Case-control Family Study Research Articles

Cardiovascular diseases in grandparents and the risk of congenital heart diseases in grandchildren.

Hyperglycemia, dyslipidemia and hyperhomocysteinemia are associated with both adult cardiovascular disease (CVD) and having a child with a congenital heart disease (CHD). We investigated associations between CVD in grandparents and the risk of CHD in grandchildren. In a case-control family study, we obtained detailed questionnaire information on CVD and CHD in 247 families with a CHD child and 203 families without a CHD child. Grandparents with CVD or intermittent claudication (IC) were significantly associated with an increased risk for CHD in grandchildren [OR 1.39 (95% CI 1.03-1.89) and OR 2.77 (95% CI 1.02-7.56), respectively]. The risk of CHD grandchildren was particularly increased in paternal grandfathers with CVD [OR 1.85 (95% CI 1.01-3.37)]. Overall, having a grandparent with CVD increased the risk for CHD in the grandchild by 1.65 (95% CI 1.12-2.41). After adjustment for potential maternal confounders, this risk was 1.44 (95% CI 0.94-2.21). Having two or more grandparents with CVD was associated with an approximately threefold risk for CHD grandchildren [OR adjusted 2.72 (95% CI 1.08-6.89)]. Our data suggest that CVD and IC in grandparents are associated with an increased risk of having a CHD grandchild. These first findings may be explained by shared causality of derangements in metabolic pathways and are in line with the fetal origins of health and disease.

Association of genetic risk severity with ADHD clinical characteristics

This study sought to examine the association between the cumulative risk severity conferred by the total number of attention-deficit/hyperactivity disorder (ADHD) risk alleles of the DAT1 3'UTR variable number tandem repeat (VNTR), DRD4 Exon 3 VNTR, and 5-HTTLPR with ADHD characteristics, clinical correlates, and functional outcomes in a pediatric sample. Participants were derived from case-control family studies of boys and girls diagnosed with ADHD, a genetic linkage study of families with children with ADHD, and a family genetic study of pediatric bipolar disorder. Caucasian children 18 and younger with and without ADHD and with available genetic data were included in this analysis (N = 591). The association of genetic risk severity with sociodemographic, clinical characteristics, neuropsychological, emotional, and behavioral correlates was examined in the entire sample, in the sample with ADHD, and in the sample without ADHD, respectively. Greater genetic risk severity was significantly associated with the presence of disruptive behavior disorders in the entire sample and oppositional defiant disorder in participants with ADHD. Greater genetic risk severity was also associated with the absence of anxiety disorders, specifically with the absence of agoraphobia in the context of ADHD. Additionally, one ADHD symptom was significantly associated with greater genetic risk severity. Genetic risk severity is significantly associated with ADHD clinical characteristics and co-morbid disorders, and the nature of these associations may vary on the type (externalizing vs. internalizing) of the disorder.

Tobacco habits in nocturnal frontal lobe epilepsy

The beneficial effect of nicotine has been reported in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) patients, but not tested in sporadic cases. Recently, a nicotine defect in the arousal pathway has been hypothesized even in sporadic NFLE patients and their relatives. This case–control family study was designed to test whether NFLE subjects were more likely to use tobacco than controls, as an indirect marker of cholinergic arousal system dysregulation. At least four relatives were included for each NFLE proband and control. Each subject was questioned about tobacco habits; 434 individuals were recruited. Moreover, we compared NFLE patients with age- and sex-matched controls to determine whether they are more likely to use tobacco. We found a slightly higher trend of tobacco use in NFLE probands compared to that in control subjects; we did not find any significant difference in the distribution of tobacco use among NFLE group compared to that in the control group.

Robust methods for detecting familial aggregation of a quantitative trait in matched case–control family studies

Assessing familial aggregation of a disease or its underlying quantitative traits is often undertaken as the first step in the investigation of possible genetic causes. When some major confounding variables are known and difficult to be quantified, the matched case–control family design provides an opportunity to eliminate biased results. In such a design, cases and matched controls are ascertained first, with subsequent recruitment of other members in their families. For the study of complex diseases, many continuously distributed quantitative traits or biomedical evaluations are of primary clinical and health significance, and distributions of these continuous outcomes are frequently skewed or non-normal. A non-normal distributed outcome may lead some standard statistical methods to suffer from loss of substantial power. To deal with the problem, in this study, we thus propose a rank-based test for detecting familial aggregation of a quantitative trait with the use of a within-cluster resampling process. According to our simulation studies, the proposed test expresses qualified and robust power performance. Specifically, the proposed test is slightly less powerful than the generalized estimating equations approach if the trait is normally distributed, and it is apparently more powerful if the trait distribution is essentially skewed or heavy-tailed. A user-friendly R-script and an executable file to perform the proposed test are available online to allow its implementation on ordinary research.

