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Ascertainment
Kinds of Ascertainment Terms modified by Ascertainment Selected AbstractsSpectrum of chronic kidney disease in HIV-infected patientsHIV MEDICINE, Issue 6 2009LJ Campbell Objectives The aim of the study was to investigate the prevalence and aetiology of chronic kidney disease (CKD) and trends in estimated glomerular filtration rate (eGFR) in HIV-infected patients. Methods Ascertainment and review of CKD cases among patients attending King's College and Brighton Hospitals, UK were carried out. CKD was defined as eGFR <60 mL/min for ,3 months. Longitudinal eGFR slopes were produced to examine trends in renal function before, during and after exposure to indinavir (IDV) or tenofovir (TFV). Results CKD prevalence was 2.4%. While HIV-associated nephropathy accounted for 62% of CKD in black patients, 95% of CKD in white/other patients was associated with diabetes mellitus, hypertension, atherosclerosis and/or drug toxicity. Exposure to IDV or TFV was associated with an accelerated decline in renal function (4.6-fold and 3.7-fold, respectively) in patients with CKD. In patients initiating IDV, age ,50 years increased the odds of CKD [odds ratio (OR) 4.9], while in patients initiating TFV, age ,50 years (OR 5.4) and eGFR 60,75 mL/min (OR 17.2) were associated with developing CKD. Conclusion This study highlights the importance of metabolic and vascular disease to the burden of CKD in an ageing HIV-infected cohort. In patients who developed CKD, treatment with IDV or TFV was associated with an accelerated decline in renal function. [source] Ascertainment of birth defects: The effect on completeness of adding a new source of dataJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 6 2000C Bower Background: The Western Australian (WA) Birth Defects Registry aims for complete ascertainment of birth defects in WA, but the proportions of birth defects in rural areas and in Aboriginal children are lower than in metropolitan and non-Aboriginal children. The effect on ascertainment of adding data from the Rural Paediatric Service (RPS) was investigated. Method: A file of all cases of birth defects for children born 1980,1997 and recorded on the RPS database was linked to the Registry. Results: The addition of this new data source had little effect on the overall prevalence of birth defects (an increase from 5.38 to 5.41%). There was a slightly greater effect on the prevalence of birth defects in rural residents (4.67%,4.76%) and Aboriginal children (4.55,4.78%), although the prevalence for each of these groups is still less than for metropolitan residents and non-Aboriginal infants, respectively. All major categories of birth defects were represented in the new cases and, in general, their addition made little difference to the prevalence of each category. The exception was fetal alcohol syndrome, which increased from 0.13 per 1000 to 0.18 per 1000 once the 21 new cases from the RPS were added. Conclusion: Complete ascertainment of birth defects is important in developing and evaluating preventive programs, and in investigating clusters of birth defects. [source] Breast Cancer Incidence in a Cohort of Women with Benign Breast Disease from a Multiethnic, Primary Health Care PopulationTHE BREAST JOURNAL, Issue 2 2007Maria J. Worsham PhD Abstract:, Women with benign breast diseases (BBD), particularly those with lesions classified as proliferative, have previously been reported to be at increased risk for subsequent development of breast cancer (BC). A cohort of 4970 women with biopsy-proven BBD, identified after histopathology review of BBD biopsies, was studied for determination of subsequent development of BC. We report on 4537 eligible women, 28% of whom are African-American, whose BBD mass was evaluable for pathologic assessment of breast tissue. Ascertainment of subsequent progression to BC from BBD was accomplished through examination of the tumor registries of the Henry Ford Health system, the Detroit SEER registry, and the State of Michigan cancer registry. Incidence rates (IR) are reported per 100,000 person years at risk (100 k pyr). Poisson regression models were used to evaluate the association of demographic and lesion characteristics with BC incidence, using person years at the time of BBD diagnosis as the offset variable. The estimated overall BC IR for this cohort is 452 (95% confidence interval [CI] = 394,519) per 100 k pyr. Incidence for women age 50 and older is 80% greater than for younger women (p = 0.007, IRR = 1.8, 95% CI = 1.36,2.36). Neither marital status (p = 0.91, IRR = 0.97, 95% CI = 0.73,1.29) nor race (p = 0.67, IRR = 0.9, 95% CI = 0.54,1.48) is associated with differences in BC IR. Compared with women having nonproliferative lesions, the risk for BC is greater for women with atypical ductal hyperplasia of (IRR = 5.0; 95%CI = 2.26,11.0; p < 0.001) and other proliferative lesions (IR = 1.7, 95% CI = 1.02,2.95; p = 0.04). BC risk for woman with atypical lesions is significantly higher than for women with proliferative lesions without atypia (IRR = 2.58, 95% CI = 1.35,4.90; p = 0.0039). Neither race nor marital status was a factor for BC incidence from BBD in this cohort. Age retained its importance as a predictor of risk. BBD lesion histopathology in the outcome categories of either proliferative without atypia or proliferative with atypia are significant risk factors for BC, even when adjusted for the influence of demographic characteristics. The risks associated with BBD histological classifications were not different across races. [source] QTL Mapping Under AscertainmentANNALS OF HUMAN GENETICS, Issue 6 2006J. Peng Summary Mapping quantitative trait loci (QTL) using ascertained sibships is discussed. It is shown that under the standard normality assumption of variance components analysis the efficient scores are unchanged by ascertainment, and two different schemes of ascertainment correction suggested in the literature are asymptotically equivalent. The use of conditional maximum likelihood estimators derived under the normality assumption to estimate nuisance parameters is shown to result in only a small loss of power compared to the case of known parameters, even when the distribution of phenotypes is non-normal and/or the ascertainment criterion is ill defined. [source] Refinement