Total hip reconstruction in a woman with Cornelia de Lange syndrome: a case report.

More than 250 cases of Cornelia de Lange syndrome have been reported in the medical literature, but not have described the use of hip reconstruction to correct the congenital dysplasia that may be associated with this condition. This article reports the application of a bipolar hemiarthroplasty and acetabular allograft reconstruction for a 32-year old woman with congenital dysplasia and degenerative joint disease of the hip secondary to de Lange''s syndrome. On admission, she was in considerable pain and unable to bear weight on the affected extremity. Her Harris hip score was 25. Following surgical intervention and a well-designed plan of rehabilitation, the patient''s functional status improved markedly. Her Harris hip score was 72, and her pain was alleviated.     

Ignoring Distant Genealogic Loops Leads to False-positives in Homozygosity Mapping

Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data.     

Anger and childhood sexual abuse are independently associated with irritable bowel syndrome

Objectives. Irritable bowel syndrome (IBS) presents in the absence of identifiable organic pathology. Clinical and research literature has suggested that both childhood abuse and anger are linked to functional gastrointestinal conditions including IBS. The present study tested the predictions that IBS patients, when compared to patients with an organic bowel disease (Crohn's disease), have higher levels of trait and suppressed anger, and that these mediate the link between abuse and IBS. Design. The study was a cross‐sectional multivariate comparison between groups of patients with IBS and Crohn's disease. Method. Levels of self‐reported trait and suppressed anger and recalled childhood abuse in patients with IBS (N =75) or Crohn's disease (N =76) were compared, using self‐report questionnaires and controlling for other psychological characteristics (anxiety, depression, and dissociation). Results. Trait and suppressed anger were greater in IBS patients, and differences in trait anger remained significant after controlling for other psychological variables. Childhood sexual abuse was more prevalent in IBS than Crohn's disease patients but was unrelated to trait anger. Conclusions. Higher levels of anger characterize IBS patients when compared to an organic bowel disease group, but do not explain the link between childhood abuse and IBS.     

The Sib TDT Adjusted For Age Of Disease Onset

Since the Sib‐TDT ( Spielman & Ewens, 1998 ) ignores age of disease onset, there could be loss of power in detecting linkage. In this article, we propose an adjustment for age of onset using the Cox Proportional Hazard Model ( Cox, 1972 ) with the marker allele as a covariate. The test statistic for linkage is identical to the traditional Sib‐TDT. Monte‐Carlo simulations are performed under different disease models to assess the increase in power of the age‐adjusted Sib‐TDT compared to the traditional Sib‐TDT. We extend our method to multiallelic markers. An application using data on Alzheimer's Disease is also presented.     

A Note on Allelic Tests in Case-Control Association Studies

This paper reconsiders the relevant contribution of Sasieni in the validity of allele‐based tests in case‐control genetic association studies. In particular, the author clearly demonstrates that the classical chi‐square test applied to allelic contingency tables is biased when the combined case‐control population is not in Hardy‐Weinberg equilibrium. As an alternative, he suggests using the Cochran‐Armitage test for trends by basing his argument on the fact that these two tests are asymptotically equivalent at the Hardy‐Weinberg equilibrium. However he only demonstrates the equality of the statistics when the observed genotypic proportions are strictly in equilibrium ‐ which does not formally imply the suggested, and often accepted, asymptotic behavior. In this short communication, we complement this contribution by providing the proof that allelic and trend statistics are asymptotically equivalent under the conditions mentioned above. In addition, since the ‘biased’ allelic test is still widely used in the literature, we briefly discuss the different alternatives that have been subsequently developed, based on Sasieni's conclusions.     

Serologic screening for celiac disease in children: a comparison between established assays and tests with deamidated gliadin‐derived peptides plus conjugates for both IgA and IgG antibodies

Selection of patients for diagnostic biopsy concerning celiac disease (CD) is mainly guided by the results with serological screening tests like anti‐tissue‐transglutaminase (tTG), anti‐endomysium (EmA) and anti‐gliadin (AGA) IgA. New tests using deamidated gliadin‐derived peptides (DGP) including both IgA and IgG antibodies have been developed, to cover the IgA‐deficient sera. In addition, a combined IgA and IgG DGP test, with or without human erythrocyte‐derived tTG, offers possible advantages. In order to explore the screening accuracy of the new combination tests sera from 167 children below 3 years of age were assayed. Biopsy had been taken in connection with serology in 32 of these children, 24 with histopathological CD. The results with the DGP and the combined test were congruent with the IgA antibody tests for tTG, EmA and AGA, all identifying 21 of 24 of the CD cases. Two of the CD patients were AGA‐IgA positive only (2/24), while 2 of 24 sera were AGA–IgA negative but positive in all the other tests. These results raises the question whether the modifications of the gliadin antigen not only decrease false positivity but also give more false‐negative results, a major drawback for a screening test for an important disease. Further studies have to be undertaken to explore this. Our results also stress that serologic screening of CD in children cannot be based on one test only.     

