Power and Robustness of Linkage Tests for Quantitative Traits in General Pedigrees

There are numerous statistical methods for quantitative trait linkage analysis in human studies. An ideal such method would have high power to detect genetic loci contributing to the trait, would be robust to non-normality in the phenotype distribution, would be appropriate for general pedigrees, would allow the incorporation of environmental covariates, and would be appropriate in the presence of selective sampling. We recently described a general framework for quantitative trait linkage analysis, based on generalized estimating equations, for which many current methods are special cases. This procedure is appropriate for general pedigrees and easily accommodates environmental covariates. In this paper, we use computer simulations to investigate the power robustness of a variety of linkage test statistics built upon our general framework. We also propose two novel test statistics that take account of higher moments of the phenotype distribution, in order to accommodate non-normality. These new linkage tests are shown to have high power and to be robust to non-normality. While we have not yet examined the performance of our procedures in the context of selective sampling via computer simulations, the proposed tests satisfy all of the other qualities of an ideal quantitative trait linkage analysis method.

Copulas in QTL mapping

The standard variance components method for mapping quantitative trait loci is derived on the assumption of normality. Unsurprisingly, statistical tests based on this method do not perform so well if this assumption is not satisfied. We use the statistical concept of copulas to relax the assumption of normality and derive a test that can perform well under any distribution of the continuous trait. In particular, we discuss bivariate normal copulas in the context of sib-pair studies. Our approach is illustrated by a linkage analysis of lipoprotein(a) levels, whose distribution is highly skewed. We demonstrate that the asymptotic critical levels of the test can still be calculated using the interval mapping approach. The new method can be extended to more general pedigrees and multivariate phenotypes in a similar way as the original variance components method.

A simple method to localise pleiotropic susceptibility loci using univariate linkage analyses of correlated traits

Univariate linkage analysis is used routinely to localise genes for human complex traits. Often, many traits are analysed but the significance of linkage for each trait is not corrected for multiple trait testing, which increases the experiment-wise type-I error rate. In addition, univariate analyses do not realise the full power provided by multivariate data sets. Multivariate linkage is the ideal solution but it is computationally intensive, so genome-wide analysis and evaluation of empirical significance are often prohibitive. We describe two simple methods that efficiently alleviate these caveats by combining P-values from multiple univariate linkage analyses. The first method estimates empirical pointwise and genome-wide significance between one trait and one marker when multiple traits have been tested. It is as robust as an appropriate Bonferroni adjustment, with the advantage that no assumptions are required about the number of independent tests performed. The second method estimates the significance of linkage between multiple traits and one marker and, therefore, it can be used to localise regions that harbour pleiotropic quantitative trait loci (QTL). We show that this method has greater power than individual univariate analyses to detect a pleiotropic QTL across different situations. In addition, when traits are moderately correlated and the QTL influences all traits, it can outperform formal multivariate VC analysis. This approach is computationally feasible for any number of traits and was not affected by the residual correlation between traits. We illustrate the utility of our approach with a genome scan of three asthma traits measured in families with a twin proband.

The genealogist's guide to printed pedigrees. Being a general search through genealogical, topographical, and biographical works relating to the United Kingdom, together with references to family histories, peerage claims, etc.

LC copy replaced by microfilm.

General practitioners’ experiences of the psychological aspects in the care of a dying patient

