Ascertainment Procedure Research Articles

The Decision Problem for Effective Procedures

The “somewhat vague, intuitive” notion from computability theory of an effective procedure (method) or algorithm can be fairly precisely defined even if it is not sufficiently formal and precise to belong to mathematics proper (in a narrow sense)—and even if (as many have asserted) for that reason the Church–Turing thesis is unprovable. It is proved logically that the class of effective procedures is not decidable, i.e., that there is no effective procedure for ascertaining whether a given procedure is effective. This result is proved directly from the notion itself of an effective procedure, without reliance on any (partly) mathematical lemma, conjecture, or thesis invoking recursiveness or Turing-computability. In fact, there is no reliance on anything very mathematical. The proof does not even appeal to a precise definition of ‘effective procedure’. Instead, it relies solely and entirely on a basic grasp of the intuitive notion of an effective procedure. Though the result that effectiveness is undecidable is not surprising, it is also not without significance. It has the consequence, for example, that the solution to a decision problem, if it is to be complete, must be accompanied by a separate argument that the proposed ascertainment procedure invariably terminates with the correct verdict.

Effective Procedures

The “somewhat vague, intuitive” notion from computability theory of an effective procedure (method) or algorithm can be fairly precisely defined, even if it does not have a purely mathematical definition—and even if (as many have asserted) for that reason, the Church–Turing thesis (that the effectively calculable functions on natural numbers are exactly the general recursive functions), cannot be proved. However, it is logically provable from the notion of an effective procedure, without reliance on any (partially) mathematical thesis or conjecture concerning effective procedures, such as the Church–Turing thesis, that the class of effective procedures is undecidable, i.e., that there is no effective procedure for ascertaining whether a given procedure is effective. The proof does not even appeal to a precise definition of ‘effective procedure’. Instead, it relies solely and entirely on a basic grasp of the intuitive notion of such a procedure. Though the result itself is not surprising, it is also not without significance. It has the consequence, for example, that the solution to a decision problem, if it is to be complete, must be accompanied by a separate argument that the proposed ascertainment procedure is, in fact, a decision procedure, i.e., effective—for example, that it invariably terminates with the correct verdict.

Cross-Sectional Survey on Prevalence of Attention Deficit Hyperactivity Disorder Symptoms at A Tertiary Care Health Facility in Nairobi

Cross-Sectional Survey on Prevalence of Attention Deficit Hyperactivity Disorder Symptoms at A Tertiary Care Health Facility in Nairobi

Full Likelihood Analysis of Genetic Risk with Variable Age at Onset Disease—Combining Population-Based Registry Data and Demographic Information

BackgroundIn genetic studies of rare complex diseases it is common to ascertain familial data from population based registries through all incident cases diagnosed during a pre-defined enrollment period. Such an ascertainment procedure is typically taken into account in the statistical analysis of the familial data by constructing either a retrospective or prospective likelihood expression, which conditions on the ascertainment event. Both of these approaches lead to a substantial loss of valuable data.Methodology and FindingsHere we consider instead the possibilities provided by a Bayesian approach to risk analysis, which also incorporates the ascertainment procedure and reference information concerning the genetic composition of the target population to the considered statistical model. Furthermore, the proposed Bayesian hierarchical survival model does not require the considered genotype or haplotype effects be expressed as functions of corresponding allelic effects. Our modeling strategy is illustrated by a risk analysis of type 1 diabetes mellitus (T1D) in the Finnish population-based on the HLA-A, HLA-B and DRB1 human leucocyte antigen (HLA) information available for both ascertained sibships and a large number of unrelated individuals from the Finnish bone marrow donor registry. The heterozygous genotype DR3/DR4 at the DRB1 locus was associated with the lowest predictive probability of T1D free survival to the age of 15, the estimate being 0.936 (0.926; 0.945 95% credible interval) compared to the average population T1D free survival probability of 0.995.SignificanceThe proposed statistical method can be modified to other population-based family data ascertained from a disease registry provided that the ascertainment process is well documented, and that external information concerning the sizes of birth cohorts and a suitable reference sample are available. We confirm the earlier findings from the same data concerning the HLA-DR3/4 related risks for T1D, and also provide here estimated predictive probabilities of disease free survival as a function of age.

