Biomedical subjects

Jim Stankovich

Publications and source records attributed to Jim Stankovich.

10 recordsLinked to original sources

PubMed2007

Heritability and shared environment estimates for myopia and associated ocular biometric traits: the Genes in Myopia (GEM) family study.

To examine the familial correlations, heritability (h(2)) and common environmental components (c(2)) of myopia and ocular biometric traits (all treated as continuous outcomes) in families collected through the Genes in Myopia (GEM) family study in Australia. A total of 132 pedigrees (723 participants) were recruited for this study. All individuals completed a risk factor questionnaire and underwent a detailed eye examination including spherical equivalent (SphE) and ocular biometric measurements of axial length (AL), anterior chamber depth (ACD) and corneal curvature (CC). Familial correlations were calculated and h(2) and c(2) were estimated using a variance component model that assumes a multivariate t distribution within each pedigree. Two definitions of common environments (c(2)) were considered: nuclear family (current) shared environment (Model 1) and sib-ship (childhood) shared environment (Model 2). Population ascertainment adjustment was performed using the Blue Mountains eye study dataset. The trends observed for familial correlations suggested that SphE is influenced by both environmental and genetic factors whereas AL, ACD and CC are predominantly genetically determined. This was largely confirmed by variance components modelling. Heritability estimates (adjusted for age, sex and years of education) from the best fitting ACE model (Model 2, childhood shared environment) were 0.50 +/- 0.05 for SphE, 0.73 +/- 0.04 for AL, 0.78 +/- 0.04 for ACD and 0.16 +/- 0.06 for CC. Childhood environmental effects were significant with c(2) estimated to be 0.33 +/- 0.04 for SphE, 0.06 +/- 0.03 for AL, 0.22 +/- 0.04 for ACD and 0.10 +/- 0.05 for CC. Age was associated with SphE, total years of education was associated with AL and sex was associated with all traits studied. We used a novel and conservative approach to account for and estimate common environmental effects by specifying either nuclear family or sib-ship environment when estimating heritability estimates and showed that all traits examined (SphE, AL, ACD and CC) are heritable, thus reflecting a genetic component. These traits therefore all represent candidates for quantitative trait linkage analyses.

Adult↗

PubMed2006

On the utility of data from the International HapMap Project for Australian association studies.

We compare patterns of linkage disequilibrium (LD) for 633 SNPs in two regions between samples collected in two Australian states and HapMap samples collected from Utah residents of Northern and Western (NW) European ancestry (CEU). Patterns of LD in the Australian and HapMap samples are similar, and tag SNPs chosen using HapMap genotypes perform almost as well on Australian samples as tags chosen using Australian genotypes.

Europe↗

PubMed2006

A clinical screening tool identifies autoimmune diabetes in adults.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) is defined as adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially. Diagnosing LADA has treatment implications because of the high risk of progression to insulin dependency. Currently, there are no recommendations for islet antibody testing in adult-onset diabetes. In this study, we aimed to develop a clinical screening tool to identify adults at high risk of LADA who require islet antibody testing. RESEARCH DESIGN AND METHODS: Subjects with LADA (n = 102, GAD antibody [GADA]+) and type 2 diabetes (n = 111, GADA-) (aged 30-75 years) were interviewed retrospectively. The clinical features documented were age of onset, acute symptoms of hyperglycemia, BMI, and personal and family history of autoimmune disease. Any clinical feature that was significantly more frequent in LADA was designated as a distinguishing clinical feature. In each subject, a "LADA clinical risk score," based on the total number of distinguishing features, was calculated. A prospective study of adults with newly diagnosed diabetes (n = 130) was used to determine whether the LADA clinical risk score could identify LADA. RESULTS: In the retrospective study, five clinical features were more frequent in LADA compared with type 2 diabetes at diagnosis: 1) age of onset <50 years (P < 0.0001), 2) acute symptoms (P < 0.0001), 3) BMI <25 kg/m2 (P = 0.0004), 4) personal history of autoimmune disease (P = 0.011), and 5) family history of autoimmune disease (P = 0.024). In the prospective study, the presence of at least two of these distinguishing clinical features (LADA clinical risk score > or =2) had a 90% sensitivity and 71% specificity for identifying LADA and a negative predictive value for a LADA clinical risk score < or =1 of 99%. CONCLUSIONS: At least two distinguishing clinical features are found in a majority of patients with LADA at diagnosis and can be used to identify adults with diabetes at higher risk for LADA.

Adult↗

PubMed2005

Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data.

