Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Risk scores to facilitate preoperative prediction of transfusion and large volume blood transfusion associated with adult cardiac surgery.

BACKGROUND: The aim of this study was to develop two novel risk prediction scores for transfusion and bleeding that would be used to inform treatment decisions, quality assurance, and clinical trial design in cardiac surgery. METHODS: Clinical data prospectively collected from 26 UK cardiac surgical centres and a single European centre were used to develop two risk prediction models: one for any red blood cell (RBC) transfusion, and the other for large volume blood transfusion (≥4 RBC units; LVBT), an index of severe blood loss. 'Complete case' data were available for 24 749 patients. Multiple imputation was used for missing covariate data (typically <5% per variable), with the imputed data set containing 39 970 patients. Risk models were developed in the complete case data set, with internal validation using leave-one-centre-out cross-validation. The final selected models were fitted to the imputed data set. Final risk scores were then compared with the performance of three existing scores: the Transfusion Risk and Clinical Knowledge score (TRACK), the Transfusion Risk Understanding Scoring Tool (TRUST), and the Papworth Bleeding Risk Score (BRiSc). RESULTS: The area under the receiver operating characteristic curve (AUC) was 0.77 (95% confidence interval 0.77-0.77) for the any RBC transfusion score and AUC 0.80 (0.79-0.80) for the LVBT score in the imputed data set. The LVBT model also showed excellent discrimination (Hosmer-Lemeshow P=0.32). In the imputed data set, the AUCs for the TRACK and TRUST scores for any RBC transfusion were 0.71 and 0.71, respectively, and for LVBT the AUC for the BRiSc score was 0.69. CONCLUSIONS: Two new risk scores for any RBC transfusion or LVBT among cardiac surgery patients have excellent discrimination, and could inform clinical decision making.

Pet ownership is associated with increased risk of non-atopic asthma and reduced risk of atopy in childhood: findings from a UK birth cohort.

BACKGROUND: Studies have shown an inverse association of pet ownership with allergy but inconclusive findings for asthma. OBJECTIVE: To investigate whether pet ownership during pregnancy and childhood was associated with asthma and atopy at the age of 7 in a UK population-based birth cohort. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to investigate associations of pet ownership at six time points from pregnancy to the age of 7 with asthma, atopy (grass, house dust mite, and cat skin prick test) and atopic vs. non-atopic asthma at the age of 7 using logistic regression models adjusted for child's sex, maternal history of asthma/atopy, maternal smoking during pregnancy, and family adversity. RESULTS: A total of 3768 children had complete data on pet ownership, asthma, and atopy. Compared with non-ownership, continuous ownership of any pet (before and after the age of 3) was associated with 52% lower odds of atopic asthma [odds ratio (OR) 0.48, 95% CI 0.34-0.68]. Pet ownership tended to be associated with increased risk of non-atopic asthma, particularly rabbits (OR 1.61, 1.04-2.51) and rodents (OR 1.86, 1.15-3.01), comparing continuous vs. non-ownership. Pet ownership was consistently associated with lower odds of sensitization to grass, house dust mite, and cat allergens, but rodent ownership was associated with higher odds of sensitization to rodent allergen. Differential effects of pet ownership on atopic vs. non-atopic asthma were evident for all pet types. CONCLUSIONS AND CLINICAL RELEVANCE: Pet ownership during pregnancy and childhood in this birth cohort was consistently associated with a reduced risk of aeroallergen sensitization and atopic asthma at the age of 7, but tended to be associated (particularly for rabbits and rodents) with an increased risk of non-atopic asthma. The opposing effects on atopy vs. non-atopic asthma might be considered by parents when they are deciding whether to acquire a pet.

Breast-feeding and health consequences in early childhood: is there an impact of time-dependent confounding?