A note on permutation tests for genetic association analysis of quantitative traits when variances are heterogeneous

The genetic dissection of quantitative traits, or endophenotypes, usually involves genetic linkage or association analysis in pedigrees and subsequent fine mapping association analysis in the population. The ascertainment procedure for quantitative traits often results in unequal variance of observations. For example, some phenotypes may be clinically measured whilst others are from self-reports, or phenotypes may be the average of multiple measures but with the number of measurements varying. The resulting heterogeneity of variance poses no real problem for analysis, as long as it is properly modelled and thereby taken into account. However, if statistical significance is determined using an empirical permutation procedure, it is not obvious what the units of sampling are. We investigated a number of permutation approaches in a simulation study of an association analysis between a quantitative trait and a single nucleotide polymorphism. Our simulations were designed such that we knew the true p-value of the test statistics. A number of permutation methods were compared from the regression of true on empirical p-values and the precision of the empirical p-values. We show that the best procedure involves an implicit adjustment of the original data for the effects in the model before permutation, and that other methods, some of which seemed appropriate a priori, are relatively biased.

A case–control study to assess sensitivity and specificity of a questionnaire for the detection of hip and knee osteoarthritis

To assess the performance of a telephone-administered questionnaire suitable for use in 2-phase surveys in the detection of symptomatic hip and knee osteoarthritis (OA) cases. A questionnaire was designed based on typical symptoms and self-reported OA diagnosis. Three groups of subjects were consecutively enrolled from rheumatology units at French university hospitals. The disease status, based on American College of Rheumatology criteria, was first confirmed by a rheumatologist. Subjects then completed the screening questionnaire administered by interviewers unaware of the diagnosis and the clinical examination results. Three screening strategies were evaluated. In all, 119 subjects with hip OA, 137 with knee OA, and 111 subjects with other rheumatic diseases with lower extremity symptoms were recruited. The highest sensitivity for both hip and knee OA was obtained with the strategy based on reporting the presence or absence of symptoms (>96%). The specificity of this strategy was low (42% for both joints). When taking into account the self-reported OA diagnosis, the sensitivity slightly decreased (>91%), and the specificity increased greatly, from 76% to 78%. The highest specificity was obtained with the third strategy, requiring a rheumatologist opinion (from 82% to 85%) at the expense of lower sensitivity (>90%). The questionnaire tested in this study is a simple, valid, and reliable instrument to screen symptomatic hip and knee OA. As such, it fails to reach complete accuracy and clinical examination and radiographs remain necessary for complete ascertainment procedure.

New markers for old stains: stable mRNA markers for blood and saliva identification from up to 16-year-old stains

In forensic science, the unequivocal identification of the cellular origin of crime scene samples used for DNA profiling can provide crucial information for crime scene reconstruction. We have previously shown that various mRNA markers from genes with expression patterns specific for blood and saliva can be established from whole-genome expression analysis of time-wise degraded samples and were stable enough to specifically identify blood and saliva stains up to 180 days of age. Here, we showed that nine blood-specific and five saliva-specific mRNA markers can be amplified successfully and reliably in much older blood (13-16 years) and saliva (2-6 years) stains, respectively, suggesting their suitability for tissue identification in forensic case work. Moreover, our findings imply that forensic RNA testing can be reliable and robust if degraded samples are considered in the marker ascertainment procedure, with promising expectations beyond tissue identification purposes.

Prevalence in Two-Phase Surveys: Accuracy of Screening Procedure and Corrected Estimates

Two-phase surveys often are used to estimate prevalence, in particular when the disease is rare or the case ascertainment procedure difficult and/or costly. However, few authors of such surveys take into account the sensitivity error associated with the use of a screening procedure in the first phase and its imprecision in correcting the prevalence estimate and confidence interval. Two examples of two-phase surveys of rheumatic diseases (hip and knee osteoarthritis, rheumatoid arthritis and spondyloarthropathies) are used to present methodological approaches to obtain corrected prevalence estimates. Two methods for assessing the accuracy of the screening procedure are described--two-phase pilot and case-control designs--that are best suited for frequent and rare diseases, respectively, and naive and corrected estimates of prevalence compared. When the sensitivity error is not taken into account, prevalence is underestimated, as is, especially, the width of its confidence interval. In our examples, the corrected confidence interval width increased up to 50% as compared with naïve one. The screening procedure accuracy should be thoroughly assessed in two-phase prevalence surveys and prevalence estimates and their confidence intervals corrected accordingly.

