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J Whitehead

Publications and source records attributed to J Whitehead.

At least 55 records · Page 3Linked to original sources
PubMed1995

A parametric multistate model for the analysis of carcinogenicity experiments.

A fully parametric multistate model is explored for the analysis of animal carcinogenicity experiments in which the time of tumour onset is not known. This model does not require assumptions about tumour lethality or cause of death judgements and can be fitted in the absence of sacrifice data. The model is constructed as a three-state model with simple parametric forms for the transition rates. Maximum likelihood methods are used to estimate the transition rates and different treatment groups are compared using likelihood ratio tests. Selection of an appropriate model and methods to assess the fit of the model are illustrated with data from animal experiments. Comparisons with standard methods are made.

Animals↗
PubMed1995

Randomised consent designs in cancer clinical trials.

In 1977, Zelen proposed a new design for clinical trials with the aim of increasing recruitment by avoiding some of the problems associated with obtaining informed consent. These 'randomised consent' designs have proved controversial, and have not often been used. This paper explains the statistical aspects of single and double randomised consent designs and reviews some of the ethical issues. All identified published cancer treatment trials using a randomised consent design are considered in some detail. Reasons for and against the use of these designs are summarised.

Ethics, Medical↗
PubMed1995

Practice variability and transfer of a racket skill.

This study used a forehand hitting task to explore the effect of racket variability on 'out of range' transfer. 48 11-yr.-old girls were randomly assigned to four treatment groups of Random Variability, Blocked Variability, Specific, and Control. The experimental groups had 32 trials for 4 successive days after which all groups were tested on 4 transfer conditions. Retention tests were given after 1, 4, and 8 days and the data were examined for treatment, range, and occasion effects. Analysis showed the superiority of practice over no practice, variable over specific practice, and random over blocked variability for transfer with two 'out of range' dimensions. Accuracy decayed between the transfer tests. These results are consistent with schema theory, and it is recommended that physical education teachers should focus variable practice on task dimensions that are new to their classes.

Child↗
PubMed1995

Chelation of organoarsenate with dimercaptosuccinic acid.

Alkane arsenate herbicides are available commercially, and their acute toxicity has been well documented in previous studies. Animal studies have indicated that dimercaptosuccinic acid (DMSA) can be used as an oral chelating agent. A 20-y-old white male cocaine addict attempted suicide by drinking approximately 500 ml of a 16% monosodium methanearsenate solution. He vomited 10 or more times and was admitted to the intensive care unit with impending shock and early liver and renal involvement. Four 5-day courses of 30 mg DMSA/kg/24 h were given. This brought the serum arsenic level from 2,871 micrograms/L to 6 micrograms/L, and his urine arsenic level from 78,920 micrograms/L to 21 micrograms/L in 30 d. Renal function tests returned to normal, with normal renal creatinine clearance, normal blood urea nitrogen and serum creatinine. However liver functions were abnormal, with elevation of serum transaminases, which later proved secondary to chronic hepatitis. No side effects of DMSA was encountered during the therapy. DMSA was successfully used to detoxify acute organoarsenate poisoning in a clinical setting, supporting experimental reports in the literature.

Administration, Oral↗
PubMed1995

Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis.

OBJECTIVE: To compare the rate of radiographic progression in knee osteoarthritis (OA) comparing indomethacin with placebo and tiaprofenic acid with placebo. METHODS: Rate of radiographic progression of OA of the knees was studied in 812 patients randomized double blind parallel group study at 20 rheumatology clinics in the United Kingdom and analyzed sequentially. Patients received either indomethacin 25 mg three times daily, tiaprofenic acid 300 mg twice daily, or matched placebo. All had access to paracetamol as a rescue analgesic. Joint space narrowing was measured by a 6 point grading scale, using radiographs taken with a standardized technique at recruitment and annually thereafter. RESULTS: Three hundred and seventy six patients completed at least one year of study medication and therefore contributed evaluable results. More than twice as many patients showed deterioration in the indomethacin group as in the placebo group; of 170 available patients at the 3rd interim analysis, 40 of 85 receiving indomethacin had deteriorated compared to 19 of 85 receiving placebo, a statistically significant difference (p = 0.009). No statistically significant difference (p = 0.308) was found between tiaprofenic acid and placebo at the 7th interim analysis, the conclusion of the study. CONCLUSION: Indomethacin increased the rate of radiological deterioration of joint space in patients with OA of the knee; tiaprofenic acid did not.

Adult↗
PubMed1994

On the development of the Medical Research Council trial of alpha-interferon in metastatic renal carcinoma. Urological Working Party Renal Carcinoma Subgroup.