Objective: General practitioners (GPs) play an integral role in addressing the psychological needs of palliative care patients and their families. This qualitative study investigated psychosocial issues faced by GPs in the management of patients receiving palliative care and investigated the themes relevant to the psychosocial care of dying patients. Method: Fifteen general practitioners whose patient had been recently referred to the Mt. Olivet Palliative Home Care Services in Brisbane participated in an individual case review discussions guided by key questions within a semistructured format. These interviews focused on the psychosocial aspects of care and management of the referred patient, including aspects of the doctor/patient relationship, experience of delivering diagnosis and prognosis, addressing the psychological concerns of the patients' family, and the doctors' personal experiences, reactions, and responses. Qualitative analysis was conducted on the transcripts of these interviews. Results: The significant themes that emerged related to perceived barriers to exploration of emotional concerns, including spiritual issues, and the discussion of prognosis and dying, the perception of patients' responses/coping styles, and the GP's personal experience of the care (usually expressed in terms of identification with patient). Significance of results: The findings indicate the significant challenges facing clinicians in discussions with patients and families about death, to exploring the patient's emotional responses to terminal illness and spiritual concerns for the patient and family. These qualitative date indicate important tasks in the training and clinical support for doctors providing palliative care.

Older patients request more information : a survey of use of written patient education materials in general practice

Objectives: To determine GPs' reported use of written education materials with older patients and older patients' reported receipt of these materials. To determine GPs' and older patients' perceptions of written materials.---------- Method: Using self-report questionnaires, two populations were surveyed; a randomised sample of 50 GPs (29 males and 21 females) practising in Brisbane's southern suburbs and a convenience sample of 188 older community-dwelling people (aged over 64 years).----------- Results: All GPs reported using written materials with patients, although 28% had not given any to the Last 10 patients. This increased to 46% when patients were older. Twenty percent of patients wanted more written information from their GP, while some GPs believed that older patients preferred verbal information and gave out written information only when they perceived patient interest. All GPs reported giving written materials at the time of consultation and over two thirds discussed the content with patients. Just over 50% of patients reported receiving written information from GPs in the Last six months and only hall of these again discussed it directly with their GP. Overall, patients were more positive than GPs about the value of written education materials.---------- Conclusions: Older patients' desire for written information may be better met if they are more assertive in requesting this of GPs and GPs may better serve their patients' needs if they make written information more readily available to them. Better access to materials and more financial incentives to give them out might also increase GPs' use of written materials.

Maternal age and paternal age are associated with distinct childhood behavioural outcomes in a general population birth cohort

Abstract Background Recent studies show that advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism, bipolar disorder and schizophrenia. A body of evidence also suggests that individuals who develop schizophrenia show subtle deviations in a range of behavioural domains during their childhood. The aim of the study was to examine the relationship between paternal and maternal ages and selected behavioural measures in children using a large birth cohort. Method Participants were singleton children (n = 21,753) drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 7 years. The main analyses examined the relationship between parental age and behavioural measures when adjusted for a range of potentially confounding variables, including age of the other parent, maternal race, socio-economic measures, sex, gestation length, maternal marital status, parental mental illness, and child's age-at-testing. Results Advanced paternal age was associated with a significantly increased risk of adverse ‘externalizing’ behaviours at age seven years. For every five year increase in paternal age, the odds of higher ‘externalizing’ behaviours was increased by 12% (OR = 1.12; 95% CI = 1.03, 1.21, p < 0.0001). The relationship persisted after adjusting for potential confounding factors. ‘Internalizing’ behavioural outcome was not associated with advanced paternal age. In contrast, advanced maternal age was significantly protective against adverse ‘externalizing’ behavioural outcomes, but associated with an increased risk of adverse ‘internalizing’ behavioural outcomes. Discussion The offspring of older fathers show a distinctly different pattern of behaviours compared to the offspring of older mothers. The diverse socio-cultural and biologically-mediated factors that underpin these findings remain to be clarified. In light of secular trends related to delayed parenthood, the mechanisms underlying these findings warrant closer scrutiny.

Should mental health issues be addressed in primary care, and can it be done? Views of rural general practitioners in Queensland

Objective: The aim of this paper was to examine self-efficacy and perceived appropriateness among rural general practitioners (GPs) in regards to screening and intervention for physical, lifestyle and mental health issues. ----- Method: Fifty GPs from 25 practices in eight rural Queensland towns completed a written survey designed for the study. ----- Results: General practitioners rated opportunistic screening or assessment for smoking and for detection of relapse of mental disorders as the most appropriate, with even cardiovascular and diabetes risk falling behind these. Self-efficacy was highest for medical disorders for smoking assessment. It was significantly lower for alcohol, mental health issues, and addressing risks of physical disorder in people with mental disorders. ----- Conclusions: High appropriateness ratings suggest that current strategies to boost self-efficacy of GPs in addressing mental health issues are timely.

