Biomedical subjects

Silke Schmidt

Publications and source records attributed to Silke Schmidt.

At least 37 records · Page 2Linked to original sources

PubMed2005

Development of the WHOQOL-old module.

This paper describes the development of an add-on module for the WHOQOL measures of quality of life (QoL) for use with older adults. The add-on module, known as the WHOQOL-OLD, was derived following standard WHOQOL methodology. In the pilot phase of the study, 22 centres from around the world carried out focus groups with older adults, with carers, and with professionals working with older adults in order to identify gaps in the coverage of the WHOQOL-100 that were relevant for QoL in older adults. Items generated from the focus groups were then tested in over 7400 respondents from the centres, with items being tested and reduced using both classical and modern psychometric methods. These analyses indicated a further gap in the coverage of the items, so further items were generated that specifically assessed intimate relations in older adults. A field trial study was then carried out in a further approximately 5500 respondents, again with the use of both classical and modern psychometric methods. The outcome of this second round of data collection and analysis is a 24-item 6-facet module which can be used in conjunction with the WHOQOL-BREF or the WHOQOL-100 for assessment of QoL in older adults.

Aged↗

PubMed2005

Comparing age-related macular degeneration phenotype in probands from singleton and multiplex families.

PURPOSE: To compare age-related macular degeneration (AMD) phenotype between probands in singleton and multiplex families to determine whether data from these two groups may be combined for consolidated genetic analyses. DESIGN: Retrospective case-control study. METHODS: Individuals 55 years of age or older with AMD were identified. Complete histories and examinations were recorded, 35-mm fundus photographs obtained, and macular findings graded. Detailed information was recorded, including the presence of extramacular and peripheral drusen, peripheral reticular pigmentary change, posterior vitreous detachment, and iris color. Comparisons were performed between probands from singleton and multiplex families. RESULTS: There was no statistically significant difference in grade between the 411 singleton and 125 multiplex probands (P = .52), and the distribution of grades was similar between the two groups. No statistically significant difference was found between proband groups with respect to the presence or extent of small (P = .48), intermediate (P = .72), and large drusen (P = .74) and retinal pigment epithelium hyper- (P = .76) and hypopigmentation (P = .55); in the presence or grade of peripheral reticular pigment change; the presence of geographic atrophy in exudative disease, extramacular drusen, or posterior vitreous detachment; lens status; iris color; visual acuity; intraocular pressure; optic nerve cupping; and body mass index. A statistically significant difference between the two groups was noted in the presence of peripheral drusen (P = .0001). CONCLUSIONS: Singleton and multiplex AMD probands share a similar phenotype. This suggests that multiplex and singleton data can be combined for consolidated genetic analyses.

Aged↗

PubMed2004

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.

Adult↗

PubMed2004

Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping.

To explore the potential value of recently developed high-density linkage mapping methods in the analysis of complex disease we have regenotyped five nuclear families first studied in the 1996 UK multiple sclerosis linkage genome screen, using Applied Biosystems high-density microsatellite linkage mapping set, the Illumina BeadArray linkage mapping panel (version 3) and the Affymetrix GeneChip Human Mapping 10K array. We found that genotyping success, information extraction and genotyping accuracy were improved with all systems. These improvements were particularly marked with the SNP-based methods (Illumina and Affymetrix), with little difference between these. The extent of additional information extracted is considerable, indicating that reanalysis of existing multiplex families using these newer systems would substantially increase power.

Chromosome Mapping↗

PubMed2004

Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12.