of 2q and 7p loci in a large multiplex NTD family,BIRTH DEFECTS RESEARCH, Issue 6 2008Demetra S. Stamm Abstract BACKGROUND: NTDs are considered complex disorders that arise from an interaction between genetic and environmental factors. NTD family 8776 is a large multigenerational Caucasian family that provides a unique resource for the genetic analysis of NTDs. Previous linkage analysis using a genome-wide SNP screen in family 8776 with multipoint nonparametric mapping methods identified maximum LOD* scores of ,3.0 mapping to 2q33.1,q35 and 7p21.1,pter. METHODS: We ascertained an additional nuclear branch of 8776 and conducted additional linkage analysis, fine mapping, and haplotyping. Expression data from lymphoblast cell lines were used to prioritize candidate genes within the minimum candidate intervals. Genomic copy number changes were evaluated using BAC tiling arrays and subtelomeric fluorescent in situ hybridization probes. RESULTS: Increased evidence for linkage was observed with LOD* scores of ,3.3 for both regions. Haplotype analyses narrowed the minimum candidate intervals to a 20.3 Mb region in 2q33.1,q35 between markers rs1050347 and D2S434, and an 8.3 Mb region in 7p21.1,21.3 between a novel marker 7M0547 and rs28177. Within these candidate regions, 16 genes were screened for mutations; however, no obvious causative NTD mutation was identified. Evaluation of chromosomal aberrations using comparative genomic hybridization arrays, subtelomeric fluorescent in situ hybridization, and copy number variant detection techniques within the 2q and 7p regions did not detect any chromosomal abnormalities. CONCLUSIONS: This large NTD family has identified two genomic regions that may harbor NTD susceptibility genes. Ascertainment of another branch of family 8776 and additional fine mapping permitted a 9.1 Mb reduction of the NTD candidate interval on chromosome 7 and 37.3 Mb on chromosome 2 from previously published data. Identification of one or more NTD susceptibility genes in this family could provide insight into genes that may affect other NTD families. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc. [source] Differential risks to males and females for congenital malformations among 2.5 million California births, 1989,1997BIRTH DEFECTS RESEARCH, Issue 12 2003Gary M. Shaw Abstract BACKGROUND Although many studies have observed variations in the prevalence of specific malformations by sex, there is a lack of population-based data on potential malformation prevalence differences by sex at birth. METHODS Our objective was to explore differences in the prevalence of structural congenital malformation phenotypes between sexes in a California population of 2.5 million live- and stillbirths, using data from a population-based active surveillance system. Ascertainment was performed among offspring of California women who delivered in nonmilitary hospitals during the period of 1989,1997. Malformations were grouped according to the four-digit malformation codes of the British Pediatric Association. RESULTS Overall, 32,619 males and 21,835 females were considered to have structural congenital malformations, with prevalences of 2.52% and 1.76%, respectively. Thus, males demonstrated a malformation prevalence that was 22% higher than that in females. Using a criterion of a 40% increase or decrease in the relative risk for males, increased risks for 15 and decreased risks for 17 specific malformation categories were observed. Increased risks were associated with most organ systems, with the notable exception of the nervous system (increased risks for nervous system malformations were observed among female births). Risks were not substantially influenced by adjusting for maternal age, race/ethnicity, parity, or education. CONCLUSIONS Our observations extend the relatively few studies that have investigated differential prevalences of a large number of specific structural malformations between male and female births. Birth Defects Research (Part A) 67:000,000, 2003. © 2003 Wiley-Liss, Inc. [source] Congenital malformations in infants whose mothers reported the use of folic acid in early pregnancy in Sweden.CONGENITAL ANOMALIES, Issue 4 2007A prospective population study ABSTRACT The use of folic acid prior to conception is generally recommended for the prevention of birth defects, notably neural tube defects. In a previous study from Sweden, based on interviews of women in early pregnancy, no such effect was found on the general malformation rate, but data for neural tube defects were scarce. Using data from the Swedish Medical Birth Register for the years 1995,2004, 20 891 women were identified who reported the use of folic acid in early pregnancy, but not of anticonvulsants. These women were compared to all other women who gave birth during the study period. Malformations in the infants born were identified from multiple sources. No reduction in the general malformation rate was seen among infants born to women who reported the use of folic acid (OR = 1.09, 95% CI 1.02,1.17) and no effect of neural tube defect rate was seen (RR = 1.35, 95% CI 0.82,2.22), based on 16 infants with neural tube defect whose mother reported the use of folic acid. No effect was seen on the rates of other malformations except for cardiac defects, where a statistically significant increased risk (notably for severe defects) was found (OR = 1.19, 95% CI 1.05,1.35). The effect of various deficiencies in data collection is discussed, but is unlikely to explain the lack of protective effect noticed. So far, it has not been possible to demonstrate a beneficial effect of folic acid supplementation on malformation risk in Sweden. A more complete ascertainment and detailed timing and dosage of folic acid use in a prospective study is recommended. [source] Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studiesDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2009Philip A. May Abstract Researching the epidemiology and estimating the prevalence of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) for mainstream populations anywhere in the world has presented a challenge to researchers. Three major approaches have been used in the past: surveillance and record review systems, clinic-based studies, and active case ascertainment methods. The literature on each of these methods is