Cigarette smoking as a risk factor for other substance misuse: 10-year study of individuals with and without attention-deficit hyperactivity disorder

We previously documented that cigarette smoking is a risk factor for subsequent alcohol and drug misuse and dependence in adolescent girls with attention-deficit hyperactivity disorder (ADHD). To revisit this hypothesis with a large longitudinal sample of both genders followed up for 10 years into young adulthood. We used data from two identically designed, longitudinal, case-control family studies of boys and girls with and without ADHD ascertained from psychiatric and paediatric sources. We studied 165 individuals with ADHD and 374 controls followed up longitudinally and masked for 10 years. We assessed ADHD, smoking and substance use status using structured diagnostic interviews. We tested the association between cigarette smoking and subsequent substance use outcomes using Cox proportional hazard regression models. Youth with ADHD who smoked cigarettes (n = 27) were significantly more likely to subsequently develop drug misuse and dependence compared with youth with ADHD who did not smoke (n = 138, P<0.05). These results confirm that cigarette smoking increases the risk for subsequent drug and alcohol use disorders among individuals with ADHD. These findings have important public health implications, and underscore the already pressing need to prevent smoking in children with ADHD.

Familial aggregation of idiopathic normal pressure hydrocephalus: Novel familial case and a family study of the NPH triad in an iNPH patient cohort

ObjectiveIdiopathic normal pressure hydrocephalus (iNPH) is considered sporadic, yet familial cases involving single pedigrees are being increasingly recognized. As current evidence does not extend beyond isolated pedigrees, we aimed to determine the putative heritability of iNPH by examining the prevalence of the iNPH triad among the family members of iNPH probands. MethodWe present a case–control family study of the iNPH symptom triad among the relatives of iNPH patients (n=20) identified from a cohort of patients undergoing CSF diversion and matched comparison subjects (n=21). A total of 291 first-degree relatives from 41 families were characterized using semi-structured family history interviews. Independent from the family study, we present a novel well-characterized familial case of iNPH. Results≥2 insidious, progressive and idiopathic iNPH symptoms were identified among first degree relatives in 6 iNPH pedigrees (2 multiply affected) and 1 control pedigree, with an incidence of 7.1% among iNPH relatives and 0.7% among control relatives (OR=11.53). Gait disturbance and memory impairment began at a younger age among the relatives of iNPH probands. Independent of our family study, we present a novel case report of a large iNPH pedigree with multiple affected relatives. InterpretationOur family study and novel familial case suggest familial aggregation of iNPH. A larger family study with full characterization of affected and unaffected relatives is warranted. Confirmation of heritability may allow identification of individuals at high-risk for iNPH, early intervention, and improved aetiological elucidation.

Are obstetrical, perinatal, and infantile difficulties associated with pediatric bipolar disorder?

Despite increasing acknowledgement of bipolar disorder (BD) in childhood, there is a paucity of literature that has investigated obstetrical, perinatal, and infantile difficulties and their potential link with BD. To this end, we examined difficulties during delivery, immediate post-birth, and infancy and the association with BD in childhood. From two similarly designed, ongoing, longitudinal, case-control family studies of pediatric BD (N = 327 families), we analyzed 338 children and adolescents [mean (± standard deviation) age: 12.00 ± 3.37 years]. We stratified them into three groups: healthy controls (N = 98), BD probands (N = 120), and their non-affected siblings (N = 120). All families were comprehensively assessed with a structured psychiatric diagnostic interview for psychopathology and substance use. Mothers were directly questioned regarding the pregnancy, delivery, and infancy difficulties that occurred with each child using a module from the Diagnostic Interview for Children and Adolescents-Parent Version (DICA-P). Mothers of BD subjects were more likely to report difficulties during infancy than mothers of controls [odds ratio (95% confidence interval) = 6.6 (3.0, 14.6)]. Specifically, children with BD were more likely to have been reported as a stiffened infant [7.2 (1.1, 47.1)] and more likely to have experienced 'other' infantile difficulties [including acting colicky; 4.9 (1.3, 18.8)] compared to controls. We found no significant differences between groups in regards to obstetrical or perinatal difficulties (all p values > 0.05). While our results add to previous literature on obstetrical and perinatal difficulties and BD, they also highlight characteristics in infancy that may be prognostic indicators for pediatric BD.