BACKGROUND: Age-related macular degeneration (AMD) is a complex disorder that is responsible for the majority of central vision loss in older adults living in developed countries. Phenotypic and genetic heterogeneity complicate the analysis of genome-wide scans for AMD susceptibility loci. The ordered subset analysis (OSA) method is an approach for reducing heterogeneity, increasing statistical power for detecting linkage, and helping to define the most informative data set for follow-up analysis. OSA assesses the linkage evidence in subsets of potentially more homogeneous families by rank-ordering family-specific lod scores with respect to trait-associated covariates or phenotypic features. Here, we present results of incorporating five continuous covariates into our genome-wide linkage analysis of 389 microsatellite markers in 62 multiplex families: Body mass index (BMI), systolic (SBP) and diastolic (DBP) blood pressure, intraocular pressure (IOP), and pack-years of cigarette smoking. Chromosome-wide significance of increases in nonparametric multipoint lod scores in covariate-defined subsets relative to the overall sample was assessed by permutation. RESULTS: Using a correction for testing multiple covariates, statistically significant lod score increases were observed for two chromosomal regions: 14q13 with a lod score of 3.2 in 28 families with average IOP </= 15.5 (p = 0.002), and 6q14 with a lod score of 1.6 in eight families with average BMI >/= 30.1 (p = 0.0004). On chromosome 16p12, nominally significant lod score increases (p </= 0.05), up to a lod score of 2.9 in 32 families, were observed with several covariate orderings. While less significant, this was the only region where linkage evidence was associated with multiple clinically meaningful covariates and the only nominally significant finding when analysis was restricted to advanced forms of AMD. Families with linkage to 16p12 had higher averages of SBP, IOP and BMI and were primarily affected with neovascular AMD. For all three regions, linkage signals at or very near the peak marker have previously been reported. CONCLUSION: Our results suggest that a susceptibility gene on chromosome 16p12 may predispose to AMD, particularly to the neovascular form, and that further research into the previously suggested association of neovascular AMD and systemic hypertension is warranted.

Aged↗

PubMed2004

The performance of the screener to identify children with special health care needs in a European sample of children with chronic conditions.

In the field of paediatric health care, measures based on consequences of health conditions have been recently developed to screen for children with special health care needs. These tools have been primarily used in survey research. The aim of this cross-sectional clinical study is to test the performance of a screener for identifying children with special health care needs (CSHCN) in a population of children with chronic conditions diagnosed and treated in different European paediatric hospitals. In the current study, the screener was employed in a sample of children with different chronic conditions (asthma, arthritis, dermatitis, epilepsy, cystic fibrosis, diabetes and cerebral palsy) across seven European countries; 456 parents of children, aged 4-7, 8-12, and 13-16 years, responded to the screener items. The study included a range of clinical measures to assess the severity of the conditions as well measures on functional health status. The prevalence of children identified positively with the CSHCN screener was 80%, which was higher than in survey estimates in the United States. Considerable variation in the screener classification was found between chronic conditions with cystic fibrosis and epilepsy showing higher rates, and skin conditions lower rates. There was no significant relationship between the screener classification and functional limitation. Findings of this study support in general the validity of the children with special health care needs screener, which shows, however, a differential validity across specific conditions. Several clinical and theoretical explanations for the lack of identifying some children with chronic conditions and the considerable variation between the conditions are discussed.

Adolescent↗

PubMed2004

Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions.

Age-related maculopathy (ARM), or age-related macular degeneration, is one of the most common causes of visual impairment in the elderly population of developed nations. In a combined analysis of two previous genomewide scans that included 391 families, containing up to 452 affected sib pairs, we found linkage evidence in four regions: 1q31, 9p13, 10q26, and 17q25. We now have added a third set of families and have performed an integrated analysis incorporating 530 families and up to 736 affected sib pairs. Under three diagnostic models, we have conducted linkage analyses using parametric (heterogeneity LOD [HLOD] scores under an autosomal dominant model) and nonparametric (Sall statistic) methods. There is ongoing evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. If we treat the third set of families as a replication set, then two regions (10q26 and 17q25) are replicated, with LOD scores >1.0. If we pool all our data together, then four regions (1q31, 2q14.3, 10q26, and 17q25) show HLOD or Sall scores > or =2.0. Within the 1q31 region, we observed an HLOD of 2.72 (genomewide P=.061) under our least stringent diagnostic model, whereas the 17q25 region contained a maximal HLOD of 3.53 (genomewide P=.007) under our intermediate diagnostic model. We have evaluated our results with respect to the findings from several new independent genomewide linkage studies and also have completed ordered subset analyses (OSAs) with apolipoprotein E alleles, smoking history, and age at onset as stratifying covariates. The OSAs generate the interesting hypothesis that the effect of smoking on the risk of ARM is accentuated by a gene in the 10q26 region--a region implicated by four other studies.