reviewed citing the strengths, weaknesses, prevalence results, and other practical considerations for each method. Previous conclusions about the prevalence of FAS and total FASD in the United States (US) population are summarized. Active approaches which provide clinical outreach, recruitment, and diagnostic services in specific populations have been demonstrated to produce the highest prevalence estimates. We then describe and review studies utilizing in-school screening and diagnosis, a special type of active case ascertainment. Selected results from a number of in-school studies in South Africa, Italy, and the US are highlighted. The particular focus of the review is on the nature of the data produced from in-school methods and the specific prevalence rates of FAS and total FASD which have emanated from them. We conclude that FAS and other FASD are more prevalent in school populations, and therefore the general population, than previously estimated. We believe that the prevalence of FAS in typical, mixed-racial, and mixed-socioeconomic populations of the US is at least 2 to 7 per 1,000. Regarding all levels of FASD, we estimate that the current prevalence of FASD in populations of younger school children may be as high as 2,5% in the US and some Western European countries. © 2009 Wiley-Liss, Inc. Dev Disabil Res Rev 2009; 15:176,192. [source] The changing prevalence of diagnosed diabetes and its associated vascular complications in a large region of the UK*DIABETIC MEDICINE, Issue 6 2010C. L. Morgan Diabet. Med. 27, 673,678 (2010) Abstract Aims, To characterize the prevalence of diabetes in a large health district in 2004 and compare it with a previous estimate made in 1996. Methods, The study population comprised the resident population of Cardiff and the Vale of Glamorgan. Routine record linkage was used to identify patients from various sources of hospital and mortality data. Patients with diabetes were identified according to biochemistry test results, coding on routine data or attendance at a diabetes-related clinic. Diabetes-related complications were ascribed according to coding on routine data. Results, It was possible to identify 17 088 people with diabetes alive on 1 January 2005. Of these patients, 9064 (53.0%) were male and 8024 (47.0%) were female. Mean age (± sd) was 59.6 ± 18.9 years for males and 61.2 ± 20.4 years for females. The crude prevalence of diabetes in 2005 was 3.9% (3.4% adjusted) compared with 2.5% in 1996 (2.3% adjusted). With the exception of females aged , 75 years, the prevalence of diabetes increased in all age- and sex-specific subgroups. Within the 2005 cohort, over two-thirds has no recorded complications compared with approximately one half of the 1996 cohort. The prevalence of individual complications decreased, with the exception of renal complications. Conclusions, The prevalence of identified diabetes appears to have increased substantially over a relatively short period of 9 years to 2004. The increase in prevalence was 46%, with an increase in numbers of patients with diabetes of 53%. A number of factors are likely to have contributed to this, including an increase in case ascertainment. [source] A 10-year (1996,2005) prospective study of the incidence of Type 1 diabetes in Moscow in the age group 0,14 yearsDIABETIC MEDICINE, Issue 8 2008E. A. Pronina Abstract Aims To provide data on the incidence of Type 1 diabetes (T1D) in Moscow, determined prospectively from 1996 to 2005 for a total of > 10 million subjects aged < 15 years. Methods Data on T1D incidence in patients with newly discovered T1D resident in Moscow diagnosed between 1 January 1996 and 31 December 2005 were analysed. Primary ascertainment was based in endocrinology departments of children's hospitals in Moscow. A secondary source were the archives of Moscow Region where patients are registered to obtain exemption from paying for medication. Results We identified 2031 new cases of T1D patients with a degree of ascertainment through primary and secondary sources of 94%. Overall the incidence rate of the disease was 12.9 per 100 000 per year (95% confidence interval 12.3, 13.4). The cumulative risk of the disease was 0.28 per 1000 in the age group 0,4 years, 0.84 in the age group 5,9 years and 1.8 in the age group 10,14 years. The incidence rate in girls increased by a mean of 6% per year in all age groups (P < 0.05 for all comparisons), whereas in boys it increased by a mean of 7% in the age group 10,14 years. Thirty percent of cases presented with diabetic ketoacidosis and coma at diagnosis, whereas hyperglycaemia without ketonuria was present in 20% of patients. Conclusions This is the first study to report on validated incidence data for T1D in Moscow. We conclude that the incidence of T1D in Moscow is comparable to that of those European countries having intermediate incidence rates, and that the incidence is increasing. [source] Candidate genes for cannabis use disorders: findings, challenges and directionsADDICTION, Issue 4 2009Arpana Agrawal ABSTRACT Aim Twin studies have shown that cannabis use disorders (abuse/dependence) are highly heritable. This review aims to: (i) review existing linkage studies of cannabis use disorders and (ii) review gene association studies, to identify potential candidate genes, including those that have been tested for composite substance use disorders and (iii) to highlight challenges in the genomic study of cannabis use disorders. Methods Peer-reviewed linkage and candidate gene association studies are reviewed. Results Four linkage studies are reviewed: results from these have homed in on regions on chromosomes 1, 3, 4, 9, 14, 17 and 18, which harbor candidates of predicted biological relevance, such as monoglyceride lipase (MGLL) on chromosome 3, but also novel genes, including ELTD1[epidermal growth factor (EGF), latrophilin and seven transmembrane domain containing 1] on chromosome 1. Gene association studies are presented for (a) genes posited to have specific influences on cannabis use disorders: CNR1, CB2, FAAH, MGLL, TRPV1 and GPR55 and (b) genes from various neurotransmitter systems that are likely to exert a non-specific influence on risk of cannabis use disorders, e.g. GABRA2, DRD2 and OPRM1. Conclusions There are challenges associated with (i) understanding biological complexity underlying cannabis use