Beyond "misunderstanding": written information and decisions about taking part in a genetic epidemiology study.

Although the need to obtain "informed" consent is institutionalised as a principle of ethical practice in research, there is persistent evidence that the meanings people attribute to research tend to be substantially at variance with what might be deemed "correct". One dominant account in the ethics literature has been to treat apparent "misunderstandings" as a technical problem, to be fixed through improving the written information given to research candidates. We aimed to explore theoretically and empirically the role of written information in "informing" participants in research.

Genomewide association analysis of coronary artery disease.

Background: Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease.

Methods: We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls).

Sternomastoid, rib cage, and expiratory muscle activity during weaning failure.

We hypothesized that patients who fail weaning from mechanical ventilation recruit their inspiratory rib cage muscles sooner than they recruit their expiratory muscles, and that rib cage muscle recruitment is accompanied by recruitment of sternomastoid muscles. Accordingly, we measured sternomastoid electrical activity and changes in esophageal (DeltaPes) and gastric pressure (DeltaPga) in 11 weaning-failure and 8 weaning-success patients. At the start of trial, failure patients exhibited a higher DeltaPga-to-DeltaPes ratio than did success patients (P = 0.

Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction.

Leukotrienes are implicated in the pathogenesis of coronary artery disease. Recently two haplotypes (HapA and HapB) in the gene encoding ALOX5AP (arachidonate 5-lipoxygenase-activating protein), the main regulator of 5-lipoxygenase, have been associated with a doubling of the risk of myocardial infarction. Studies have also shown that treatment with a leukotriene inhibitor reduces biomarkers of coronary risk in patients carrying HapA, raising the possibility of developing genotype-specific therapy.

Public health professionals' perceptions toward provision of health protection in England: a survey of expectations of Primary Care Trusts and Health Protection Units in the delivery of health protection.

Background: Effective health protection requires systematised responses with clear accountabilities. In England, Primary Care Trusts and the Health Protection Agency both have statutory responsibilities for health protection. A Memorandum of Understanding identifies responsibilities of both parties, but there is a potential lack of clarity about responsibility for specific health protection functions.

Variable performance of weaning-predictor tests: role of Bayes' theorem and spectrum and test-referral bias.

Objective: We examined whether variation in reported reliability of the frequency-to-tidal volume ratio (f/V(T)) in predicting weaning success is explained by spectrum and test-referral bias, as reflected by variation in pretest probability of success.

Design: Two authors extracted data from all studies on reliability of f/V(T) as a weaning predictor.

Results: Prevalence of successful weaning in studies of f/V(T) revealed significant heterogeneity; mean success rate was 0.

Remembrance of weaning past: the seminal papers.

The approach to ventilator weaning has changed considerably over the past 30 years. Change has resulted from research in three areas: pathophysiology, weaning-predictor testing, and weaning techniques. Physiology research illuminated the mechanisms of weaning failure.

Tumour necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease.

We aimed to examine the role of tumour necrosis factor gene complex polymorphisms in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that individuals possessing polymorphic variants associated with higher tumour necrosis factor (TNF) secretion would be more susceptible to and/or have more severe disease. Patients with COPD and population controls underwent detailed clinical phenotyping.

Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population.

Background: Blood pressure (BP) is a heritable trait of major public health concern. The WNK1 and WNK4 genes, which encode proteins in the WNK family of serine-threonine kinases, are involved in renal electrolyte homeostasis. Mutations in the WNK1 and WNK4 genes cause a rare monogenic hypertensive syndrome, pseudohypoaldosteronism type II.

Key concepts in genetic epidemiology.

This article is the first in a series of seven that will provide an overview of central concepts and topical issues in modern genetic epidemiology. In this article, we provide an overall framework for investigating the role of familial factors, especially genetic determinants, in the causation of complex diseases such as diabetes. The discrete steps of the framework to be outlined integrate the biological science underlying modern genetics and the population science underpinning mainstream epidemiology.

Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure.

A population-based study of a quantitative trait may be seriously compromised when the trait is subject to the effects of a treatment. For example, in a typical study of quantitative blood pressure (BP) 15 per cent or more of middle-aged subjects may take antihypertensive treatment. Without appropriate correction, this can lead to substantial shrinkage in the estimated effect of aetiological determinants of scientific interest and a marked reduction in statistical power.