BACKGROUND: Estimated effects of breast-feeding on childhood health vary between studies, possibly due to confounding by baseline maternal and child characteristics. Possible time-dependent confounding has received little consideration. Our aim was to evaluate the impact of such confounding. METHODS: We estimated the relationship between cumulative exclusive breast-feeding up to 6 months and wheezing, rash and body mass index (BMI) at 12 months [in the Whistler cohort (n = 494) and PROBIT (n = 11,463)], and wheezing, rash, asthma, hay fever, eczema, allergy and BMI at age 6.5 years (PROBIT). We adjusted for time-dependent confounding by weight, length, rash, respiratory illness and day care attendance using marginal structural models (MSMs). RESULTS: Weight and day care attendance appeared potential time-dependent confounders, since these predicted breast-feeding status and were influenced by previous breast-feeding. However, adjustment for time-dependent confounders did not markedly change the estimated associations. For example, in PROBIT the adjusted increase in BMI at 12 months per 1-month increase in exclusive breast-feeding was 0.04 (95% CI -0.09 to 0.01) using logistic regression and -0.06 (95% CI -0.11 to -0.01) using MSM. In Whistler, these estimates were each -0.05 (95% CI -0.10 to 0.00). CONCLUSIONS: In two cohort studies, there was little evidence of time-dependent confounding by weight, length, rash, respiratory illness or day care attendance of the effects of breast-feeding on early childhood health.

Design and preliminary recruitment results of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

BACKGROUND: Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. METHODS: Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50-69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up. RESULTS: Among randomised practices, 271 (68%) in the intervention arm (198,114 men) and 302 (78%) in the control arm (221,929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices). CONCLUSIONS: The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening.

Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.

BACKGROUND: Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES: To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES: Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS: Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS: Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION: Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS: The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS: BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The diagnostic utility and cost-effectiveness of selective nerve root blocks in patients considered for lumbar decompression surgery: a systematic review and economic model.

BACKGROUND: Diagnostic selective nerve root block (SNRB) involves injection of local anaesthetic, sometimes in conjunction with corticosteroids, around spinal nerves. It is used to identify symptomatic nerve roots in patients with probable radicular pain that is not fully concordant with imaging findings. OBJECTIVES: (1) Determine the diagnostic accuracy of SNRB in patients with low back and radiating pain in a lower limb; (2) evaluate whether or not accuracy varies by patient subgroups; (3) review injection-related adverse events; and (4) evaluate the cost-effectiveness of SNRB. DATA SOURCES: MEDLINE, EMBASE, Science Citation Index, Bioscience Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACS) and grey literature databases were searched from inception to August 2011. Reference lists of included studies were screened. METHODS: A systematic review (SR) of studies that assessed the accuracy of SNRB or adverse events in patients with low back pain and symptoms in a lower limb for the diagnosis of lumbar radiculopathy. Study quality was assessed using the quality assessment of diagnostic accuracy studies (QUADAS)-2 checklist. We used random-effects meta-analysis to pool diagnostic accuracy data. Decision tree and Markov models were developed, combining SR results with information on the costs and outcomes of surgical and non-surgical care. Uncertainty was assessed using probabilistic and deterministic sensitivity analyses. RESULTS: Five studies assessed diagnostic accuracy: three diagnostic cohort and two within-patient case-control studies. All were judged to be at high risk of bias and had high concerns regarding applicability. In individual studies, sensitivity ranged from 57% [95% confidence interval (CI) 43% to 70%] to 100% (95% CI 76% to 100%) and specificity from 9.5% (95% CI 1% to 30%) to 86% (95% CI 76% to 93%). The most reliable estimate was judged to come from two cohort studies that used post-surgery outcome as the reference standard; summary sensitivity and specificity were 93% (95% CI 86% to 97%) and 26% (95% CI 5% to 68%), respectively. No study provided sufficient detail to judge whether or not accuracy varied by patient subgroup. Seven studies assessed adverse events. There were no major or permanent complications; minor complications were reported in 0-6% of patients. The addition of SNRB to the diagnostic work-up was not cost-effective with an incremental cost per quality-adjusted life-year of £1,576,007. Sensitivity analyses confirmed that SNRB was unlikely to be a cost-effective method for diagnosis and planning surgical therapy. LIMITATIONS: We identified very few studies; all were at high risk of bias. The conduct and interpretation of SNRBs varied and there was no gold standard for diagnosis. Limited information about the impact of SNRB on subsequent care and the long-term costs and benefits of surgery increased uncertainty about cost-effectiveness. CONCLUSIONS: There were few studies that estimated the diagnostic accuracy of SNRB in patients with radiculopathy and all were limited by the difficulty of making a reference standard diagnosis. Summary estimates suggest that specificity is low, but results are based on a small number of studies at a high risk of bias. Based on current weak evidence, it is unlikely that SNRB is a cost-effective method for identifying the symptomatic nerve root prior to lumbar spine surgery. Future research should focus on randomised controlled trials to evaluate whether or not SNRB improves patient outcomes at acceptable cost. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database.