disorders (including the need to study gene,gene and gene,environment interactions), (ii) using diagnostic versus quantitative phenotypes, (iii) delineating which stage of cannabis involvement (e.g. use versus misuse) genes influence and (iv) problems of sample ascertainment. [source] Validation of a brief screening instrument for the ascertainment of epilepsyEPILEPSIA, Issue 2 2010Ruth Ottman Summary Purpose:, To validate a brief screening instrument for identifying people with epilepsy in epidemiologic or genetic studies. Methods:, We designed a nine-question screening instrument for epilepsy and administered it by telephone to individuals with medical record,documented epilepsy (lifetime history of ,2 unprovoked seizures, n = 168) or isolated unprovoked seizure (n = 54), and individuals who were seizure-free on medical record review (n = 120), from a population-based study using Rochester Epidemiology Project resources. Interviewers were blinded to record-review findings. Results:, Sensitivity (the proportion of individuals who screened positive among affected individuals) was 96% for epilepsy and 87% for isolated unprovoked seizure. The false positive rate (FPR, the proportion who screened positive among seizure-free individuals) was 7%. The estimated positive predictive value (PPV) for epilepsy was 23%, assuming a lifetime prevalence of 2% in the population. Use of only a single question asking whether the subject had ever had epilepsy or a seizure disorder resulted in sensitivity 76%, FPR 0.8%, and estimated PPV 66%. Subjects with epilepsy were more likely to screen positive with this question if they were diagnosed after 1964 or continued to have seizures for at least 5 years after diagnosis. Discussion:, Given its high sensitivity, our instrument may be useful for the first stage of screening for epilepsy; however, the PPV of 23% suggests that only about one in four screen-positive individuals will be truly affected. Screening with a single question asking about epilepsy yields a higher PPV but lower sensitivity, and screen-positive subjects may be biased toward more severe epilepsy. [source] Autosomal Dominant Inheritance of Centrotemporal Sharp Waves in Rolandic Epilepsy FamiliesEPILEPSIA, Issue 12 2007Bhavna Bali Summary Purpose: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well-designed family segregation analysis study. Methods: Probands with rolandic epilepsy were collected through unambiguous single ascertainment. Siblings in the age range 4,16 years underwent sleep-deprived EEG; observations from those who remained awake were omitted. CTS were rated as present or absent by two independent observers blinded to the study hypothesis and subject identities. We computed the segregation ratio of CTS, corrected for ascertainment. We tested the segregation ratio estimate for consistency with dominant and recessive modes of inheritance, and compared the observed sex ratio of those affected with CTS for consistency with sex linkage. Results: Thirty siblings from 23 families underwent EEG examination. Twenty-three showed evidence of sleep in their EEG recordings. Eleven of 23 recordings demonstrated CTS, yielding a corrected segregation ratio of 0.48 (95% CI: 0.27,0.69). The male to female ratio of CTS affectedness was approximately equal. Conclusions: The segregation ratio of CTS in rolandic epilepsy families is consistent with a highly penetrant autosomal dominant inheritance, with equal sex ratio. Autosomal recessive and X-linked inheritance are rejected. The CTS locus might act in combination with one or more loci to produce the phenotype of rolandic epilepsy. [source] National and Regional Prevalence of Self-reported Epilepsy in CanadaEPILEPSIA, Issue 12 2004José F. Tellez-Zenteno Summary:,Purpose: To assess the point prevalence of self-described epilepsy in the general population nationally, provincially, and in different groups of interest. Methods: We analyzed data from two national health surveys, the National Population Health Survey (NPHS, N = 49,000) and the Community Health Survey (CHS, N = 130,882). Both surveys captured sociodemographic information, as well as age, sex, education, ethnicity, household income, and labor force status of participants. Epilepsy was ascertained with only one question in both surveys. "Do you have epilepsy diagnosed by a health professional?" (NPHS) and "Do you have epilepsy?" (CHS). Prevalences were age-adjusted by using national standard populations at the time of each survey. Exact 95% confidence intervals were obtained. Results: In the NPHS, 241 of 49,026 subjects described themselves as having been diagnosed with epilepsy, yielding a weighted point prevalence of 5.2 per 1,000 [95% confidence interval (CI), 4.9,5.4]. In the CHS, 835 of 130,822 subjects described themselves as having epilepsy, yielding a weighted point prevalence of 5.6 per 1,000 (95% CI, 5.1,6.0). Trends in differences in prevalence among some Canadian provinces were observed. Prevalence was statistically significantly higher in groups with the lowest educational level, lowest income, and in those unemployed in the previous year. Prevalence also was higher in nonimmigrants than in immigrants. Conclusions: The overall and group-specific results are in keeping with those obtained in other developed countries by using different ascertainment methods. We discuss methodologic aspects related to the ascertainment of epilepsy in both surveys, and to the validity and implications of our findings. [source] Screening for fetal alcohol syndrome: is it feasible and necessary?ADDICTION BIOLOGY, Issue 2 2000Larry Burd The potential to utilize screening strategies to improve the identification and outcome of persons with fetal alcohol syndrome (FAS) is reviewed. FAS is a condition where screening and surveillance activities would be appropriate. Development of FAS screening and surveillance programs is encouraged because the disorder is expensive. People with FAS have poor outcomes as adults with less than 10% living independently. Several useful tools and models are available. Screening would improve ascertainment and prevalence estimates. Early identification could improve access to services and long term outcome, secondary disabilities and, by extension, excess disability in affected children could be decreased. Lastly, mothers who are at the