p = 0.042). CONCLUSIONS: Our analysis revealed that only a small proportion of persons changed their residence between AIDS diagnosis and death. Geographic mobility was the greatest among persons with AIDS residing outside of the regions where the overwhelming majority of persons with AIDS in this country reside.

Acquired Immunodeficiency Syndrome↗
PubMed1997

A one-year trial to assess the value of orlistat in the management of obesity.

OBJECTIVES: This paper describes the methodology of a multicentre study designed to assess the efficacy and tolerability of orlistat 120 mg tid as therapy for inducing weight loss in excess of that achieved with a moderately calorie-restricted diet alone. The results from a single centre are presented to illustrate the nature of the response. DESIGN: This was a double-blind, randomized, parallel-group, placebo-controlled multicentre study. A four-week, single-blind, placebo run-in period preceded a 52 week double-blind treatment period during which patients received either orlistat or placebo three times a day. At the start of the run-in period, all patients were placed on a diet containing approximately 30% of calories as fat and designed to cause an energy deficit of approximately 600 kcal/d. SUBJECTS: Patients of either sex, more than 18 y of age, with a body mass index (BMI) between 30 and 43 kg/m2 were eligible for enrolment. MEASUREMENTS: Efficacy assessments included: measurements of body weight; anthropometry; quality of life; blood pressure; serum lipids; fasting serum glucose and insulin. Safety assessments included: adverse events; vital signs; ECG; renal and gallbladder ultrasound; haematology; serum biochemistry. OUTCOME: In the single centre there was a reduction in body weight of 5.5 +/- 4.5 (s.d.) kg (5.7% reduction) in the placebo group and 8.6 +/- 5.4kg in the orlistat-treated group (8.4% reduction) by six months. Thereafter, the placebo group tended to relapse whereas the orlistat group maintained their loss (2.6% vs 8.4% reduction from initial value at 52 weeks). Total and LDL cholesterol fell by 0.05 mmol/l (1.6%) and 0.14 mmol/l (4.2%), respectively, in orlistat treated patients. The drop-out rate was 48% in the placebo group and 39% in the orlistat group. Intestinal symptoms related to orlistat were significantly increased compared to placebo but were well tolerated. Fat soluble vitamin levels remained within the normal range in the treatment group; the reduction seen in alpha-tocopherol levels in patients receiving orlistat was normalized by the decrease in plasma cholesterol concentrations. Beta-carotene and vitamin D concentrations also decreased in orlistat-treated patients. CONCLUSIONS: This preliminary analysis suggests that orlistat, when used with a health-promoting low-fat and moderately energy-restricted diet, confers advantages in the long-term management of obesity.

Adult↗
PubMed1996

Sequential designs for equivalence studies.

Sequential designs are increasingly being used in major clinical trials concerning life-threatening diseases. So far most applications have concerned trials designed to establish whether an experimental treatment is superior to a control. However, many trials are conducted with the objective of showing that an experimental treatment is equivalent to a control. This paper concerns the application of sequential designs to equivalence trials. Criteria for claiming equivalence are reviewed and compared, and methods first developed in the context of bioequivalence are described. Appropriate sequential procedures are identified. A simulated example, based on a clinical comparison of bronchodilators, is used to illustrate both the double triangular test and a comparable procedure constructed from alpha-spending functions.

Albuterol↗
PubMed1996

Case report: immunoglobulin M-mediated, temperature-dependent neutrophil agglutination as a cause of pseudoneutropenia.

The authors report the case of a 77-year-old man in whom intermittent neutropenia developed during a prolonged hospitalization. Laboratory records revealed wide variations in the patient's routine leukocyte counts. Examination of the peripheral smear revealed clumps of 2-3 polymorphonuclear leukocytes throughout the slide and large aggregates (> 50 cells) along the smear edges. Neutrophil clumping also was observed in blood anticoagulated with citrate or heparin. Replacement of patient plasma with saline prevented agglutination. Addition of patient plasma or serum to normal cells induced neutrophil agglutination. Holding the patients blood at 37 degrees C prevented agglutination, which occurred spontaneously and more exuberantly as the temperature was reduced to 22 degrees C. Flow cytometry revealed immunoglobulin M on neutrophil surfaces. Spontaneous agglutination resolved 6 months after resection of the patient's subsequently diagnosed colon cancer. This is the first report of immunoglobulin M-induced neutrophil clumping occurring in the setting of malignancy, and the first reported immunoglobulin M not to require ethylenediaminetetraacetic acid as a cofactor for agglutination.

Adult↗
PubMed1996

Issues in development of a protocol to evaluate children's reasoning about ability and effort in sport.

This study developed a protocol to identify in a sporting activity the developmental stages in differentiating effort and ability derived by Nicholls in 1978 from cognitive tasks. 32 boys aged 8 to 13 years were shown videoclips depicting two performers on a split-screen shooting at off-screen baskets with unequal effort. False scores were presented to indicate that the sporadic worker scored the same as or higher than the consistent worker. Subjects were then interviewed about the performers' ability and effort, and their responses were categorized using Nicholls' criteria for developmental level. The responses showed the same developmental stages derived from cognitive tasks, with some new interpretations specific to this psychomotor task. Issues of generalizability are discussed and alternative protocols recommended.

Adolescent↗