Chromosomes, Human, Pair 1↗

PubMed2004

Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26.

PURPOSE: Age-related macular degeneration (AMD) is a retinal degenerative disease that is the leading cause of blindness worldwide in individuals over the age of 60. Although the etiology of AMD remains largely unknown, numerous studies have suggested both genetic and environmental influences. A previous study of affected multiplex families identified four chromosomal regions that potentially harbor AMD susceptibility genes. The purpose of our study was to further investigate these regions with additional microsatellite marker coverage in our independent data set. METHODS: We examined regions on chromosomes 1q, 9p, 10q, and 17q for genetic linkage in our 70 multiplex families (consisting of 133 affected sibpairs). Two point heterogeneity LOD score (HLOD) and nonparametric LOD score (MLS) analyses were performed for disease models defined by the most severe status in either eye. Conditional analyses were performed using apolipoprotein E (APOE) alleles as covariates in semiparametric LOD (LOD*) score calculations. RESULTS: Regions on chromosomes 1q, 9p, and 17q did not provide evidence of linkage in our data set. However, markers D10S1230 and D10S1656 on chromosome 10q26 generated maximum HLOD scores of 1.52 and 1.13, respectively. Marker D10S1230 also generated an MLS score of 1.56 in stage 4 and 5 individuals. Controlling for the potential effect of the APOE-epsilon4 allele did not substantially alter these scores. CONCLUSIONS: With the inclusion of this study, at least five AMD data sets provide support of genetic linkage to 10q26. Such consistency and confirmation of evidence strongly suggests that this region should be the subject of further detailed genomic efforts for the disease.

Chromosome Mapping↗

PubMed2004

Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis.

A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.

Adult↗

PubMed2004

Brief report: Development and pilot testing of a coping questionnaire for children and adolescents with chronic health conditions.

OBJECTIVE: The current paper describes the development, pilot testing, and item reduction process of a coping questionnaire for children and adolescents with chronic health conditions. METHODS: A pilot test with 188 children and adolescents was conducted in six European countries. Included in the test were children and adolescents (ages ranging 8-18 years) with various chronic health conditions-asthma, epilepsy, diabetes, arthritis, atopic dermatitis, cerebral palsy, or cystic fibrosis. Based on the focus groups with the children and adolescents and on expert consulting, items were developed and translated into the participants' respective languages. Data were analyzed according to predefined psychometric and content criteria. RESULTS: Analyses resulted in a selection of 29 out of 50 items for the final coping questionnaire with six domains: Acceptance alpha = .83, Avoidance alpha = .72, Cognitive-Palliative alpha = .69, Distance alpha = .70, Emotional Reaction alpha = .82, and Wishful Thinking alpha = .81. CONCLUSIONS: This study developed a short reliable international questionnaire to assess coping strategies of children and adolescents with chronic health conditions. Ongoing research will investigate the validity of this new coping questionnaire.

Adaptation, Psychological↗

PubMed2003

Adjusting for covariates on a slippery slope: linkage analysis of change over time.

BACKGROUND: We analyzed the Genetic Analysis Workshop 13 (GAW13) simulated data to contrast and compare different methods for the genetic linkage analysis of hypertension and change in blood pressure over time. We also examined methods for incorporating covariates into the linkage analysis. We used methods for quantitative trait loci (QTL) linkage analysis with and without covariates and affected sib-pair (ASP) analysis of hypertension followed by ordered subset analysis (OSA), using variables associated with change in blood pressure over time. RESULTS: Four of the five baseline genes and one of the three slope genes were not detected by any method using conventional criteria. OSA detected baseline gene b35 on chromosome 13 when using the slope in blood pressure to adjust for change over time. Slope gene s10 was detected by the ASP analysis and slope gene s11 was detected by QTL linkage analysis as well as by OSA analysis. Analysis of null chromosomes, i.e., chromosomes without genes, did not reveal significant increases in type I error. However, there were a number of genes indirectly related to blood pressure detected by a variety of methods. CONCLUSIONS: We noted that there is no obvious first choice of analysis software for analyzing a complicated model, such as the one underlying the GAW13 simulated data. Inclusion of covariates and longitudinal data can improve localization of genes for complex traits but it is not always clear how best to do this. It remains a worthwhile task to apply several different approaches since one method is not always the best.