Familial Autoimmunity in Systemic Sclerosis — Results of a French-based Case-Control Family Study

To assess the prevalence of autoimmune diseases in first-degree relatives of patients with systemic sclerosis (SSc), and to compare those results with control families in order to identify patterns of autoimmune diseases in relatives. A retrospective case-control postal questionnaire survey was performed in France to recruit patients with SSc belonging to an association of patients with SSc and unrelated age-matched and sex-matched controls. Each participant was asked to self-report on the existence of autoimmune diseases in their first-degree relatives. The prevalence of autoimmune diseases in the families of patients with SSc was compared with the corresponding prevalence in the families of controls. A total of 121 families out of 373 (32.4%) with a member having SSc reported at least 1 autoimmune disease in 1 or more first-degree relatives. The most frequent autoimmune diseases in SSc families when adjusted for family size were autoimmune thyroid disease (AITD; 4.9%), rheumatoid arthritis (4.1%), psoriasis (3.9%), and type 1 diabetes mellitus (2.9%). Compared with control families, AITD and connective tissue diseases (SSc, systemic lupus erythematosus, or Sjögren's syndrome) were more likely to occur in families with SSc (p = 0.01 and p = 0.01, respectively), with OR of 3.20 (95% CI 1.25-8.18) and 5.20 (95% CI 1.22-21.8). In contrast, inflammatory bowel disease was less likely to occur within families with SSc (p = 0.02, OR 0.29, 95% CI 0.11-0.80). In addition, the coexistence of more than 1 autoimmune disease in the index SSc case was associated with familial aggregation of autoimmune diseases. Our results show that autoimmune diseases cluster within families of patients with SSc. This supports the notion that these diseases might arise on a shared genetic basis underlying several autoimmune phenotypes.

Rare variants in the ATMgene and risk of breast cancer

IntroductionThe ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.MethodsTo investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants.ResultsIn the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant.ConclusionsThe risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.

Missing genetic information in case-control family data with general semi-parametric shared frailty model

Case-control family data are now widely used to examine the role of gene-environment interactions in the etiology of complex diseases. In these types of studies, exposure levels are obtained retrospectively and, frequently, information on most risk factors of interest is available on the probands but not on their relatives. In this work we consider correlated failure time data arising from population-based case-control family studies with missing genotypes of relatives. We present a new method for estimating the age-dependent marginalized hazard function. The proposed technique has two major advantages: (1) it is based on the pseudo full likelihood function rather than a pseudo composite likelihood function, which usually suffers from substantial efficiency loss; (2) the cumulative baseline hazard function is estimated using a two-stage estimator instead of an iterative process. We assess the performance of the proposed methodology with simulation studies, and illustrate its utility on a real data example.

Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: A common mechanism?

Retrospective observations disclosed an overlap between parasomnias and nocturnal frontal lobe epilepsy (NFLE) not only in patients but also in their relatives, suggesting a possible common pathogenetic mechanism. This study aimed to verify whether relatives of patients with NFLE have a higher frequency of parasomnias, namely arousal disorders, and thereby shed light on the still unknown pathophysiologic mechanisms underlying NFLE. We undertook a case-control family study in which we recruited NFLE probands and healthy controls, matched for age, sex, education, and geographic origin. At least four relatives were included for each proband and control. Each subject underwent a standardized interview, with application of the International Classification of Sleep Disorders-Revised (ICSD-R 2001) minimal criteria to diagnose the lifetime prevalence of the main parasomnias. Four hundred fifty-eight individuals were recruited: 33 NFLE probands, 200 relatives of probands, 31 controls, and 194 control relatives. All NFLE probands but one have sporadic NFLE. The lifetime prevalence of the following parasomnias differed in proband relatives versus control relatives: arousal disorders [odds ratio (OR) 4.7, 95% confidence interval (CI) 2.0-11.6; p < 0.001] and nightmares (OR 2.6, 95% CI 1.6-4.2; p < 0.001) were more frequent among NFLE proband relatives. In the secondary analysis comparing NFLE probands to controls, arousal disorders (OR 6.3, 95% CI 1.3-31.7; p = 0.023) and bruxism (OR 5.4, 95% CI 1.3-21.7; p = 0.017) were more frequent among NFLE probands. The higher frequency of arousal disorders in NFLE families suggests an intrinsic link between parasomnias and NFLE and an abnormal (possibly cholinergic) arousal system as a common pathophysiologic mechanism.