This paper describes the steps taken by the British Medical Research Council (MRC) in developing the MRC RE01 trial, a randomized clinical trial for patients with metastatic renal cancer; we discuss the reasons for adopting a triangular sequential design and the impact that this has upon the monitoring of the trial. It had been suggested to the MRC that a trial of biological agents for metastatic renal carcinoma should be initiated. The Cancer Therapy Committee (CTC) of the MRC, through its associated site specific working parties, is responsible for designing and co-ordinating randomized trials of alternative treatments in cancer in solid tumours. Since no MRC working party for renal carcinoma existed at that time, development began by the formation of an ad hoc group set up under the auspices of the CTC. They assessed, by means of a postal questionnaire, U.K. interest in the trials of, and modalities utilized for, treatment of renal cancer. The responses focused attention on the important questions to ask and indicated the level of potential collaboration. These responses and related clinical and statistical issues suggested a protocol to compare medroxy-progesterone acetate (MPA) against alpha-interferon (alpha-IFN). In view of the special problems of comparing an expensive and potentially toxic therapy with an inexpensive and non-toxic standard, a sequential design was used rather than a fixed sample size design. Statistical issues raised and solutions provided are described. The method of establishing the trial data monitoring committee and a brief review of mortality from renal carcinoma in England and Wales are also included. The trial opened to patient recruitment on 1 January 1992. The formal statements regarding statistical issues that appear in the formal trial protocol (RE01) are set out in the Appendix.

Aged↗
PubMed1993

Sample size calculations for ordered categorical data.

Many clinical trials yield data on an ordered categorical scale such as very good, good, moderate, poor. Under the assumption of proportional odds, such data can be analysed using techniques of logistic regression. In simple comparisons of two treatments this approach becomes equivalent to the Mann-Whitney test. In this paper sample size formulae consistent with an eventual logistic regression analysis are derived. The influence on efficiency of the number and breadth of categories will be examined. Effects of misclassification and of stratification are discussed, and examples of the calculations are given.

Bias↗
PubMed1993

Mammographic calcifications and risk of subsequent breast cancer.

BACKGROUND: Women with proliferative benign breast lesions are at increased risk of breast cancer, and some studies have provided evidence that microscopic calcifications in such lesions enhance the risk. PURPOSE: This study was performed to determine whether calcifications on mammograms are predictive of subsequent breast cancer. METHODS: Data for this study were collected on women enrolled at four of the clinics that participated in the Breast Cancer Detection and Demonstration Project (BCDDP). The presence, morphology, and distribution of calcifications visualized on baseline mammograms for 686 women who developed breast cancer over a 7- to 10-year period of follow-up were compared with those for 1357 controls who remained cancer free. We also compared presence and types of calcifications in breasts in which cancer subsequently developed with those in the contralateral breast. RESULTS: Calcifications were evident at baseline in at least one breast in 381 (55.5%) of 686 cases and in 606 (44.7%) of 1357 controls. The estimated relative risk (RR) of breast cancer was 1.68 in women with calcifications, compared with those having none. There was a statistically significant trend of increasing risk with number of breasts with calcifications; RR increased from 1.28 to 2.14 in women with calcifications in one and both breasts, respectively. In women with unilateral calcifications, RR was greater for the breast in which the calcification occurred (1.48) than for the opposite breast (1.08). The elevated risk persisted for more than 6 years from identification of the calcification, suggesting that these lesions were not indicative of existing carcinomas detected later. Risk was greatest in women with clustered calcifications of any morphology or linearly distributed punctate calcifications (RR = 3.64), and the cancer in women with such calcifications was 4.65 times more likely to occur in the involved breast than in the contralateral breast. Multiple and scattered punctate calcifications, and those of any number or distribution that were ring-shaped or linear, were also associated with subsequent risk of breast cancer (RR = 2.09 and 1.76, respectively) but were not strongly predictive of the side on which the breast cancer occurred. Risk was not altered in women with single punctate or large conglomerate calcifications, although the cancers that subsequently occurred in women with the latter lesions were over three times more likely to develop in the breast with the calcification than in the opposite breast. CONCLUSIONS: These findings are consistent with previously reported relationships between breast cancer and specific histologic types of noninvasive breast lesions. Some types of mammographic calcifications appear to be independent risk factors for breast cancer. IMPLICATIONS: If these results are confirmed by other investigators, mammographic calcifications could serve as an additional indicator of women at high risk for breast cancer who may benefit from intensified follow-up.

Breast Diseases↗
PubMed1993

A simulated sequential analysis based on data from two MRC trials.

The motivation for proposing sequential methods for cancer clinical trials is presented, and the methodology examined by re-analysing two completed phase III cancer trials of the Lung Cancer Working Party of the British Medical Research Council. The reanalysis proceeds as if the trials had been designed with a planned series of interim analyses governing stopping. Specifically, the triangular and double-triangular tests were applied. The sequential reanalysis gave a substantial reduction in the number of patient required, and deaths observed, for conclusions to be reached in comparison with the completed studies. In each case, the sequential analysis was stratified for baseline prognostic factors which were seen to be important at the first interim analysis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Interim analyses and stopping rules in cancer clinical trials.