Blood Pressure↗

PubMed2003

Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.

An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

Alleles↗

PubMed2003

Current issues in cross-cultural quality of life instrument development.

As a result of an increased demand for international cooperation in health care, cross-cultural quality of life (QOL) measures have been developed and tested. At present, a considerable number of QOL instruments are available in various languages, and some have been validated and normed in specific countries. Different approaches highlighting specific tasks have been used, and standards and guidelines for cross-cultural development and testing are now available. However, specific populations, such as persons with disabilities or chronic health conditions as well as minorities, have been neglected in international research. This article presents the current issues confronting cross-cultural instrument development in QOL. It describes the steps of international QOL instrument development and highlights some of the challenges, referring in particular to an ongoing project devoted to children with disabilities and chronic conditions.

Activities of Daily Living↗

PubMed2003

Design of the Genetics of Early Onset Cardiovascular Disease (GENECARD) study.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of death and a leading cause of disability in the developed world. Early onset (premature) coronary artery disease (EOCAD) is known to have a particularly strong genetic component. However, the actual genes leading to this increased risk of CAD remain obscure. METHODS: The primary goal of the Genetics of Early Onset Cardiovascular Disease (GENECARD) study is to perform a genetic linkage study in 920 families with at least 1 sibling pair having EOCAD. The study sites include a US network of 15 cardiology practices and 5 additional sites located in Europe and the United States. We propose to identify chromosomal regions associated with increased susceptibility to EOCAD in this large sample of affected sibling pairs and nuclear families, where EOCAD is defined on the basis of having acute coronary syndrome (unstable angina or myocardial infarction), a revascularization procedure, or a positive functional imaging study at or before the age of 50 years in men or 55 years in women. To identify which genomic regions and genes are associated with increased susceptibility to EOCAD, we will use a comprehensive strategy comprising genomic screening, fine mapping, candidate gene analysis, and family-based association studies. RESULTS: Herein we describe the clinical characteristics, family history, and risk factor profiles of the 1168 members from 438 nuclear families included in the first, exploratory analysis. Analysis of the study population revealed a strong concordance of known cardiac risk factors among affected sibling pairs. There was significant concordance (P <. 01) among siblings with EOCAD for presence of diabetes (78% concordance), dyslipoproteinemia (67%), obesity (63%), and hypertension (56%). This level of concordance of risk factors among siblings might be expected, given the significant genetic components demonstrated for these metabolic susceptibility traits. However, there was also substantial sibling pair concordance (P <.01) for smoking history (74%), regular alcohol consumption (81%), and sedentary lifestyle (63%), environmental traits without known inherited predisposition. CONCLUSIONS: Analyses such as these will have implications for stratifying populations for the statistical analysis of the genome scan and on the choice of covariates for the follow-up studies of the initial genome screen analysis.

Adult↗

PubMed2003

Reproductive factors and familial predisposition for breast cancer by age 50 years. A case-control-family study for assessing main effects and possible gene-environment interaction.