BACKGROUND: Chronic fatigue syndrome (CFS) is relatively common and disabling. Over 8000 patients attend adult services each year, yet little is known about the outcome of patients attending NHS services. AIM: Investigate the outcome of patients with CFS and what factors predict outcome. DESIGN: Longitudinal patient cohort. METHODS: We used data from six CFS/ME (myalgic encephalomyelitis) specialist services to measure changes in fatigue (Chalder Fatigue Scale), physical function (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and pain (visual analogue pain rating scale) between clinical assessment and 8-20 months of follow-up. We used multivariable linear regression to investigate baseline factors associated with outcomes at follow-up. RESULTS: Baseline data obtained at clinical assessment were available for 1643 patients, of whom 834 (51%) had complete follow-up data. There were improvements in fatigue [mean difference from assessment to outcome: -6.8; 95% confidence interval (CI) -7.4 to -6.2; P < 0.001]; physical function (4.4; 95% CI 3.0-5.8; P < 0.001), anxiety (-0.6; 95% CI -0.9 to -0.3; P < 0.001), depression (-1.6; 95% CI -1.9 to -1.4; P < 0.001) and pain (-5.3; 95% CI -7.0 to -3.6; P < 0.001). Worse fatigue, physical function and pain at clinical assessment predicted a worse outcome for fatigue at follow-up. Older age, increased pain and physical function at assessment were associated with poorer physical function at follow-up. CONCLUSION: Patients who attend NHS specialist CFS/ME services can expect similar improvements in fatigue, anxiety and depression to participants receiving cognitive behavioural therapy and graded exercise therapy in a recent trial, but are likely to experience less improvement in physical function. Outcomes were predicted by fatigue, disability and pain at assessment.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Methods for dealing with time-dependent confounding.

Longitudinal studies, where data are repeatedly collected on subjects over a period, are common in medical research. When estimating the effect of a time-varying treatment or exposure on an outcome of interest measured at a later time, standard methods fail to give consistent estimators in the presence of time-varying confounders if those confounders are themselves affected by the treatment. Robins and colleagues have proposed several alternative methods that, provided certain assumptions hold, avoid the problems associated with standard approaches. They include the g-computation formula, inverse probability weighted estimation of marginal structural models and g-estimation of structural nested models. In this tutorial, we give a description of each of these methods, exploring the links and differences between them and the reasons for choosing one over the others in different settings.

Changes in the geography of suicide in young men: England and Wales 1981--2005.

BACKGROUND: Suicide rates changed considerably in men aged <45 years in England and Wales between 1980 and 2005. The impact of these changes on the geographic distribution of suicide is unknown. METHODS: Mapping of geo-coded standardised mortality ratios for suicide in 1113 census tracts (mean population 46 000) in England and Wales, smoothed using Bayesian hierarchical models, for 15-44 year old men during 1981-1985, 1991-1995 and 2001-2005. RESULTS: Young male suicide rates rose by 50% between the early 1980s and the 1990s but declined to pre-1980 levels by 2005. The spatial distribution of suicide changed markedly over these years. The 'bull's-eye' pattern of increases in suicide rates from the suburbs to the centre of London was abolished, although they persisted in other major cities. Suicide rates among young men in Wales changed from being relatively lower than other regions to being considerably higher. Similarly, by 2001-2005 suicide rates in northern and south western regions were relatively higher than elsewhere with the predominant feature being a north-west/ south-east divide in suicide. These changes in the spatial epidemiology of suicide were not explained by changes in area levels of single person households, unemployment or the unmarried population. CONCLUSION: There has been a marked change in the spatial epidemiology of suicide in young men in the last 25 years, particularly in central London where the RR of suicide has declined and Wales where risks have risen. These changes do not appear to be explained by recognised suicide risk factors and require investigation to inform prevention strategies.