highest risk to have additional children with FAS could be identified and offered treatment. While both screening and surveillance activities are discussed, the principle focus of this article is a review of the screening process. Two screening tools and several screening methodologies for FAS are available. Since no test will be appropriate in all settings, screening tests need to be selected depending on the setting and population of interest. Screening for FAS should be conducted in a variety of settings and in populations of both high and moderate risk. The results would also provide important data to influence public policy development and resource allocation. Appropriate evaluation of the efficacy, efficiency and effectiveness of FAS screening tools and methodologies would be important before utilization in screening programs. [source] A national stroke quality register: 12 years experience from a participating hospitalEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2007P. Appelros Registration of all hospitalized stroke patients is practiced in Sweden in order to assess care quality. Data in this register, Riks-Stroke (RS), may be biased due to incomplete registration. The purpose of this paper was to report changes in stroke outcome in relation to fluctuations in registration. Patients registered in RS at a hospital during the period 1994,2005 were analyzed. Case fatality at 28 days, living conditions, and activities of daily living (ADL) performance at 3 months were correlated to the number of patients registered and follow-up frequency. A total of 4994 stroke cases were registered during the period. A high annual registration rate was significantly correlated to a high case fatality ratio. A low annual follow-up rate was associated with a low proportion of patients living in their own home without any need of help. Quality parameters are sensible for selection bias, which make them difficult to compare over time and between hospitals. We suggest that by weighing outcome data against stroke severity, safer conclusions may be drawn. Additionally, hospitals considering setting up quality registers should make every effort to attain complete case ascertainment at all times, including patients managed outside the hospital, in order to avoid selection bias. [source] A two-fold difference in the age-adjusted prevalences of Parkinson's disease between the island of Als and the Faroe IslandsEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2000L. Wermuth With the aim of comparing the previously found high prevalence of idiopathic Parkinson's disease (PD) in the Faroe Islands with the prevalence of PD in an area of Denmark, we used the same case-finding methods for case ascertainment and the same strict criteria to diagnose PD on the island of Als. During the last year before the prevalence date (1 January 1998), we found in various registries from pharmacies, hospital, private neurologist and general practioners 121 patients with suspected Parkinsonism out of 56 839 inhabitants on the island of Als. After exclusion of those who had other diseases, a total of 79 patients were left for further examinations. Among these we found 58 with PD. The overall prevalence of PD was estimated to be 102.0 and the age-adjusted prevalence to be 98.3 per 100 000 persons compared with 187.6 and 209.0 in the Faroe Islands. Compared with the previous results from the Faroe Islands (prevalence date 1 July 1995) we found an even lower mean age at onset of PD symptoms and at onset of treatment, a lower proportion of definite PD and a lower average dose of levodopa. We therefore conclude that the two-fold higher prevalence in the Faroe Islands than on the island of Als was not due to an early diagnosis and a higher ascertainment of cases with mild PD, which was suggested as being one possible explanation for our previous finding of a high prevalence of PD in the Faroe Islands. [source] Summary of contributions to GAW Group 15: family-based samples are useful in identifying common polymorphisms associated with complex traitsGENETIC EPIDEMIOLOGY, Issue S1 2009Stacey Knight Abstract Traditionally, family-based samples have been used for genetic analyses of single-gene traits caused by rare but highly penetrant risk variants. The utility of family-based genetic data for analyzing common complex traits is unclear and contains numerous challenges. To assess the utility as well as to address these challenges, members of Genetic Analysis Workshop 16 Group 15 analyzed Framingham Heart Study data using family-based designs ranging from parent,offspring trios to large pedigrees. We investigated different methods including traditional linkage tests, family-based association tests, and population-based tests that correct for relatedness between subjects, and tests to detect parent-of-origin effects. The analyses presented an assortment of positive findings. One contribution found increased power to detect epistatic effects through linkage using ascertainment of sibships based on extreme quantitative values or presence of disease associated with the quantitative value. Another contribution found four single-nucleotide polymorphisms (SNPs) showing a maternal effect, two SNPs with an imprinting effect, and one SNP having both effects on a binary high blood pressure trait. Finally, three contributions illustrated the advantage of using population-based methods to detect association to complex binary or quantitative traits. Our findings highlight the contribution of family-based samples to the genetic dissection of complex traits. Genet. Epidemiol. 33 (Suppl. 