Implementation of a combined association-linkage model for quantitative traits in linear mixed model procedures of statistical packages

Atransmission disequilibrium test for quantitative traits which combines association and linkage analyses is currently available in several dedicated software packages. We describe how to implement such models in linear mixed model procedures that are available in widely used statistical packages such as SPSS. We also briefly mention a few extensions of the model that become naturally available once the model is implemented in such procedures. Genotyping of many microsatellite markers or single nucleotide polymorphisms (SNPs) over the entire genome is becoming increasingly common in human genetics. In those high-resolution maps the average distance between microsatellite markers may be as small as 5 cM and between SNPs one half cM or less. At those small distances it becomes fairly likely that some markers in the set are in linkage disequilibrium (LD) with a gene affecting the trait (a so-called quantitative trait locus or QTL if the trait or the vulnerability distribution is quantitative). Different alleles or combinations of alleles of the markers or SNPs can then be associated with different trait means. Association studies are conducted to discover such allelic effects. Abecasis et al. (2000) generalized the model proposed by Fulker et al. (1999) for combined linkage and association tests, within and between families. The Fulker-Abecasis or F-A model is implemented in the program QTD

Theory and Practice in Quantitative Genetics

With the rapid advances in molecular biology, the near completion of the human genome, the development of appropriate statistical genetic methods and the availability of the necessary computing power, the identification of quantitative trait loci has now become a realistic prospect for quantitative geneticists. We briefly describe the theoretical biometrical foundations underlying quantitative genetics. These theoretical underpinnings are translated into mathematical equations that allow the assessment of the contribution of observed (using DNA samples) and unobserved (using known genetic relationships) genetic variation to population variance in quantitative traits. Several statistical models for quantitative genetic analyses are described, such as models for the classical twin design, multivariate and longitudinal genetic analyses, extended twin analyses, and linkage and association analyses. For each, we show how the theoretical biometrical model can be translated into algebraic equations that may be used to generate scripts for statistical genetic software packages, such as Mx, Lisrel, SOLAR, or MERLIN. For using the former program a web-library (available from http://www.psy.vu.nl/mxbib) has been developed of freely available scripts that can be used to conduct all genetic analyses described in this paper

Methods of synthesizing qualitative research studies for health technology assessment

OBJECTIVES Synthesizing qualitative research is an important means of ensuring the needs, preferences, and experiences of patients are taken into account by service providers and policy makers, but the range of methods available can appear confusing. This study presents the methods for synthesizing qualitative research most used in health research to-date and, specifically those with a potential role in health technology assessment. METHODS To identify reviews conducted using the eight main methods for synthesizing qualitative studies, nine electronic databases were searched using key terms including meta-ethnography and synthesis. A summary table groups the identified reviews by their use of the eight methods, highlighting the methods used most generally and specifically in relation to health technology assessment topics. RESULTS Although there is debate about how best to identify and quality appraise qualitative research for synthesis, 107 reviews were identified using one of the eight main methods. Four methods (meta-ethnography, meta-study, meta-summary, and thematic synthesis) have been most widely used and have a role within health technology assessment. Meta-ethnography is the leading method for synthesizing qualitative health research. Thematic synthesis is also useful for integrating qualitative and quantitative findings. Four other methods (critical interpretive synthesis, grounded theory synthesis, meta-interpretation, and cross-case analysis) have been under-used in health research and their potential in health technology assessments is currently under-developed. CONCLUSIONS Synthesizing individual qualitative studies has becoming increasingly common in recent years. Although this is still an emerging research discipline such an approach is one means of promoting the patient-centeredness of health technology assessments

Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460-467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2. © 2006 Springer Science+Business Media, Inc

Speed, Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research?

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD

Validity and reproducibility of a physical activity questionnaire for older adults: questionnaire versus accelerometer for assessing physical activity in older adults

BACKGROUND: Physical activity (PA) is important in older adults for the maintenance of functional ability. Assessing PA may be difficult. Few PA questionnaires have been compared to activity monitors. We examined reproducibility and validity of the self-administered Longitudinal Ageing Study Amsterdam Physical Activity Questionnaire (LAPAQ) against a triaxial accelerometer (ACTR) (Sensewear(®) Pro) in older adults. METHODS: Participants wore the ACTR continuously for two weeks. After 2 (T [time] = 1) and 4 (T = 2) weeks, participants completed the LAPAQ. Since the LAPAQ asks about 2 weeks' worth of physical activity, the ACTR and LAPAQ coincided at T1. T2 was used to assess the reproducibility of the LAPAQ results only. We calculated Pearson's correlation coefficients (PCC) to examine reproducibility and validity. For visualization, we used scatterplots and Bland-Altman plots. With a receiver operating characteristics (ROC) curve we assessed how well the LAPAQ identifies older adults whose activity level is below official recommendations. RESULTS: A total of 89 persons were included. Of the participants, 48% were men; median age was 73, and median body mass index was 25. The 2-week mean total duration of activity was 2788 (ACTR, T = 1), 2439 (LAPAQ T = 1), and 1994 (LAPAQ T = 2) minutes. As a reference, 2 full weeks contained 20,160 minutes. Reproducibility of the LAPAQ was moderate (PCC 0.68, 95% CI 0.55-0.80). The median difference between LAPAQ at T = 1 and the ACTR (LAPAQ minus ACTR) was -510 minutes and the PCC was 0.25 (95% CI 0.07-0.44). The area under the ROC curve was 0.73 (95% CI 0.59-0.86). CONCLUSION: LAPAQ underestimates PA and seems unsuitable for exact measurement in older adults. However, it may be used to determine if a person's PA level is below the recommended leve