Polymorphisms in Interleukin-15 Gene on Chromosome 4q31.2 Are Associated with Psoriasis Vulgaris in Chinese Population

Through a series of linkage analyses in a large Chinese family cohort of psoriasis, we previously identified and confirmed a non-HLA psoriasis linkage locus PSORS9 within a small region at 4q31.2-32.1. Within the critical region of the PSORS9 locus, IL-15 has been long recognized as a strong candidate gene for psoriasis. In this study, we investigated the association between IL-15 genetic polymorphisms and psoriasis in a large Chinese sample. Highly significant evidence for association was identified at a single-nucleotide polymorphism (SNP) (g.96516A --> T) within the 3'-untranslated region (UTR) of the IL-15 gene (P=0.00006, after correction for multiple testing). Haplotype analysis using the SNPs within the 3'UTR region also provided strong supporting evidence for association (P=0.00005), where we identified a haplotype of the 3'UTR region of IL-15 associated with increased risk to psoriasis (odds ratio=1.65). This association was also supported by the results of our expression activity analyses, where we demonstrated that the identified risk haplotype is associated with an increased activity of IL-15. Therefore, we provided early evidence for the important role of IL-15 genetic variants in the pathogenesis of psoriasis, probably by increasing interleukin production and inflammation in the lesions of psoriasis.

Twin concordances test for ascertained trichotomous traits data

In human genetics, twin studies are widely underwent for investigation of the genetic influence on diseases. There are several measures that had been proposed to evaluate the similarity between two twins for dichotomous traits when the twins are sampled at random. These measures include the correlations, odds ratios, and casewise and pairwise concordances. When data are sampled through an ascertainment procedure, truncated data are formed. Under this circumstance, odds ratio cannot be defined and correlations cannot be correctly estimated. However, concordance measures for dichotomous traits can still be estimated using the likelihood method. On the other hand, though theoretically concordance measures can be extended to trichotomous traits, how to define them and to derive their estimators for ascertained trichotomous traits data have not been thoroughly discussed. In this study, we aim to address several relevant issues for ascertained trichotomous traits data. We define two new (casewise and pairwise) concordance measures for trichotomous traits and demonstrate how to apply a so-called 'self-contained subsets method (SCSM)' to estimation of twin concordances for ascertained data. We show that this method can obtain the same estimates as the likelihood method in an easier way and derive the asymptotic variances of the SCSM estimates under ascertainment. We establish the testing procedure for test of the equality of concordance measures between monozygotic twin pairs and dizygotic twin pairs, and illustrate the methods with a real data set and conduct Monte Carlo simulation to investigate its power performance.

Epidemiology and phenomenology of obsessive-compulsive disorder in non-referred young adolescents

The aim of this study was to investigate the frequency and phenomenology of obsessive-compulsive disorder (OCD) and subclinical OCD in a non-referred population of young Polish adolescents. A two stage ascertainment procedure (school screening and diagnostic evaluation) was used to identify affected individuals. In the first stage, 3,100 pupils were asked to complete the Polish version of the 20-item Leyton Obsessional Inventory-Child Version (LOI-CV). In the diagnostic stage, the presence of obsessions and compulsions was assessed with the author's structured interview questionnaire based on DSM-IV and ICD-10 diagnostic criteria for OCD; the Polish version of the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was used to rate the symptom severity. A frequency of 0.38 % was found for OCD and 2.7 % for subclinical OCD. There was no significant difference in the phenomenology, demographic characteristic or socio-familial variables comparing the diagnosed OCD and subclinical OCD subjects. The identified OCD cases had characteristics similar to those of previously described clinical and non-referred samples.

Persistence of Attention-Deficit/Hyperactivity Disorder into adulthood: what have we learned from the prospective follow-up studies?

