Peter Fayers

Initiation of hypertension in utero and its amplification throughout life.

OBJECTIVE--To determine whether the relation between high blood pressure and low birth weight is initiated in utero or during infancy, and whether it changes with age. DESIGN--A longitudinal study of children and three follow up studies of adults. SETTING--Farnborough, Preston, and Hertfordshire, England, and a national sample in Britain. SUBJECTS--1895 children aged 0-10 years, 3240 men and women aged 36 years, 459 men and women aged 46-54 years, and 1231 men and women aged 59-71 years. The birth weight of all subjects had been recorded. MAIN OUTCOME MEASURE--Systolic blood pressure. RESULTS--At all ages beyond infancy people who had lower birth weight had higher systolic blood pressure. Systolic blood pressure was not related to growth during infancy independently of birth weight. The relation between systolic pressure and birth weight became larger with increasing age so that, after current body mass was allowed for, systolic pressure at ages 64-71 years decreased by 5.2 mm Hg (95% confidence interval 1.8 to 8.6) for every kg increase in birth weight. CONCLUSIONS--Essential hypertension is initiated in fetal life. A raised blood pressure is then amplified from infancy to old age, perhaps by a positive feedback mechanism.

Quality of life assessment in clinical trials—guidelines and a checklist for protocol writers: the U.K. Medical Research Council experience

Many clinical trials groups now routinely consider including Quality of Life (QoL) assessment in trials. Indeed, several have policies stating that QoL should be considered as a potential endpoint in all new trials and that if it is not to be evaluated the applicants should justify not doing so. However, inclusion of QoL in clinical trials presents a number of difficult organisational issues, and serious problems in compliance have frequently been reported. Thus, in multicentre clinical trials many of the expected QoL questionnaires fail to be successfully completed and returned, although a few groups have claimed high success rates. However, it is well recognised that if questionnaires are missing, there may be bias in the interpretation of trial results, and the estimates of treatment differences and the overall level of QoL may be inaccurate and misleading. Hence it is important to seek methods of improving compliance, at the level of both the participating institution and the patient. We describe a number of methods for addressing these issues, which we suggest should be considered by all those writing clinical trial protocols involving QoL assessment. These are based upon over a decade of experience with assessing QoL in Medical Research Council (MRC) cancer clinical trials. In particular, we provide a checklist for points that should be covered in protocols. Examples are given from a range of current MRC Cancer Trials Office protocols, which it is proposed might act as templates when writing new protocols.

Double data entry: what value, what price?

We challenge the notion that double data entry is either sufficient or necessary to ensure good-quality data in clinical trials. Although we do not completely reject that notion, we quantify some of the effects that poor quality data have on final study results in terms of estimation, significance testing, and power. By introducing digit errors into simulated blood pressure measurements we demonstrate that simple range checks allow us to detect (and therefore correct) the main errors that impact the final study results and conclusions. The errors that cannot easily be detected by such range checks, although possibly numerous, are shown to be of little importance in drawing the correct conclusions from the statistical analysis of data. Exploratory data analysis cannot identify all errors that a second data entry would detect, but on the other hand, not all errors that are found by exploratory data analysis are detectable by double data entry. Double data entry is concerned solely with ensuring, to a high degree of certainty, that what is recorded on the case record form is transcribed into the database. Exploratory data analysis looks beyond the case record form to challenge the plausibility of the written data. In this sense, the second entering of data has some benefit, but the use of exploratory data analysis methods, either as data entry is ongoing or at the end of data entry and as the first stage in an analysis strategy, should always be mandatory.

Blood pressure in first 10 years of life: the Brompton study.

OBJECTIVES--To determine the normal range of blood pressure and its pattern of change in the first 10 years of life. To estimate at what age (if any) children consistently appear in one part of the blood pressure distribution and at what age familial correlations in blood pressure become significant. DESIGN--Longitudinal cohort study. SETTING--South east England. SUBJECTS--2088 children of both sexes born consecutively in Farnborough Hospital, Kent, and their parents. MAIN OUTCOME MEASURE--Blood pressure measured by Doppler ultrasonography and sphygmomanometry. RESULTS--Systolic blood pressure rose from a mean of 88.5 mm Hg at age 6 months to 96.2 mm Hg at 8 years measured with a 8 cm cuff and from 89.1 mm Hg at age 5 years to 94.3 mm Hg at age 10 years measured with a 12 cm cuff. The larger cuff gave blood pressure readings about 6 mm Hg lower. This effect was independent of body weight and arm circumference. Diastolic blood pressure rose from 57.8 mm Hg at 5 years to 61.8 mm Hg at 10 years (12 cm cuff). There was only about 1 mm Hg difference between sexes. Blood pressure was correlated with weight, weight adjusted for height, height, and arm circumference at all ages studied. The correlation coefficient of repeated yearly measurements increased steadily with age from 0.28 at 2 years to 0.59 at 10 years. The correlation coefficients between childs blood pressure and mothers average blood pressure increased from 0.1 at age 1 year to 0.23 at age 10. CONCLUSIONS--Blood pressure changes relatively little between the ages of 6 months and 10 years. Yet because of the increasing strength of between occasion and family correlations, children are more consistently occupying a specific part of the blood pressure distribution as they grow older. Studies in children should help determine why some adults have hypertension and others do not.