The effect of injecting drug use history on disease progression and death among HIV-positive individuals initiating combination antiretroviral therapy: collaborative cohort analysis.

BACKGROUND: We examined whether determinants of disease progression and causes of death differ between injecting drug users (IDUs) and non-IDUs who initiate combination antiretroviral therapy (cART). METHODS: The ART Cohort Collaboration combines data from participating cohort studies on cART-naïve adults from cART initiation. We used Cox models to estimate hazard ratios for death and AIDS among IDUs and non-IDUs. The cumulative incidence of specific causes of death was calculated and compared using methods that allow for competing risks. RESULTS: Data on 6269 IDUs and 37 774 non-IDUs were analysed. Compared with non-IDUs, a lower proportion of IDUs initiated cART with a CD4 cell count <200 cells/µL or had a prior diagnosis of AIDS. Mortality rates were higher in IDUs than in non-IDUs (2.08 vs. 1.04 per 100 person-years, respectively; P<0.001). Lower baseline CD4 cell count, higher baseline HIV viral load, clinical AIDS at baseline, and later year of cART initiation were associated with disease progression in both groups. However, the inverse association of baseline CD4 cell count with AIDS and death appeared stronger in non-IDUs than in IDUs. The risk of death from each specific cause was higher in IDUs than non-IDUs, with particularly marked increases in risk for liver-related deaths, and those from violence and non-AIDS infection. CONCLUSION: While liver-related deaths and deaths from direct effects of substance abuse appear to explain much of the excess mortality in IDUs, they are at increased risk for many other causes of death, which may relate to suboptimal management of HIV disease in these individuals.

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study.

OBJECTIVE: The aim of the study was to describe trends in CD4 cell counts in HIV-infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends. METHODS: Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviralnaïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post-cART virological failure. Effects of post-cART virological failure (>1000 HIV-1 RNA copies/mL) on subsequent CD4 cell counts were evaluated. FINDINGS: A total of 7069 participants were included in the analysis (median follow-up in all baseline CD4 cell count groups was ≥ 35 months). Among participants without virological failure ≥ 6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥ 6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load. CONCLUSIONS: Post-cART CD4 cell counts are strongly related to pre-cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.

Association of secular trends in unemployment with suicide in Taiwan, 1959-2007: a time-series analysis.

OBJECTIVE: Despite the wealth of research investigating the association of unemployment with suicide in the West, few studies have investigated the association in non-Western countries. This study aimed to investigate the relationship between secular trends in unemployment and suicide in Taiwan. STUDY DESIGN: Time-series analysis. METHODS: Overall and age-specific suicide rates (1959-2007) for Taiwanese men and women aged 15 years or above were calculated from national population and mortality statistics. The association of secular trends in unemployment with suicide was investigated graphically and using time-series modelling (Prais-Winsten regression). RESULTS: Rises in unemployment were associated with an increase in male suicide rates, but evidence for an association in females was limited. In the model controlling for changes in gross domestic product (GDP) per capita, GDP growth, divorce and female labour force participation, for every 1% rise in unemployment, male suicide rates increased by 3.1 (95% confidence interval 1.4-4.8) per 100,000. There is no evidence for a difference in the strength of association between men of different ages. CONCLUSION: Trends in suicide, particularly for adult males, appear to be influenced by unemployment. The results have implications for suicide prevention, in particular for societies facing acute rises in unemployment during recessions.

Association between school absence and physical function in paediatric chronic fatigue syndrome/myalgic encephalopathy.