Longitudinal studies of children with Attention-Deficit/Hyperactivity Disorder (ADHD) into adolescence have all reported high rates of ADHD. However, findings from studies into adulthood are inconsistent. This article reviews factors that may account for disparate rates found in adult follow-ups, and recommends optimal methodologies for prospective studies of children with ADHD in particular and childhood mental disorders in general. Follow-up studies of children with ADHD into adulthood are critically reviewed to identify factors that influence adult ADHD prevalence estimates. Four factors are identified: (1) ascertainment procedure, (2) attrition rate, (3) reporting source, and (4) disorder criteria. Estimates of the proportion of children with ADHD who will experience symptoms of the childhood syndrome in adulthood are likely to vary considerably, as a function of multiple factors. Several recommendations are made for designing future follow-up investigations.

New explicit expressions for relative frequencies of single-nucleotide polymorphisms with application to statistical inference on population growth.

We present new methodology for calculating sampling distributions of single-nucleotide polymorphism (SNP) frequencies in populations with time-varying size. Our approach is based on deriving analytical expressions for frequencies of SNPs. Analytical expressions allow for computations that are faster and more accurate than Monte Carlo simulations. In contrast to other articles showing analytical formulas for frequencies of SNPs, we derive expressions that contain coefficients that do not explode when the genealogy size increases. We also provide analytical formulas to describe the way in which the ascertainment procedure modifies SNP distributions. Using our methods, we study the power to test the hypothesis of exponential population expansion vs. the hypothesis of evolution with constant population size. We also analyze some of the available SNP data and we compare our results of demographic parameters estimation to those obtained in previous studies in population genetics. The analyzed data seem consistent with the hypothesis of past population growth of modern humans. The analysis of the data also shows a very strong sensitivity of estimated demographic parameters to changes of the model of the ascertainment procedure.

The prevalence of Tourette syndrome in 13-14-year-olds in mainstream schools.

This study's aim was to estimate the prevalence and describe the clinical characteristics of Tourette syndrome (TS) in 13-14-year-old schoolchildren attending mainstream secondary schools. A three-stage ascertainment procedure was used to identify those who had TS. First, all 1012 Year 9 pupils were screened for tics using validated self-report questionnaires, which were completed by parents, teachers, and pupils. Data were available from at least one informant for 918 (90.7%) subjects. Tics were identified in 189 (18.7%) pupils. Second, families were contacted and a semistructured interview was carried out to determine whether they had TS. Finally, to ensure that the diagnosis of TS was correct, all those assessed as having TS were systematically assessed by an expert clinician in the field of TS. Seven young people were identified as fulfilling the criteria for TS, giving a minimum prevalence rate amongst 13-14-year-olds of 0.76% (95% CI 0.31 to 1.57) and a more realistic estimate of 1.85% (95% CI 1.00 to 2.95). Behavioural problems, in particular hyperkinetic disorder, were frequently associated with the TS group. These findings lend further support to the contention that the prevalence of TS in the community has hitherto been underestimated, though the symptoms may be generally milder than cases of TS presenting to clinics. This study supports the need for vigilance for TS in school-age children in primary care and in educational settings, so that children with this potentially serious disorder can be identified and assessed and effective management packages can be formulated to address their needs, when necessary.

Variance-Components QTL linkage analysis of selected and non-normal samples: conditioning on trait values.

Standard variance-components quantitative trait loci (QTL) linkage analysis can produce an elevated rate of type 1 errors when applied to selected samples and non-normal data. Here we describe an adjustment of the log-likelihood function based on conditioning on trait values. This leads to a likelihood ratio test that is valid in selected samples and non-normal data, and equal in power to alternative methods for analyzing selected samples that require knowledge of the ascertainment procedure or the trait values of non-selected individuals.

Validation of linkage by sampling based on environmental exposures.

After detecting linkage in one sample, most researchers will attempt to validate this finding in another sample. Three strategies for validating a primary linkage were compared, with a focus on methods that might be appropriate in the presence of gene x environment interaction. First, a validation sample was collected and analyzed using the same ascertainment procedure and methods as the primary sample. Second, a sample of families with particular exposure patterns were ascertained subsequent to a significant test for heterogeneity due to the exposure in the primary sample. A third strategy ascertained by exposure status when exposure-defined subgroup tests were significant in the primary sample. The second strategy reduced the number of false positive linkage signals identified through exposure subgroup identification (i.e., the third strategy), but in this GAW11 data that contained no qualitative gene x environment interactions, it had poor sensitivity. Power to detect heterogeneity depends on the differences in risk between exposed and unexposed.