BACKGROUND: The effect of environmental/lifestyle factors on breast cancer risk may be modified by genetic predisposition. METHODS: In a population-based case-control-family study performed in Germany including 706 cases by age 50 years, 1381 population, and 252 sister controls, we investigated main effects for environmental/lifestyle factors and genetic susceptibility and gene-environment interaction (G x E). Different surrogate measures for genetic predisposition using pedigree information were used: first-degree family history of breast or ovarian cancer; and gene carrier probability using a genetic model based on rare dominant genes. Possible G x E interaction was studied by (1) logistic regression using cases and population controls including an interaction term; (2) comparing results using sister controls and population controls; (3) case-only analysis with logistic regression and (4) a mixture logistic model. RESULTS: Familial predisposition showed the strongest main effect and the estimated gene carrier probability gave the best fit. High parity and longer duration of breastfeeding reduced breast cancer risk significantly, a history of abortions increased risk and age at menarche showed no significant effect. We found significant G x E interaction between parity and genetic susceptibility using different surrogate measures. In women most likely to have a high genetic susceptibility, high parity was less protective. Later age at menarche was protective in women with a positive family history. No evidence for G x E interaction was found for breastfeeding and abortion. CONCLUSIONS: These findings corroborate results from other studies and provide further evidence that the magnitude of protection from parity is reduced in women most likely to have a genetic risk in spite of the limitations of using surrogate genetic measures.

Abortion, Therapeutic↗

PubMed2003

Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy.

PURPOSE: Age-related maculopathy (ARM) is one of the most common causes of blindness in older adults worldwide. Sequence variants in a gene coding for a retina-specific ATP-binding cassette (ABCA4) transporter protein, which is responsible for a phenotypically similar Mendelian form of retinal disease, were proposed to increase the risk of ARM. To examine the potential relationship of ABCA4 sequence variation and ARM risk in an independent data set, a clinically well-characterized population of 165 multiplex patients with ARM from 70 families, 33 unaffected relatives, and 59 unrelated control subjects with confirmed absence of ARM was screened for variants in any of the 50 exons and exon-intron boundaries of this gene. METHODS: A combination of denaturing high-performance liquid chromatography (DHPLC) and bidirectional sequencing was used to detect ABCA4 sequence variants. The data set was analyzed with both case-control and family-based association analysis methods. RESULTS: No evidence was found of significantly different allele frequencies of ABCA4 sequence variants in patients compared with control subjects, and no evidence for association or cosegregation with disease in family-based analyses. CONCLUSIONS: This study confirmed the very high degree of ABCA4 sequence polymorphism in the general population, which makes the detection of potential disease-associated alleles particularly challenging. While this study does not definitively exclude ABCA4 from contributing to a small or moderate fraction of ARM, it adds to the body of evidence suggesting that ABCA4 is not a major susceptibility gene for this disorder.

ATP-Binding Cassette Transporters↗

PubMed2002

Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P=.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P=.03), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P=.02).

Adolescent↗

PubMed2002

Attachment and coping with chronic disease.

BACKGROUND: In this clinical study, attachment theory was applied to research in the field of coping with chronic disease. The approach was to integrate concepts of coping within a framework of attachment theory. It was hypothesised that attachment concepts have an influence on coping strategies, and that they may predict the subjective emotional and physical health status during the course of medical treatment. METHOD: One hundred fifty patients were investigated with an adult attachment interview (AAPR coding system) and a coping interview (Bernese Coping Modes). Self-reported coping modes, social support, the subjective health status and quality of life were also assessed by self-report measures at two or more sampling points of measurement. Three subsamples of patients, suffering from (a) breast cancer, (b) chronic leg ulcers and (c) alopecia, were studied in order to include a broad range of subjective impairment caused by a disease. RESULTS: Findings indicate a moderate statistical effect of attachment patterns on coping strategies when controlling the influence of confounding variables. Insecure attachment was related to less flexible coping. Coping strategies also differed between the different types of insecure attachment; however, there were differences depending on the perspective of the coping behaviour (self- vs. observer ratings) as well. From the observer perspective, ambivalently attached individuals showed more negative emotional coping while avoidantly attached individuals showed more diverting strategies. In the self-report, ambivalently attached patients revealed hyperactivating tendencies in their coping behaviour while avoidantly attached individuals revealed deactivating tendencies. CONCLUSION: As a conclusion, two levels of coping should be differentiated. One level strongly corresponds with affect regulation, in particular the regulation of attachment-related emotions and concerns, while the other level shows a stronger tendency to outwardly oriented coping. A more secure attachment might be considered to be an important inner resource in the emotional adaptation to chronic diseases.

Adaptation, Psychological↗