1):S99,S104, 2009. © 2009 Wiley-Liss, Inc. [source] PEL: an unbiased method for estimating age-dependent genetic disease risk from pedigree data unselected for family historyGENETIC EPIDEMIOLOGY, Issue 5 2009F. Alarcon Abstract Providing valid risk estimates of a genetic disease with variable age of onset is a major challenge for prevention strategies. When data are obtained from pedigrees ascertained through affected individuals, an adjustment for ascertainment bias is necessary. This article focuses on ascertainment through at least one affected and presents an estimation method based on maximum likelihood, called the Proband's phenotype exclusion likelihood or PEL for estimating age-dependent penetrance using disease status and genotypic information of family members in pedigrees unselected for family history. We studied the properties of the PEL and compared with another method, the prospective likelihood, in terms of bias and efficiency in risk estimate. For that purpose, family samples were simulated under various disease risk models and under various ascertainment patterns. We showed that, whatever the genetic model and the ascertainment scheme, the PEL provided unbiased estimates, whereas the prospective likelihood exhibited some bias in a number of situations. As an illustration, we estimated the disease risk for transthyretin amyloid neuropathy from a French sample and a Portuguese sample and for BRCA1/2 associated breast cancer from a sample ascertained on early-onset breast cancer cases. Genet. Epidemiol. 33:379,385, 2009. © 2008 Wiley-Liss, Inc. [source] Estimating haplotype relative risks in complex disease from unphased SNPs data in families using a likelihood adjusted for ascertainmentGENETIC EPIDEMIOLOGY, Issue 8 2006J. Carayol Abstract The understanding of complex diseases and insights to improve their medical management may be achieved through the deduction of how specific haplotypes may play a joint effect to change relative risk information. In this paper we describe an ascertainment adjusted likelihood-based method to estimate haplotype relative risks using pooled family data coming from association and/or linkage studies that were used to identify specific haplotypes. Haplotype-based analysis tends to require a large amount of parameters to capture all the information that leads to efficiency problems. An adaptation of the Stochastic Expectation Maximization algorithm is used for haplotypes inference from genotypic data and to reduce the number of nuisance parameters for risk estimation. Using different simulations, we show that this method provides unbiased relative risk estimates even in case of departure from Hardy-Weinberg equilibrium. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] The estimation of sibling genetic risk parameters revisitedGENETIC EPIDEMIOLOGY, Issue 4 2004Guohua Zou Abstract This report points out that some sibling genetic risk parameters can be regarded as the ratios of the characteristic values in the ascertainment subpopulation. Based on this observation, we reconsider Olson and Cordell's ([2000] Genet. Epidemiol. 18:217,235) and Cordell and Olson's ([2000] Genet. Epidemiol. 18:307,321) estimators, and re-derive these estimators. Furthermore, we provide the closed-form variance estimators. Simulation results suggest that our proposed estimators perform very well, and single ascertainment may be better than complete ascertainment for estimating these genetic parameters. © 2004 Wiley-Liss, Inc. [source] Properties of case/pseudocontrol analysis for genetic association studies: Effects of recombination, ascertainment, and multiple affected offspringGENETIC EPIDEMIOLOGY, Issue 3 2004Heather J. Cordell Abstract The case/pseudocontrol approach is a general framework for family-based association analysis, incorporating several previously proposed methods such as the transmission/disequilibrium test and log-linear modelling of parent-of-origin effects. In this report, I examine the properties of methods based on a case/pseudocontrol approach when applied to a linked marker rather than (or in addition to) the true disease locus or loci, and when applied to sibships that have been ascertained on, or that may simply contain, multiple affected sibs. Through simulations and analytical calculations, I show that the expected values of the observed relative risk parameters (estimating quantities such as effects due to a child's own genotype, maternal genotype, and parent-of-origin) depend crucially on the ascertainment scheme used, as well as on whether there is non-negligible recombination between the true disease locus and the locus under study. In the presence of either recombination or ascertainment on multiple affected offspring, methods based on conditioning on parental genotypes are shown to give unbiased genotype relative risk estimates at the true disease locus (or loci) but biased estimates of population genotype relative risks at a linked marker, suggesting that the resulting estimates may be misleading when used to predict the power of future studies. Methods that allow for exchangeability of parental genotypes are shown (in the presence of either recombination or ascertainment on multiple affected offspring) to produce false-positive evidence of maternal genotype effects when there are true parent-of-origin or mother-child interaction effects, even when analyzing the true locus. These results suggest that care should be taken in both the interpretation and application of parameter estimates obtained from family-based genetic association studies. © 2004 Wiley-Liss, Inc. [source] Candidate-gene association studies with pedigree data: Controlling for environmental covariatesGENETIC EPIDEMIOLOGY, Issue 4 2003S.L. Slager Abstract Case-control studies provide an important epidemiological tool to evaluate candidate genes. There are many different study designs available. We focus on a more recently proposed design, which we call a multiplex case-control (MCC) design. This design compares allele frequencies between related cases, each of whom are sampled from multiplex families, and unrelated controls. Since within-family genotype correlations will exist, statistical methods will need to take this into account. Moreover, there is a need to develop methods to simultaneously control for potential confounders in the analysis. Generalized estimating equations (GEE) are one approach to analyze this type of data; however, this approach can have singularity problems when estimating the correlation matrix. To allow for modeling of other covariates, we extend our previously developed method to a more general model-based approach. Our proposed methods use the score statistic, derived from a composite likelihood. We propose three different approaches to estimate the variance of this statistic. Under random ascertainment of pedigrees, score tests have correct type I error rates; however, pedigrees are not randomly ascertained. Thus, through simulations, we test the validity and power of the score tests under different ascertainment schemes, and an illustration