Genome wide association studies using high throughput technology are already being conducted despite the significant hurdles that need to be overcome (Nat Rev Genet 6:95-108, 2005; Nat Rev Genet 6:109-118, 2005). Methods for detecting haplotype association signals in genome wide haplotype datasets are as yet very limited. Much methodological research has already been devoted to linkage disequilibrium (LD) fine mapping where the focus is the identification of the disease locus rather than the detection of a disease signal. Applications of these approaches to genome wide scanning are limited by the strong model assumptions of the sharing process, which lead to computational complexity. We describe a new algorithm for the initial identification of disease susceptibility loci in genome wide haplotype association studies. Excess sharing of ancestral haplotypes, which indicates the presence of a disease locus, is detected with a simple, easy to interpret, chi2 based statistic. The method allows genome wide scanning for qualitative traits within reasonable computational timeframes and can serve as a first pass analysis prior to the usage of likelihood based methods, providing candidate regions and inferred susceptibility haplotypes. Our method makes no assumptions regarding the population history or the pattern of background LD. Statistical significance is evaluated with permutation tests. The method is illustrated on simulated and real data where it is applied to simple (cystic fibrosis) and complex disease (multiple sclerosis) examples. The statistic has low type I error and greater power to map disease loci over conventional single marker tests for low to moderate levels of LD.

Algorithms↗

PubMed2005

Identifying nineteenth century genealogical links from genotypes.

We have developed a likelihood method to identify moderately distant genealogical relationships from genomewide scan data. The aim is to compare the genotypes of many pairs of people and identify those pairs most likely to be related to one another. We have tested the algorithm using the genotypes of 170 Tasmanians with multiple sclerosis recruited into a haplotype association study. It is estimated from genealogical records that approximately 65% of Tasmania's current population of 470,000 are direct descendants of the 13,000 female founders living in this island state of Australia in the mid-nineteenth century. All cases and four to five relatives of each case have been genotyped with microsatellite markers at a genomewide average density of 4 cM. Previous genealogical research has identified 51 pairwise relationships linking 56 of the 170 cases. Testing the likelihood calculation on these known relative pairs, we have good power to identify relationships up to degree eight (e.g. third cousins once removed). Applying the algorithm to all other pairs of cases, we have identified a further 61 putative relative pairs, with an estimated false discovery rate of 10%. The power to identify genealogical links should increase when the new, denser sets of SNP markers are used. Except in populations where there is a searchable electronic database containing virtually all genealogical links in the past six generations, the algorithm should be a useful aid for genealogists working on gene-mapping projects, both linkage studies and association studies.

Algorithms↗

PubMed2005

Multiple sclerosis: a haplotype association study.

Results are presented from a genomewide haplotype association study on multiple sclerosis (MS) cases from Tasmania, an island state of Australia. Cases were ascertained on strict clinical and radiological grounds and on the fact that they had at least one grandparent born in the state. This enriched for early settler chromosomes among present day Tasmanians with MS and increased the chances of finding common haplotype sharing at disease predisposition loci in distant relatives sharing common ancestral haplotypes. Four-to-five close relatives were also collected for each of 170 cases and 105 population-based controls. All were genotyped at a 5cM resolution, haplotypes reconstructed and sharing estimated using an empirical approach based on sorting haplotypes to find the most common at each locus and then generating a test statistic for excess sharing in the cases based on permutation testing. Five initial loci were found where there was an excess sharing in the cases. These were fine-mapped with 10-12 additional markers. Only loci on chromosomes 6 and 10 remained after fine mapping. These loci demonstrate an increase in sharing of multi-marker haplotypes in MS cases compared to both population control transmitted haplotypes and case non-transmitted haplotypes.

Haplotypes↗

PubMed2004

Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis.

In order to resolve a multiple sclerosis (MS) susceptibility locus that we had identified in earlier work at the telomeric end of the HLA complex, we genotyped another 34 microsatellite markers (47 in total) across the class I/extended class I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265). Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11% of MS cases and 4% of controls. Direct comparison of the telomerically extended portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous haemochromatosis patients identified a common ancestry for this genomic segment, which translated into an increased frequency of the C282Y allele in 489 MS cases from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y homozygotes (1.2%), a three-fold increased rate over the general population, and 88 heterozygotes (18%) were identified. One C282Y-homozygous female was identified who had MS and was being treated for symptoms of iron overload. Interestingly, for 71 Victorian MS cases not of north western European (NWE) ancestry, a DR15-independent reduction in the frequency of the C282Y allele was observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15 ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y is increased in MS cases of NWE ancestry because it is in LD with the ancestral DR15 susceptibility haplotype (7.1) and that it does not play an independent role in predisposition to MS. However, our findings provide the impetus for further investigations into the role of iron metabolism in the severity of MS.