A clinical trial conducted according to a schedule of interim analyses written into the protocol, and stopped according to a predetermined rule, is known to statisticians as a sequential clinical trial. This methodology is becoming more widely used in trials concerning life-threatening diseases because of its ability to adjust the sample size to the emerging information on treatment efficacy. When treatments under comparison differ appreciably, small samples will be sufficient; for more subtle differences larger numbers of patients need to be recruited. Sequential methods have already been used in certain cancer clinical trials, and they are especially appropriate for such studies. In this paper the principles of sample size determination are reviewed, and the essential aspects of designing sequential trials are described. The necessity for a special form of statistical analysis following a sequential trial is explained, and the consequences of early or late stopping on the analysis are investigated. Compromises which have to be made between the formal requirements of theory and the practical realities of trial conduct are discussed.

Bayes Theorem↗
PubMed1992

Overrunning and underrunning in sequential clinical trials.

In a sequential (or group sequential) clinical trial the fulfillment of some pre-specified stopping rule will cause recruitment to be terminated. However, for various reasons, data on patients treated according to protocol may continue to accumulate for some time afterward. This phenomenon is called overrunning. On the other hand, a sequential clinical trial might be abandoned before the stopping rule has been fulfilled. This is called underrunning. In both of these situations the procedure for validly analyzing the study is unclear. In this paper we first review the arguments for sequential methodology and the practical way in which it can be integrated with normal clinical trial conduct. Turning next to the special situations of overrunning and underrunning, the conditions under which a valid analysis is possible are identified, and a method of analysis based on the frequentist philosophy is presented. The likelihood of first gaining and then losing significance due to overrunning and its consequences are examined. Examples based on experience with real studies are presented.

Clinical Trials as Topic↗
PubMed1992

Riboflavin deficiency and iron absorption in adult Gambian men.

Iron absorption from 3.38 mg 58Fe was measured in riboflavin-deficient Gambian men with haemoglobin (Hb) less than 11.5 g/dl before and after oral riboflavin therapy, and the results compared with a group not receiving riboflavin. Riboflavin status (as determined by erythrocyte glutathione reductase activation coefficient) and Hb increased in teh riboflavin-supplemented but not placebo group. Plasma ferritin levels were low and did not change in either group. There was very wide variation in percentage iron absorption between individuals and also within single individuals on two separate occasions but no measurable change with riboflavin supplementation. The results of the study indicate that the efficiency of iron utilization is impaired in riboflavin deficiency, but that iron absorption is unaffected.

Administration, Oral↗
PubMed1992

Estimating the ventilation-perfusion distribution: an ill-posed integral equation problem.

The distribution of ventilation-perfusion ratio over the lung is a useful indicator of the efficiency of lung function. Information about this distribution can be obtained by observing the retention in blood of inert gases passed through the lung. These retentions are related to the ventilation-perfusion distribution through an ill-posed integral equation. An unusual feature of this problem of estimating the ventilation-perfusion distribution is the small amount of data available; typically there are just six data points, as only six gases are used in the experiment. A nonparametric smoothing method is compared to a simpler method that models the distribution as a histogram with five classes. Results from the smoothing method are found to be very unstable. In contrast, the simpler method gives stable solutions with parameters that are physiologically meaningful. It is concluded that while such smoothing methods may be useful for solving some ill-posed integral equation problems, the simpler method is preferable when data are scarce.

Animals↗
PubMed1991

A random effects model for ordinal responses from a crossover trial.

Crossover studies have been successfully conducted in the case of continuous responses. Existing procedures of analysis for ordinal responses, on the other hand, are rarely satisfactory unless strict, usually unrealistic, assumptions are made. In this paper we investigate a random effects model and show that the model is simple and general. Interpretation of parameters is easy, though with a complicated fitting procedure.

Clinical Trials as Topic↗
PubMed1991

A general parametric approach to the meta-analysis of randomized clinical trials.

Meta-analysis provides a systematic and quantitative approach to the summary of results from randomized studies. Whilst many authors have published actual meta-analyses concerning specific therapeutic questions, less has been published about comprehensive methodology. This article presents a general parametric approach, which utilizes efficient score statistics and Fisher's information, and relates this to different methods suggested by previous authors. Normally distributed, binary, ordinal and survival data are considered. Both the fixed effects and random effects model for treatments are described.

Humans↗
PubMed1991

Analysis of failure time data with ordinal categories of response.

When failure times are observed, additional information concerning the type of failure is often recorded. A method which simultaneously models the failure times and additional information in the form of ordinal categories is discussed. An application to clinical trial data, in which the failure times are times of onset of headache, and the headaches are classified into the ordinal categories mild, moderate and severe, illustrates how this method may be used and how the final model can be interpreted. The continuation ratio model, which is used in this method, is described in detail.

Clinical Trials as Topic↗