of our methods, applied to data from a prostate cancer study, is presented. We find that our robust score statistic has estimated type I error rates within the expected range for all situations we considered whereas the other two statistics have inflated type I error rates under nonrandom ascertainment schemes. We also find GEE to fail at least 5% of the time for each simulation configuration; at times, the failure rate reaches above 80%. In summary, our robust method may be the only current regression analysis method available for MCC data. Genet Epidemiol 24:273,283, 2003. © 2003 Wiley-Liss, Inc. [source] Optimal designs for estimating penetrance of rare mutations of a disease-susceptibility geneGENETIC EPIDEMIOLOGY, Issue 3 2003Gail Gong Abstract Many clinical decisions require accurate estimates of disease risks associated with mutations of known disease-susceptibility genes. Such risk estimation is difficult when the mutations are rare. We used computer simulations to compare the performance of estimates obtained from two types of designs based on family data. In the first (clinic-based designs), families are ascertained because they meet certain criteria concerning multiple disease occurrences among family members. In the second (population-based designs), families are sampled through a population-based registry of affected individuals called probands, with oversampling of probands whose families are more likely to segregate mutations. We generated family structures, genotypes, and phenotypes using models that reflect the frequencies and penetrances of mutations of the BRCA1/2 genes. We studied the effects of risk heterogeneity due to unmeasured, shared risk factors by including risk variation due to unmeasured genotypes of another gene. The simulations were chosen to mimic the ascertainment and selection processes commonly used in the two types of designs. We found that penetrance estimates from both designs are nearly unbiased in the absence of unmeasured shared risk factors, but are biased upward in the presence of such factors. The bias increases with increasing variation in risks across genotypes of the second gene. However, it is small compared to the standard error of the estimates. Standard errors from population-based designs are roughly twice those from clinic-based designs with the same number of families. Using the root-mean-square error as a measure of performance, we found that in all instances, the clinic-based designs gave more accurate estimates than did the population-based designs with the same numbers of families. Rough variance calculations suggest that clinic-based designs give more accurate estimates because they include more identified mutation carriers. Genet Epidemiol 24:173,180, 2003. © 2003 Wiley-Liss, Inc. [source] Robustness of inference on measured covariates to misspecification of genetic random effects in family studiesGENETIC EPIDEMIOLOGY, Issue 1 2003Ruth M.Pfeiffer Abstract Family studies to identify disease-related genes frequently collect only families with multiple cases. It is often desirable to determine if risk factors that are known to influence disease risk in the general population also play a role in the study families. If so, these factors should be incorporated into the genetic analysis to control for confounding. Pfeiffer et al. [2001 Biometrika 88: 933,948] proposed a variance components or random effects model to account for common familial effects and for different genetic correlations among family members. After adjusting for ascertainment, they found maximum likelihood estimates of the measured exposure effects. Although it is appealing that this model accounts for genetic correlations as well as for the ascertainment of families, in order to perform an analysis one needs to specify the distribution of random genetic effects. The current work investigates the robustness of the proposed model with respect to various misspecifications of genetic random effects in simulations. When the true underlying genetic mechanism is polygenic with a small dominant component, or Mendelian with low allele frequency and penetrance, the effects of misspecification on the estimation of fixed effects in the model are negligible. The model is applied to data from a family study on nasopharyngeal carcinoma in Taiwan. Genet Epidemiol 24:14,23, 2003. © 2003 Wiley-Liss, Inc. [source] Power and robustness of a score test for linkage analysis of quantitative traits using identity by descent data on sib pairsGENETIC EPIDEMIOLOGY, Issue 4 2001Darlene R. Goldstein Abstract Identification of genes involved in complex traits by traditional (lod score) linkage analysis is difficult due to many complicating factors. An unfortunate drawback of non-parametric procedures in general, though, is their low power to detect genetic effects. Recently, Dudoit and Speed [2000] proposed using a (likelihood-based) score test for detecting linkage with IBD data on sib pairs. This method uses the likelihood for ,, the recombination fraction between a trait locus and a marker locus, conditional on the phenotypes of the two sibs to test the null hypothesis of no linkage (, = ˝). Although a genetic model must be specified, the approach offers several advantages. This paper presents results of simulation studies characterizing the power and robustness properties of this score test for linkage, and compares the power of the test to the Haseman-Elston and modified Haseman-Elston tests. The score test is seen to have impressively high power across a broad range of true and assumed models, particularly under multiple ascertainment. Assuming an additive model with a moderate allele frequency, in the range of p = 0.2 to 0.5, along with heritability H = 0.3 and a moderate residual correlation , = 0.2 resulted in a very good overall performance across a wide range of trait-generating models. Generally, our results indicate that this score test for linkage offers a high degree of protection against wrong assumptions due to its strong robustness when used with the recommended additive model. Genet. Epidemiol. 