OBJECTIVE: To investigate factors associated with school attendance and physical function in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). DESIGN: Cross-sectional study. SETTING: Regional specialist CFS/ME service. PATIENTS: Children and young people aged under 18 years. OUTCOME MEASURES: Self-reported school attendance and physical function measured using the physical function subscale of the Short Form 36. METHODS: Linear and logistic regression analysis of data from self-completed assessment forms on children attending a regional specialist service between 2004 and 2007. Analyses were done in two groups of children: with a completed Spence Children's Anxiety Scale (SCAS) and with a completed Hospital Anxiety and Depression Scale (HADS). RESULTS: Of 211 children with CFS/ME, 62% attended 40% of school or less. In children with completed SCAS, those with better physical function were more likely to attend school (adjusted odds ratio (OR) 1.70; 95% CI 1.36 to 2.13). This was also true for those with completed HADS (adjusted OR 2.05; 95% CI 1.4 to 3.01). Increasing fatigue and pain and low mood were associated with worse physical function. There was no evidence that anxiety, gender, age at assessment, family history of CFS/ME or time from onset of symptoms to assessment in clinic were associated with school attendance or physical function. IMPLICATIONS: Paediatricians should recognise that reduced school attendance is associated with reduced physical function rather than anxiety. Improving school attendance in children with CFS/ME should focus on evidence-based interventions to improve physical function, particularly concentrating on interventions that are likely to reduce pain and fatigue.

Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood.

BACKGROUND: Patterns of wheezing during early childhood may indicate differences in aetiology and prognosis of respiratory illnesses. Improved characterisation of wheezing phenotypes could lead to the identification of environmental influences on the development of asthma and airway diseases in predisposed individuals. METHODS: Data collected on wheezing at seven time points from birth to 7 years from 6265 children in a longitudinal birth cohort (the ALSPAC study) were analysed. Latent class analysis was used to assign phenotypes based on patterns of wheezing. Measures of atopy, airway function (forced expiratory volume in 1 s (FEV(1)), mid forced expiratory flow (FEF(25-75))) and bronchial responsiveness were made at 7-9 years of age. RESULTS: Six phenotypes were identified. The strongest associations with atopy and airway responsiveness were found for intermediate onset (18 months) wheezing (OR for atopy 8.36, 95% CI 5.2 to 13.4; mean difference in dose response to methacholine 1.76, 95% CI 1.41 to 2.12 %FEV(1) per mumol, compared with infrequent/never wheeze phenotype). Late onset wheezing (after 42 months) was also associated with atopy (OR 6.6, 95% CI 4.7 to 9.4) and airway responsiveness (mean difference 1.61, 95% CI 1.37 to 1.85 %FEV(1) per mumol). Transient and prolonged early wheeze were not associated with atopy but were weakly associated with increased airway responsiveness and persistent wheeze had intermediate associations with these outcomes. CONCLUSIONS: The wheezing phenotypes most strongly associated with atopy and airway responsiveness were characterised by onset after age 18 months. This has potential implications for the timing of environmental influences on the initiation of atopic wheezing in early childhood.

The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort.

BACKGROUND: A recent study suggested a link between folate metabolism and atopy, based on a positive association between a common polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and allergic sensitization in Danish adults. OBJECTIVE: We investigated the associations between MTHFR C677T and allergy or atopy in a large, population-based birth cohort of children and their mothers, the Avon Longitudinal Study of Parents and Children (ALSPAC). We also looked for evidence of a pre-natal effect of maternal folate metabolism on subsequent atopic disease in the offspring. METHODS: Mothers were recruited in pregnancy and the children followed from birth. Atopy in the child was assessed at 7-8 years of age by skin prick tests to common allergens. Asthma was defined as a physician diagnosis and current symptoms at 71/2 years of age. Asthma and allergy status of the mothers were obtained from self-completion questionnaires. RESULTS: Data on MTHFR C677T genotype and allergy were available for 5364 children and on allergy and/or asthma for 7356 mothers. In children, the prevalence of atopy was 20.0% and asthma 10.0% whereas in mothers, the prevalence of self-reported allergy was 42.7% and asthma 11.5%. Atopy in the child was associated with male gender (P<0.001), less tobacco smoke exposure and higher maternal education. MTHFR C677T genotype was not associated with social factors or dietary folate intake. We found no evidence of associations between the MTHFR C677T variant allele and atopy, allergy or asthma in mothers or children. There was no evidence to support an effect of maternal MTHFR C677T genotype on atopy in the offspring. CONCLUSION: The results of this study do not support the hypothesis that impaired folate metabolism is associated with allergy in adults or children in this population.