DNA Primers↗

PubMed2003

Tonography demonstrates reduced facility of outflow of aqueous humor in myocilin mutation carriers.

PURPOSE: To demonstrate the effect in vivo of the myocilin gene mutation Thr377Met on outflow facility of aqueous humor, as measured by tonography. MATERIALS AND METHODS: Forty-two members of a pedigree known to carry the Thr377Met mutation were examined for glaucoma, evaluated with tonography, and screened for myocilin mutations. Tonography was used to calculate the coefficient of aqueous outflow facility (C), as well as the ratio of the resting intraocular pressure to C (P(0)/C). Subjects were reexamined for glaucoma 5 years after tonography. RESULTS: Seven subjects were excluded because of previous treatment known to alter facility of aqueous outflow. The mean outflow facility of the eyes of the 12 subjects carrying the Thr377Met mutation was significantly reduced compared with the 23 non-carriers' eyes using both C (P<0.001) and P(0)/C (P<0.001). Reduced outflow facility was also demonstrated in those mutation carriers who were not yet expressing clinical signs of glaucoma or ocular hypertension when measured using C (P = 0.015) and P(0)/C (P = 0.001). After 5 years, progression towards glaucoma had occurred in 5 of the myocilin mutation-carriers, 2 of whom showed bilateral progression; 3 carriers remained completely normal. Four subjects had bilateral glaucoma at the outset and remained unchanged. The carriers' eyes that progressed towards glaucoma had reduced outflow facility compared with those that remained normal, although the difference was not statistically significant. CONCLUSIONS: Carriers of the myocilin Thr377Met mutation have reduced outflow facility, which may be detected prior to developing glaucoma. Tonography was not seen to be clinically useful in predicting progression towards glaucoma.

Aqueous Humor↗

PubMed2002

The apolipoprotein epsilon4 gene is associated with elevated risk of normal tension glaucoma.

PURPOSE: Inheritance of a particular apolipoprotein E gene polymorphism, the epsilon4 allele, has been associated with elevated risk for Alzheimer's disease and a poor outcome following head injury. The neuronal injury associated with Alzheimer's disease and brain injury may have a number of similarities with the nerve cell changes associated with glaucoma. Thus, we have investigated the association of inheritance of apolipoprotein E allelic isoforms (epsilon2, [epsilon]3, and epsilon4) with relative risk for different forms of glaucoma. METHODS: Apolipoprotein E genotype was examined in a Tasmanian population sample comprised of glaucoma sufferers with elevated or normal intraocular pressure and compared to a control sample of elderly Tasmanians without glaucoma. RESULTS: Approximately twice as many normal tension (38.0%) and high tension (34.2%) glaucoma cases possessed an epsilon4 allele compared to control cases (18.9%). The odds of epsilon4 carriers having normal tension glaucoma were significantly greater than for epsilon3 homozygotes (odds ratio 2.45, 95% confidence interval [1.02-5.91]) even after adjusting for age and gender (odd ratio 2.87 [1.02-8.05]). The increased odds of high tension glaucoma among [epsilon]4 allele carriers were not significant (adjusted odds ratio 1.53 [0.64-3.68]). CONCLUSIONS: The data indicate that, in the Tasmanian population, inheritance of the [epsilon]4 allele is associated with elevated risk for glaucomatous changes that are not related to increased intraocular pressure.

Aged↗

PubMed2002

Misclassification due to body hair and seasonal variation on melanin density estimates for skin type using spectrophotometry.

Recent advances have enabled quite accurate estimations of cutaneous melanin density by spectrophotometry using reflectance of light at wavelengths 400 and 420 nm. Our purpose was to assess the effect of body hair and seasonal variation at the upper inner arm and buttock on measurements of melanin density. We estimated melanin density of 104 volunteers at 3-monthly intervals over 12 months both before and after shaving. Removing body hair at the upper inner arm had no effect, but substantially reduced melanin estimates at the buttock in men. Significant seasonal variation was only observed at the upper inner arm, with highest readings in summer-autumn. In case-control studies, misclassification due to body hair at the buttock and seasonal variation at the upper inner arm could affect the observed odds ratio substantially. However, both sources of error can be reduced by careful attention to key aspects of study design.

Adult↗