20:415,431, 2001. © 2001 Wiley-Liss, Inc. [source] Stoppage: An issue for segregation analysisGENETIC EPIDEMIOLOGY, Issue 3 2001S.L. Slager Abstract Segregation analysis assumes that the observed family-size distribution (FSD), i.e., distribution of number of offspring among nuclear families, is independent of the segregation ratio p. However, for certain serious diseases with early onset and diagnosis (e.g., autism), parents may change their original desired family size, based on having one or more affected children, thus violating that assumption. Here we investigate "stoppage," the situation in which such parents have fewer children than originally planned. Following Brookfield et al. [J Med Genet 25:181,185, 1988], we define a stoppage probability d that after the birth of an affected child, parents will stop having children and thus not reach their original desired family size. We first derive the full correct likelihood for a simple segregation analysis as a function of p, d, and the ascertainment probability ,. We show that p can be estimated from this likelihood if the FSD is known. Then, we show that under "random" ascertainment, the presence of stoppage does not bias estimates of p. However, for other ascertanment schemes, we show that is not the case. We use a simulation study to assess the magnitude of bias, and we demonstrate that ignoring the effect of stoppage can seroiusly bias the estimates of p when the FSD is ignored. In conclusion, stoppage, a realistic scenario for some complex diseases, can represent a serious and potentially intractable problem for segregation analysis. Genet. Epidemiol. 20:328,339, 2001. © 2001 Wiley-Liss, Inc. [source] Complete ascertainment of intragenic copy number mutations (CNMs) in the CFTR gene and its implications for CNM formation at other autosomal loci,HUMAN MUTATION, Issue 4 2010Sylvia Quemener Abstract Over the last 20 years since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more than 1,600 different putatively pathological CFTR mutations have been identified. Until now, however, copy number mutations (CNMs) involving the CFTR gene have not been methodically analyzed, resulting almost certainly in the underascertainment of CFTR gene duplications compared with deletions. Here, high-resolution array comparative genomic hybridization (averaging one interrogating probe every 95,bp) was used to analyze the entire length of the CFTR gene (189,kb) in 233 cystic fibrosis chromosomes lacking conventional mutations. We succeeded in identifying five duplication CNMs that would otherwise have been refractory to analysis. Based upon findings from this and other studies, we propose that deletion and duplication CNMs in the human autosomal genome are likely to be generated in the proportion of approximately 2,3:1. We further postulate that intragenic gene duplication CNMs in other disease loci may have been routinely underascertained. Finally, our analysis of ±20,bp flanking each of the 40 CFTR breakpoints characterized at the DNA sequence level provide support for the emerging concept that non-B DNA conformations in combination with specific sequence motifs predispose to both recurring and nonrecurring genomic rearrangements. Hum Mutat 31:1,8, 2010. © 2010 Wiley-Liss, Inc. [source] Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab studyINTERNAL MEDICINE JOURNAL, Issue 1 2009E. L. M. Barr Abstract Epidemiological studies often rely on self-reported cardiovascular disease (CVD) information, but this may be inaccurate. We investigated the accuracy of self-reported CVD (myocardial infarction, stroke, coronary artery bypass surgery and coronary artery angioplasty) during the follow up of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Self-reported CVD events, including the date of the event and hospital admission details, were collected with an interviewer-administered questionnaire. Of the 276 self-reported CVD events, 188 (68.1%) were verified by adjudication of medical records. Furthermore, linkage to the statewide Western Australian Hospital Morbidity Database (WAHMD) showed that CVD events were unlikely to be missed, with only 0.2% of those denying any CVD event being recorded as having had an event on the WAHMD. The adjudication of medical records was as accurate as record linkage to the WAHMD for validation of self-reported CVD, but combining the results from both methods of ascertainment improved CVD event identification. [source] Epidemiology of primary systemic vasculitis in the Australian Capital Territory and south-eastern New South WalesINTERNAL MEDICINE JOURNAL, Issue 11 2008A. S. Ormerod Abstract Background:, The aim of the study was to determine the epidemiology of primary systemic vasculitis in the Australian Capital Territory and the surrounding rural region between 1995 and 2005. Methods:, Cases were ascertained by a medical record search according to international consensus classification criteria. For antineutrophil cytoplasmic antibody-associated vasculitides, ascertainment was corroborated by a search of all positive antineutrophil cytoplasmic antibody serology during the study period. Denominators were obtained from region-specific census data collected during the study period. Prevalence, incidence and patient characteristics for primary systemic vasculitides were determined for two 5-year periods, 1995,1999 and 2000,2004. Results:, We identified 41 cases of primary systemic vasculitides (Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg,Strauss syndrome or polyarteritis nodosa) between 1995 and 1999 and 67 between 2000 and 2004, giving prevalences of 95/million (95% confidence interval (CI) 76.9,116.1) and 148/million (95%CI 125.1,173.9), respectively. Annual incidence was similar in both periods (approximately 17/year per million adult population). Disease-specific incidences (per million per year) for each of the two periods were 8.8 and 8.4 for WG, 2.3 and 5.0 for MPA, 2.3 and 2.2 for Churg,Strauss syndrome and 2.3 and 1.1 for polyarteritis nodosa. The rural incidence of MPA was 13.9 (95%CI 7.7,23.5) compared with 1.6 (95%CI 0.2,7.2) in the city and there was a trend towards a higher incidence of WG in rural than urban areas. Conclusion:, The overall incidence of primary systemic vasculitides is similar to that reported from other developed countries. WG is more common in south-eastern Australia than in southern Europe, whereas MPA is less common. There was a trend towards higher incidence of antineutrophil cytoplasmic antibody-associated vasculitides in rural than urban areas. [source] | |||||||||||||||||||||||||||||||||||||