Methodological and Statistical Issues of Quality of Life (QoL) and Economic Evaluation in Cancer Clinical Trials: Report of a Workshop

In recent years, quality of life (QoL) and economic evaluations have become increasingly important as additional outcome measures in cancer clinical trials. However, both fields of research are relatively new and in need of finding solutions to a substantial number of specific methodological problems. This paper reports on the proceedings of a symposium aimed at summarising and discussing some of the most contentious methodological and statistical issues in QoL and economic evaluations. In addition, possible solutions are indicated and the most pertinent areas of research are identified. Issues specific to QoL evaluations that are addressed include clinically meaningful changes in QoL scores; how to analyse QoL data and to handle missing and censored data and integration of length of life and QoL outcomes. Issues specific to economic evaluations are the advantages and disadvantages of various outcome measures; statistical methods to analyse economic data and choice of decision criteria and analytical perspective. How to perform QoL and economic evaluations in large and simple trials and whether the gap between QoL and utility measures can be bridged are also discussed.

Blood pressure survey in a population of newborn infants.

Systolic blood pressure in the arm was measured in infants at the ages of 4 to 6 days and 5 to 7 weeks by the Doppler ultrasound technique. At the age of 4 to 6 days the mean blood pressure (+/- SE of mean) in 469 sleeping infants was 70-7 +/- 0-3 mm Hg, rising at 5 to 7 weeks to 89-7 +/- 0-9 mm Hg (in 144 infants). In 252 infants awake at 5 to 7 weeks blood pressure was 96-8 +/- 0-6 mm Hg. In 391 infants in whom measurements were made on both occasions blood pressure at 4 to 6 days was significantly related to blood pressure at 5 to 7 weeks. Thus those infants with relatively high blood pressures at 4 to 6 days showed a weak tendency to have relatively high blood pressures at 5 to 7 weeks. In this trend continues with age it would suggest that the tendency to develop hypertension may already be demonstrable at the age of 4 to 6 days.

EFFECT OF FEEDING HABIT ON WEIGHT IN INFANCY

A population study of 758 infants born at the same hospital showed that weight at the ages of six week and six months was not significantly related to breast or bottle feeding, the early introduction of solids, or the sodium content of bottle feeds. Weight at six weeks was related to the volume and energy content of the feeds which were examined in those bobies that were bottle-fed alone. Although analysis of a single feed showed that mothers mixed feeds incorrectly, there was no evidence that mixing of overstrength feeds leads to obesity.

Blood pressure in the first 6 weeks of life.

Systolic blood pressure was measured at frequent intervals during the first 6 weeks of life in 99 normal neonates. Blood pressure rose from a mean of 70 mmHg at age 2 days, to 93 mmHg at age 6 weeks in babies awake; the majority of this rise (14 mmHg) took place in the first 2 weeks of life. The blood pressure measured when infants were asleep was lower than in those awake, but increased in a similar manner. Blood pressure of infants at 2 days was not significantly affected by method of delivery, or by the anaesthesia or analgesia that the mothers received in labour. It was not related to the Apgar score at one or five minutes.

UKCCCR register of U.K. cancer trials

The UKCCCR Register of U.K. Cancer Trials comprises an on-line database of all randomized trials of cancer therapy, whether phase III or randomized phase II trials. Both current or open trials, and closed or completed trials, are included. Abstracts of any publications associated with the trials are also included. The UKCCCR Register is the initial component of a larger European register of trials. This article describes the structure and content of the database, the PC program for data entry, and the Unix-based browsing software for interactive access over networks. Problems of ensuring complete and comprehensive registration of trials, and sources of information, are also reviewed.

Randomization in clinical trials and experimental molecular medicine

Randomization has become a standard procedure for clinical trial design, and is also widely used in other areas of biological research. This article will examine the reasons why randomization has become a sine qua non in some areas, yet remains far less widely adopted in experimental studies of molecular medicine. Should randomization be used routinely in the design of most laboratory experiments?