Investigation of linkage and association/linkage disequilibrium of HLA A‐, DQA1‐, DQB1‐, and DRB1‐alleles in 69 sib‐pair‐ and 89 trio‐families with schizophrenia

The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib‐pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA‐ DRB1*11 (chi‐square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301—DQA1*501—DRB1*11 (chi‐square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31. © 2002 Wiley‐Liss, Inc.     

The Essence of Linkage‐based Imprinting Detection: Comparing Power,Type 1 Error,and the Effects of Confounders in Two Different Analysis Approaches

Imprinting is critical to understanding disease expression. It can be detected using linkage information, but the effects of potential confounders (heterogeneity, sex‐specific penetrance, and sex‐biased ascertainment) have not been explored. We examine power and confounders in two imprinting detection approaches, and we explore imprinting‐linkage interaction. One method (PP) models imprinting by maximising lod scores w.r.t. parent‐specific penetrances. The second (DRF) approximates imprinting by maximising lods over differential male‐female recombination fractions. We compared power, type 1 error, and confounder effects in these two methods, using computer‐simulated data. We varied heterogeneity, penetrance, family and dataset size, and confounders that might mimic imprinting. Without heterogeneity, PP had more imprinting‐detecting power than DRF. PP's power increased when parental affectedness status was ignored, but decreased with heterogeneity. With heterogeneity, type 1 error increased dramatically for both methods. However, DRF's power also increased under heterogeneity, more than was attributable to inflated type 1 error. Sex‐specific penetrance could increase false positives for PP but not for DRF. False positives did not increase on ascertainment through an affected “mother”. For PP, non‐penetrant individuals increased information, arguing against using affecteds‐only methods. The high type 1 error levels under some circumstances means these methods must be used cautiously.     

On the validity of the likelihood ratio test and consistency of resulting parameter estimates in joint linkage and linkage disequilibrium analysis under improperly specified parametric models

It has been shown that parametric analysis of linkage disequilibrium conditional on linkage using an overly deterministic model can be optimal for family-based association analysis. However, if one applies this strategy carelessly, there is a risk of false inference. We analyse properties of such likelihood ratio tests when the assumed disease mode of inheritance is inaccurate. Under some conditions, problems result if one is not careful to consider what null hypothesis is being tested. We show that: (a) tests for which the null hypothesis assumes the absence of both linkage and association are independent of the true mode of inheritance; (b) likelihood ratio tests assuming either linkage or association under the null hypothesis may depend on the true mode of inheritance, leading to inconsistent parameter estimates, in particular under extremely deterministic models; (c) this problem cannot be eliminated by increasing sample size or adding population controls--as sample size increases, the chance of false positive inference goes to 100%; (d) this issue can lead to systematic false positive inference of association in regions of linkage. This is important because highly deterministic models are often used intentionally in model-based analyses because they can have more power than the true model, and are implicit in many model-free analysis methods.     

Multiple Testing in the Context of Haplotype Analysis Revisited: Application to Case-Control Data

We have lately presented a testing procedure for family data which accounts for the multiple testing problem that is induced by the enormous number of different marker combinations that can be analyzed in a set of tightly linked markers. Most methods of haplotype based association analysis already require simulations to obtain an uncorrected P value for a specific marker combination. As shown before, it is nevertheless not necessary to carry out nested simulations to obtain a global P value that properly corrects for the multiple testing of different marker combinations without neglecting the dependency of the tests. We have now implemented this approach for case‐control data in our program FAMHAP, as this data structure currently plays a dominant role in the field. We consider different ways to deal with phase ambiguities and two different statistical tests for the underlying single marker combinations to obtain uncorrected P values. One test statistic is chi‐square based, the other is a haplotype trend regression. The performance of these different tests in the multiple testing situation is investigated in a large simulation study. We obtain a considerable gain in power with our global P values as opposed to Bonferroni corrected P values for all suggested test statistics. Good power was obtained both with the haplotype trend regression approach as well as with the simpler chi‐square based test. Furthermore, we conclude that the better strategy to deal with phase ambiguities is to assign to each individual its list of weighted haplotype explanations, rather than to assign to each individual its most likely haplotype explanation. Finally, we demonstrate the usefulness of our approach by a real data example.     