Concordance for sex and the pseudoautosomal gene hypothesis revisited: no evidence of increased sex concordance in a nationwide Finnish sample of siblings with paternally derived schizophrenia.

This study set out to determine, in a homogeneous sample with nationwide coverage in Finland, whether siblings treated for schizophrenia are more often of the same sex than expected by chance, and whether this is especially so when the disorder is transmitted by their fathers. Finnish social and health insurance files as well as hospital discharge registers were searched for probands with schizophrenia from a birth cohort spanning 30 years. Nuclear families were identified by cross-linkage with the national birth register, and the sex distribution observed in multiply affected sibships was compared with expected distributions by maximum likelihood analysis. In the subset of multiply affected sibships with one parent who had schizophrenia (84 fathers and 120 mothers), the observed sex distribution did not deviate from the expected pattern. However, a small and marginally significant excess of sex concordance emerged from the total sample of 1,942 sibships in which there were at least two affected members, irrespective of the parents' affection status. The results indicate that no above-chance sex concordance in sibships multiply affected with paternally transmitted schizophrenia is present in the genetically homogeneous population of Finland. In view of a virtually unbiased and complete ascertainment procedure and sample sizes one to two orders of magnitude larger than those in previous studies, the authors attribute prior findings of such a concordance to sampling artifacts or chance fluctuations and finally conclude that except for regional genetic isolates, there is no epidemiologic evidence that a gene accounting for substantial susceptibility to schizophrenia in a greater proportion of cases resides in the pseudoautosomal region of the sex chromosomes.

Ascertainment models incorporating effects of variable age of onset

In pedigree analysis, nonrandom sampling, or ascertainment through affected persons, occurs commonly, making it necessary to adjust appropriately for the ascertainment procedure in order to secure the correct interpretation of results from genetic analysis. Ascertainment models for dichotomous phenotypes are considered for disorders characterized by variable age of onset, particularly considering those instances where the probability of ascertainment may be influenced by the age of onset of the disorder. For a variety of theoretical and practical reasons, sigmoidal functions appear to be well suited to the modeling of occurrence of a binary event, such as proband status. Relevant ascertainment models incorporating a modified exponential ascertainment function having such a sigmoidal form are described, together with associated modifications to the likelihood for the ascertained pedigree. Alternative parameterizations and methods for obtaining initial estimates are also discussed.

Incidence of MS during two fifteen-year periods in the Gothenburg region of Sweden

The average annual incidence of definite and probable MS in Gothenburg was re-investigated. For 1950-1954, 1955-1959 and 1960-1964 it was 4.2, 4.2 and 4.3/100,000/year. For the five-year periods between 1974 and 1988 it was 3.0, 2.7 and 2.0/100,000/year. If possible MS was included, the corresponding incidence for 1950-1964 was 5.2, 5.3 and 5.1, and for 1974-1988 it was 3.9, 3.9 and 4.3/100,000/year. Neurological methods and diagnostic criteria were constant throughout the period. The 1950-1964 incidence was based on personally investigated cases, while the 1974-1988 incidence was based partly on review of Gothenburg neurology records. It is concluded that there has been a significant decrease in the incidence of MS in this area. However, the notified decrease may partly be explained by alterations in the case ascertainment procedure. Since the Swedish measles vaccination program started in 1971, the occurrence of measles has been declining and has practically ceased during the 1980s. The time when a possible influence of mass vaccinations against childhood diseases on MS incidence can be monitored is discussed.

A resolution of the ascertainment sampling problem: IV. Continuous phenotypes.

This paper considers ascertainment corrections for continuous phenotypes. Two main points are considered. The first is a discussion of what ascertainment corrections can be devised to ensure asymptotically unbiased parameter estimates when the nature of the ascertainment procedure is not known. The second is an analysis of the properties of various forms of ascertainment correction possible when the nature of the ascertainment procedure is known. Some ascertainment corrections are thus shown to be valid and others invalid.