Effect of media portrayals of removal of children's tissue on UK tumour bank.

Analysis of newspaper reporting shows how media scandals can affect scientific research, even when the research is not directly linked to the scandal

Meta-analysis of genetic studies using Mendelian randomization--a multivariate approach.

In traditional epidemiological studies the association between phenotype (risk factor) and disease is often biased by confounding and reverse causation. As a person's genotype is assigned by a seemingly random process, genes are potentially useful instrumental variables for adjusting for such bias. This type of adjustment combines information on the genotype-disease association and the genotype-phenotype association to estimate the phenotype-disease association and has become known as Mendelian randomization.

Covariance components models for longitudinal family data.

A longitudinal family study is an epidemiological design that involves repeated measurements over time in a sample that includes families. Such studies, that may also include relative pairs and unrelated individuals, allow closer investigation of not only the factors that cause a disease to arise, but also the genetic and environmental determinants that modulate the subsequent progression of that disease. Knowledge of such determinants may pay high dividends in terms of prognostic assessment and in the development of new treatments that may be tailored to the prognostic profile of individual patients.

Fluctuations in end-expiratory lung volume during Cheyne-Stokes respiration.

We hypothesized that patients with Cheyne-Stokes respiration exhibit periodic increases in end-expiratory lung volume, mediated by changes in breath components, postinspiratory inspiratory muscle activity, or both. Calibrated inductive plethysmography revealed that 12 of 12 patients with Cheyne-Stokes respiration experienced increases in end-expiratory volume during hyperpnea: maximum 412 +/- 112 (SE) ml (range 75-1,543 ml). Compared with quiet breathing, the breath with largest increase in end-expiratory volume had larger tidal volume (867 +/- 107 vs.

Weaning prediction: esophageal pressure monitoring complements readiness testing.

Several variables are recommended for identifying if a patient is ready for a trial of weaning from mechanical ventilation, but there is no agreement as to whether monitoring any variable during the trial enhances patient management. To determine whether repeated measurements of esophageal pressure throughout a trial are more reliable than measurements of esophageal pressure or frequency-to-VT ratio during the first minute of the trial, we studied 60 patients. A trend index that quantified esophageal pressure swings over time was more reliable than the first-minute measurements: sensitivity, 0.

Effect of closed unit policy and appointing an intensivist in a developing country.

Objective: We hypothesized that a dual strategy--instituting a closed intensive care unit (ICU) policy and simultaneously appointing an intensivist--would improve patient outcome in a university hospital of a developing country and that the benefit would increase over time.

Design: Data were prospectively collected over 5 months before the policy change (open policy) and over an initial 6 mos (early closed policy) and subsequent 12 mos (late closed policy) after the policy change.

Setting: The study was conducted at a medical ICU of a university hospital in Turkey.

Hypogonadism in men with chronic obstructive pulmonary disease: prevalence and quality of life.

We recently reported that hypogonadism does not affect respiratory muscle performance and exercise capacity in men with chronic obstructive pulmonary disease (COPD). In COPD, however, the relationship between exercise capacity and quality of life is controversial, making it unreliable to extrapolate about quality of life from exercise data. Accordingly, we determined prevalence and impact of hypogonadism on health-related quality of life in men with COPD.

Respiratory and skeletal muscles in hypogonadal men with chronic obstructive pulmonary disease.

Hypogonadism, found in about one-third of patients with chronic obstructive pulmonary disease (COPD), has potential for decreasing muscle mass and muscle performance. Compared with eugonadal patients, we hypothesized that hypogonadal patients with COPD have decreased respiratory and skeletal muscle performance. Nineteen hypogonadal and 20 eugonadal men with COPD (FEV(1) 1.

An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization.

A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person's genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure.

Effect of lung volume reduction surgery on diaphragmatic neuromechanical coupling at 2 years.

Study Objectives: We previously reported that patients with emphysema show an increase in diaphragmatic neuromechanical coupling at 3 months after lung volume reduction surgery. Diaphragmatic neuromechanical coupling was quantified as the quotient of tidal volume (normalized to total lung capacity) to tidal change in transdiaphragmatic pressure (normalized to maximal transdiaphragmatic pressure). As such, neuromechanical coupling estimates the fraction of diaphragmatic capacity used to generate tidal breathing.