A novel method,the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

The Human Genome Project was expected to individualize medicine by rapidly advancing knowledge of common complex disease through discovery of disease-causing genetic variants. However, this has proved challenging. Although linkage analysis has identified replicated chromosomal regions, subsequent detection of causal variants for complex traits has been limited. One explanation for this difficulty is that utilization of association to follow up linkage is problematic given that linkage and association are not required to co-occur. Indeed, co-occurrence is likely to occur only in special circumstances, such as Mendelian inheritance, but cannot be universally expected. To overcome this problem, we propose a novel method, the Variant Impact On Linkage Effect Test (VIOLET), which differs from other quantitative methods in that it is designed to follow up linkage by identifying variants that influence the variance explained by a quantitative trait locus. VIOLET''s performance was compared with measured genotype and combined linkage association in two data sets with quantitative traits. Using simulated data, VIOLET had high power to detect the causal variant and reduced false positives compared with standard methods. Using real data, VIOLET identified a single variant, which explained 24% of linkage; this variant exhibited only nominal association (P=0.04) using measured genotype and was not identified by combined linkage association. These results demonstrate that VIOLET is highly specific while retaining low false-negative results. In summary, VIOLET overcomes a barrier to gene discovery and thus may be broadly applicable to identify underlying genetic etiology for traits exhibiting linkage.     

High Resolution T2 Association Tests of Complex Diseases Based on Family Data

This paper proposes family based Hotelling's T² tests for high resolution linkage disequilibrium (LD) mapping or association studies of complex diseases. Assume that genotype data of multiple markers or haplotype blocks are available for a sample of nuclear families, in which some offspring are affected. Paired Hotelling's T² test statistics are proposed for a high resolution association study using parents as controls for affected offspring, based on two coding methods: haplotype/allele coding and genotype coding. The paired Hotelling's T² tests take not only the correlation between the haplotype blocks or markers into account, but also take the correlation within each parent‐offspring pair into account. The method extends two sample Hotelling's T² test statistics for population case control association studies, which are not valid for family data due to correlation of genetic data among family members. The validity of the proposed method is justified by rigorous mathematical and statistical proof under the large sample theory. The non‐centrality parameter approximations of the test statistics are calculated for power and sample size calculations. From power comparison and type I error calculations, it is shown that the test statistic based on haplotype/allele coding is advantageous over the test statistic of genotype coding. Analysis using multiple markers may provide higher power than single marker analysis. If only one marker is utilized the power of the test statistic based on haplotype/allele coding is nearly identical to that of 1‐TDT. Moreover, a permutation procedure is provided for data analysis. The method is applied to data from a German asthma family study. The results based on the paired Hotelling's T² statistic tests confirm the previous findings. However, the paired Hotelling's T² tests produce much smaller P‐values than those of the previous study. The permutation tests produce similar results to those of the previous study; moreover, additional marker combinations are shown to be significant by permutation tests. The proposed paired Hotelling's T² statistic tests are potentially powerful in mapping complex diseases. A SAS Macro, Hotel_fam.sas, has been written to implement the method for data analysis.     

Population stratifications can cause false positive linkage results if founders are untyped

We wish to draw attention to the fact that population stratifications can produce a bias towards yielding false positive linkage results when founder genotypes are missing. It is now fairly well known that misspecification of allele frequencies can produce such a bias - if a common allele is misspecified as rare then the fact that it is frequently observed among affected individuals will be incorrectly taken as evidence of increased sharing of alleles identical-by-descent (Ott, 1992). What may be less widely recognized is that similar effects can occur even if the correct population allele frequencies are used. Independently of us, Miller et al. (1995) and Gu et al. (1995) have recently shown that population stratifications can produce false positive linkage results for Lange's (1985) identity-by-state affected sib-set analysis and for the affected-pedigree-member method (APM, Weeks & Lange, 1988). In fact, the problem applies to any method of linkage analysis when applied to datasets with untyped founders.     

A Comparison of the Likelihood Ratio Test and the Variance‐Stabilising Transformation‐Based Tests for Detecting Association of Rare Variants

In a recent paper in this journal, the use of variance‐stabilising transformation techniques was proposed to overcome the problem of inadequacy in normality approximation when testing association for a low‐frequency variant in a case‐control study. It was shown that tests based on the variance‐stabilising transformations are more powerful than Fisher's exact test while controlling for type I error rate. Earlier in the journal, another study had shown that the likelihood ratio test (LRT) is superior to Fisher's exact test, Wald's test, and Pearson's χ² test in testing association for low‐frequency variants. Thus, it is of interest to make a direct comparison between the LRT and the tests based on the variance‐stabilising transformations. In this commentary, we show that the LRT and the variance‐stabilising transformation‐based tests have comparable power greater than Fisher's exact test, Wald's test, and Pearson's χ² test.     

