Clustering and meso-level variables in cross-sectional surveys: an example of food aid during the Bosnian crisis

<p>Abstract</p> <p>Background</p> <p>Focus groups, rapid assessment procedures, key informant interviews and institutional reviews of local health services provide valuable insights on health service resources and performance. A long-standing challenge of health planning is to combine this sort of qualitative evidence in a unified analysis with quantitative evidence from household surveys. A particular challenge in this regard is to take account of the neighbourhood or clustering effects, recognising that these can be informative or incidental.</p> <p>Methods</p> <p>An example of food aid and food sufficiency from the Bosnian emergency (1995-96) illustrates two Lamothe cluster-adjustments of the Mantel Haenszel (MH) procedure, one assuming a fixed odds ratio and the other allowing for informative clustering by not assuming a fixed odds ratio. We compared these with conventional generalised estimating equations and a generalised linear mixed (GLMM) model, using a Laplace adjustment.</p> <p>Results</p> <p>The MH adjustment assuming incidental clustering generated a final model very similar to GEE. The adjustment that does not assume a fixed odds ratio produced a final multivariate model and effect sizes very similar to GLMM.</p> <p>Discussion</p> <p>In medium or large data sets with stratified last stage random sampling, the cluster adjusted MH is substantially more conservative than the naïve MH computation. In the example of food aid in the Bosnian crisis, the cluster adjusted MH that does not assume a fixed odds ratio produced similar results to the GLMM, which identified informative clustering.</p

The importance of both setting and intensity of physical activity in relation to non-clinical anxiety and depression

Physical activity is associated with good physical and mental health. Current recommendations suggest that people should achieve 30 minutes of moderate-intensity activity most days of the week to gain health benefits. This activity may be accumulated in leisure time, in active commuting, at work or in the home. Here we look at the cross-sectional relationship between physical activity and mental health as measured by the HADS anxiety and depression scores in a sample of 1,742 participants from a Scottish general population survey. The participants were men and women in three age cohorts aged around 24, 44 and 64 years who, in 1995, were interviewed face to face and also self-completed the HADS depression and anxiety scale. Respondents reported their levels of physical activity at work, in the home and in leisure time; the intensities of activity were also determined. Physical activity was related to depression scores but not to anxiety scores. There was no relationship between work physical activity and depression score. Among women, depression score increased with each additional episode of vigorous home activity. In both sexes, depression score decreased with each additional episode of vigorous leisure activity, but among men the decrease in depression score with moderate leisure activity was reversed if a lot of moderate activity was undertaken. We have found a variable relationship between depression scores and various settings for physical activity. Researchers, policymakers and practitioners who are interested in the relationship between physical activity and mental health should take into account the setting for activity as well as frequency, duration and intensity of activity

Changes in the socio-demographic patterning of late adolescent health risk behaviours during the 1990s: analysis of two West of Scotland cohort studies

Background: Substance use and sexual risk behaviour affect young people's current and future health and wellbeing in many high-income countries. Our understanding of time-trends in adolescent health-risk behaviour is largely based on routinely collected survey data in school-aged adolescents (aged 15 years or less). Less is known about changes in these behaviours among older adolescents. Methods: We compared two cohorts from the same geographical area (West of Scotland), surveyed in 1990 and 2003, to: describe time-trends in measures of smoking, drinking, illicit drug use, early sexual initiation, number of opposite sex sexual partners and experience of pregnancy at age 18-19 years, both overall and stratified by gender and socioeconomic status (SES); and examine the effect of time-trends on the patterning of behaviours by gender and SES. Our analyses adjust for slight between-cohort age differences since age was positively associated with illicit drug use and pregnancy. Results: Rates of drinking, illicit drug use, early sexual initiation and experience of greater numbers of sexual partners all increased significantly between 1990 and 2003, especially among females, leading to attenuation and, for early sexual initiation, elimination, of gender differences. Most rates increased to a similar extent regardless of SES. However, rates of current smoking decreased only among those from higher SES groups. In addition, increases in 'cannabis-only' were greater among higher SES groups while use of illicit drugs other than cannabis increased more in lower SES groups. Conclusion: Marked increases in female substance use and sexual risk behaviours have implications for the long-term health and wellbeing of young women. More effective preventive measures are needed to reduce risk behaviour uptake throughout adolescence and into early adulthood. Public health strategies should reflect both the widespread prevalence of risk behaviour in young people as well as the particular vulnerability to certain risk behaviours among those from lower SES groups

Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants.

BACKGROUND: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). OBJECTIVE: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. RESULTS: A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms; P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms; P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant. CONCLUSION: The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected

PAPSS2‐related brachyolmia : clinical and radiological phenotype in 18 new cases

Brachyolmia is a skeletal dysplasia characterized by short spine‐short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short‐spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over‐faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi‐parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under‐recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester

Family Income Gradients in the Health and Health Care Access of US Children

This study sought to examine the shape and magnitude of family income gradients in US children’s health, access to care, and use of services. We analyzed cross-sectional data from the 2003 National Survey of Children’s Health, a telephone survey of 102,353 parents of children aged 0–17 years. Associations between family income [Below 100% Federal Poverty Level (FPL), 100–199% FPL, 200–299% FPL, 300–399% FPL, 400% FPL or Greater] and a set of 32 health and health care indicators were examined using linear polynomial testing and multivariate logistic regression. The percentage of children in better health increased with family income for 15 health outcomes. In multivariate logistic regression models that controlled for health insurance coverage and socio-demographic confounders, odds ratios >2 comparing the lowest to the highest income groups were noted for health conditions across both physical and developmental domains (diabetes, headaches, ear infections, learning disabilities, behavior/conduct problems, speech problems). Parent-reported global child health status, activity limitation, and oral health status showed steeper gradients than specific chronic and acute conditions. Ten measures of health care access and utilization were associated with family income in multivariate logistic regression models. Income gradients are pervasive across many health indicators at an early age. Social and health policy interventions are needed to address the multitude of factors that can affect children’s health and initiate disparities in development

Which factors engage women in deprived neighbourhoods to participate in exercise referral schemes?

ABSTRACT: BACKGROUND: Exercise referral schemes (ERS) have become a popular way of promoting physical activity. The aim of these schemes is to encourage high risk patients to exercise. In evaluating these schemes, little attention has been paid to lower socio-economic groups in a multi-ethnic urban setting. This study aimed to explore the socio-demographic and psychosocial characteristics of female participants in ERS located in deprived neighbourhoods. The second aim was to determine which elements of the intervention make it appealing to participate in the scheme. METHODS: A mixed method approach was utilized, combining a cross-sectional descriptive study and a qualitative component. In the quantitative part of the study, all female participants (n=523) filled out a registration form containing questions about socio-demographic and psychosocial characteristics. Height and weight were also measured. In the qualitative part of the study, 38 of these 523 participants were interviewed. RESULTS: The majority of the participants had a migrant background, a low level of education, no paid job and a high body mass index. Although most participants were living sedentary lives, at intake they were quite motivated to start exercising. The ERS appealed to them because of its specific elements: facilitating role of the health professional, supportive environment, financial incentive, supervision and neighbourhood setting. CONCLUSIONS: This study supports the idea that ERS interventions appeal to women from lower socio-economic groups, including ethnic minorities. The ERS seems to meet their contextual, economic and cultural needs. Since the elements that enabled the women to start exercising are specific to this ERS, we should become aware of whether this population continues to exercise after the end of the schem