Challenges faced by general practitioners and allied mental health services in providing mental health services in rural Queensland

Objective: To examine the views of rural practitioners concerning issues and challenges in mental health service delivery and possible solutions. Design: A qualitative study using individual semi-structured interviews. Setting: Eight general practices from eight rural Queensland towns, three rural mental health services and two non-government organisations, with interviews being conducted before recent changes in government-subsidised access to allied health practitioners. Participants: A sample of 37 GPs, 19 Queensland Health mental health staff and 18 participants from community organisations. Main outcome measures: Analysis of qualitative themes from questions about the key mental health issues facing the town, bow they might be addressed and what challenges would be faced in addressing them. Results: There was substantial consensus that there are significant problems with inter-service communication and liaison, and that improved collaboration and shared care will form a critical part of any effective solution. Differences between groups reflected differing organisational contexts and priorities, and limitations to the understanding each had of the challenges that other groups were facing. C onclusions: Improvements to mental health staffing and to access to allied health might increase the ability of GPs to meet the needs of less complex patients, but specific strategies to promote better integrated services are required to address the needs of rural and regional patients with complex mental health problems. The current study provides a baseline against which effects of recent initiatives to improve mental health care can be assessed.

Views of general practitioners and benzodiazepine users on benzodiazepines : a qualitative analysis

Effectively assisting benzodiazepine users to cease use requires a greater understanding of general practitioners’ (GPs)and benzodiazepine users’ views on using and ceasing benzodiazepines. This paper reports the findings from a qualitative study that examined the views of 28 GPs and 23 benzodiazepine users (BUs) in Cairns, Australia. A semistructured interview was conducted with all participants and the information gained was analysed using the Consensual Qualitative Research Approach, which allowed comparisons to be made between the views of the two groups of interviewees. There was commonality between GPs and BUs on reasons for commencing benzodiazepines, the role of dependence in continued use, and the importance of lifestyle change in its cessation. However, several differences emerged regarding commencement of use and processes of cessation. In particular, users felt there was greater need for GPs to routinely advise patients about non-pharmacological management of their problems and potential adverse consequences of long-term use before commencing benzodiazepines. Cessation could be discussed with all patients who use benzodiazepines for longer than 3 months, strategies offered to assist in management of withdrawal and anxiety, and referral to other health service providers for additional support. Lifestyle change could receive greater focus at all stages of treatment.

Burden of care and general health in families of patients with schizophrenia

Background: De-institutionalization of psychiatric patients has led to a greater emphasis on family management in the community, and family members are often overwhelmed by the demands that caring for a patient with schizophrenia involves. Most studies of family burden in schizophrenia have taken place in developed countries. The current study examined family burden and its correlates in a regional area of a medium income country in South America. Method: Sixty-five relatives of patients with schizophrenia who were attending a public mental health out-patient service in the province of Arica, Chile, were assessed on Spanish versions of the Zarit Caregiver Burden Scale and SF-36 Health Survey (SF-36). Results: Average levels of burden were very high, particularly for mothers, carers with less education, carers of younger patients and carers of patients with more hospitalisations in the previous 3 years. Kinship and number of recent hospitalisations retained unique predictive variance in a multiple regression. Burden was the strongest predictor of SF-36 subscales, and the prediction from burden remained significant after entry of other potential predictors. Conclusions: In common with families in developed countries, family members of schizophrenia patients in regional Chile reported high levels of burden and related functional and health impact. The study highlighted the support needs of carers in contexts with high rates of poverty and limited health and community resources.