Linkage studies between attention‐deficit hyperactivity disorder and the monoamine oxidase genes

Attention‐deficit hyperactivity disorder (ADHD) is a prevalent behavioral disorder in children and the etiology of this disorder is not clear. Molecular genetic and pharmacological studies suggest the involvement of dopaminergic and noradrenergic neurotransmitter systems in ADHD, e.g., several reports have found association between ADHD and the dopamine receptor gene DRD‐4, the dopamine transporter gene DAT1, and the catecholamine clearance enzyme catechol‐O‐methyltransferase. Monoamine oxidase (MAO) A and B genes encode enzymes that participate in the metabolism of neurotransmitters of the dopaminergic and noradrenergic systems. MAO inhibitors have been shown to be effective in the treatment of ADHD. Our previous studies showed an association between ADHD and the DXS7 locus, which is located in close vicinity to the MAO genes on chromosome X. These findings suggest that there might be linkage between ADHD and MAO genes. To test this hypothesis, we used the transmission/disequilibrium test (TDT) to test for linkage between a VNTR polymorphism at the MAOA(CA)_n or MAOB(GT)_n locus and DSM‐III‐R–diagnosed ADHD in 82 nuclear families of the Chinese population. The TDT analysis revealed linkage between ADHD and the MAOA(CA)_n locus (chi‐square = 15.25, df = 7, P < 0.05), but not the MAOB(GT)_n locus (chi‐square = 11.18, df = 7, P > 0.05). The data showed that ADHD was in linkage with the MAOA gene and suggested that MAOA might be a susceptibility factor for ADHD. © 2001 Wiley‐Liss, Inc.     

Candidate genes in psychiatry: An epidemiological perspective

Interest in candidate genes in psychiatry has been revived by the success of that approach in Alzheimer's disease as well as by discouragement over the results to date of searches for linkage. If mutations in candidate genes could be detected directly many of the complexities of searching for them indirectly through linkage could be avoided. As attractive as this approach may sound, mutation searches with candidate genes will introduce a new set of difficulties: the large number and low a priori probability of potential candidate genes virtually guarantees that most positive findings will be false positives. Consequently, if candidate genes are to be systematically studied, procedures need to be established for minimizing and efficiently disconfirming false positive results. © 1993 Wiley-Liss, Inc.     

Usual statistical methods for studying HLA-disease associations and linkages

Statistical methods used for the study of correlation and/or linkage between HLA and diseases susceptibility will be different according to the aim of the study. In case of a search of an association between disease character and HLA markers in unrelated populations, the methodology used will be based upon chi square and Relative Risk. In case of linkage study: multiplex families with 2 or more patients bring the most informative data. In all cases, a particular attention must be paid to criteria used for selection of patients and controls, and for studies of linkage to the hypothesis concerning mode of inheritance and penetrance required by the model chosen.     

A quick and simple method for detecting subjects with abnormal genetic background in case-control samples

It is important that case-control samples be drawn from a genetically homogeneous population in order to avoid artefactual false positive results and to enhance power to detect disease mutations and markers in linkage disequilibrium with them. Tests which simply compare overall marker allele frequencies between cases and controls will fail to identify a relatively small number of subjects drawn from a different genetic background who could usefully be discarded from the sample. Such subjects can be identified using multilocus tests, but previously described tests have been unnecessarily complex and cumbersome for this simple application. We describe a straightforward test, implemented in the CHECKHET program, which uses a measure of genetic difference and permutation procedures to rapidly identify such subjects using genotypes from multiple unlinked markers. It seems to perform reasonably well on simulated data, and with real data appears to identify two abnormal subjects within a case-control sample. We recommend that such tests be routinely applied to case-control samples once sufficient numbers of markers have been genotyped within them.     

No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family‐based study of a Palestinian Arab population

Several recent meta‐analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact‐prone case‐control design, we thought it worthwhile to examine the role of this polymorphism using a robust family‐based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi‐square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi‐square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778–780, 2000. © 2000 Wiley‐Liss, Inc.     

A family‐based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi‐square = 0.00, NS). © 2001 Wiley‐Liss, Inc.