Estimating Disease Prevalence Using Relatives of Case and Control Probands

We introduce a method of estimating disease prevalence from case-control family study data. Case-control family studies are performed to investigate the familial aggregation of disease; families are sampled via either a case or a control proband, and the resulting data contain information on disease status and covariates for the probands and their relatives. Here, we introduce estimators for overall prevalence and for covariate-stratum-specific (e.g., sex-specific) prevalence. These estimators combine the proportion of affected relatives of control probands with the proportion of affected relatives of case probands and are designed to yield approximately unbiased estimates of their population counterparts under certain commonly made assumptions. We also introduce corresponding confidence intervals designed to have good coverage properties even for small prevalences. Next, we describe simulation experiments where our estimators and intervals were applied to case-control family data sampled from fictional populations with various levels of familial aggregation. At all aggregation levels, the resulting estimates varied closely and symmetrically around their population counterparts, and the resulting intervals had good coverage properties, even for small sample sizes. Finally, we discuss the assumptions required for our estimators to be approximately unbiased, highlighting situations where an alternative estimator based only on relatives of control probands may perform better.

The influence of sex on the course and psychiatric correlates of ADHD from childhood to adolescence: A longitudinal study

Little is known about the influence of sex on the course of attention-deficit/hyperactivity disorder (ADHD) and its comorbid psychiatric conditions. The purpose of this study was to examine the effect of sex on the course and psychiatric correlates of ADHD from childhood into adolescence. Two identically designed, longitudinal, case-control family studies of male and female probands with and without ADHD and their siblings were combined. All subjects were blindly assessed with structured diagnostic interviews. Among subjects with a lifetime history of ADHD (n = 471, mean age 11.5 +/- 4.3 years at baseline), we used linear growth curve models to estimate the effect of time on the change in ADHD symptoms, and whether this effect differed by sex. We also we examined the effect of sex on the association between ADHD and the longitudinal progression of comorbid psychopathology using structural equation models. We found no evidence that sex moderated the effect of age on ADHD symptoms; in both genders, age exhibited a similar effect on the decline of ADHD symptoms. However, the female sample demonstrated greater stability in comorbid psychopathology from childhood into adolescence. Furthermore, we found that the stability of comorbid psychopathology in females remained significant after accounting for the correlation between adolescent psychopathology and adolescent ADHD. In males, childhood and adolescent comorbid psychopathology were no longer correlated when adolescent ADHD was taken into account. Our findings indicate that while the course of ADHD across childhood and adolescence did not differ between males and females, patterns of psychiatric comorbidity were conditional on sex. Future studies should explicitly test how sex modifies the associations between ADHD and risk factors and ADHD and associated functional outcomes.

VEGF Polymorphisms Are Associated With Endocardial Cushion Defects: A Family-Based Case-Control Study

Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGF gene -2578 C>A, -1154 G>A, and -634 G>C play a role in cardiogenesis. In a Dutch case-control family study of triads, 190 case and 317 control children with both parents, we investigated linkage and association between these VEGF SNPs and ECD. Allele frequencies for the three VEGF SNPs were comparable between ECD children and controls. However, VEGF alleles -2578 C and -1154 G were transmitted more frequently to children with ECD (p = 0.003 and p = 0.002), in particular perimembranous ventricular septal defects (p = 0.012 and p = 0.006). The -2578A/-1154A/-634G haplotype was associated with a reduced risk of ECD (OR 0.7; 95% CI, 0.6-1.0) and was significantly less transmitted to children with ECD (p = 0.002). In a Dutch population, we show that the VEGF 2578 C, -1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGF gene-environment interactions exposures are discussed. :

Effect of candidate gene polymorphisms on the course of attention deficit hyperactivity disorder

The main aim of this study was to examine the association between attention-deficit hyperactivity disorder (ADHD)-associated genes and the course of ADHD. Subjects were derived from identically designed case-control family studies of boys and girls with ADHD and a genetic linkage study of families with children with ADHD. Caucasian probands and family members with ADHD and with available genetic data were included in this analysis ( N = 563). The course of ADHD was compared in subjects with and without putative risk alleles ( DRD4 7-repeat allele, DAT1 10-repeat allele, and 5HTTLPR long allele). The persistence of ADHD (full or subthreshold diagnosis in the last month) was plotted using Kaplan-Meier survival functions and tested with Cox proportional hazard models. Survival analyses revealed that by 25 years of age 76% of subjects with a DRD4 7-repeat allele were estimated to have significantly more persistent ADHD compared with 66% of subjects without the risk allele. In contrast, there were no significant associations between the course of ADHD and the DAT1 10-repeat allele ( P = 0.94) and 5HTTLPR long allele. Our findings suggest that the DRD4 7-repeat allele is associated with a more persistent course of ADHD.

Population-based case-control family study on risk factors of esophageal cancer in high incidence area

To explore the risk factors of esophageal cancer (EC) in the high-incidence regions, so as to provide scientific evidence for taking effective prevention measures. A population based case-control family study was carried out. 1711 case family members in 505 families in which one of the couple or their first degree relatives suffered from EC were selected from high incidence in Henan province. Control families without neoplasm were selected from the same villages in matching conditions of age, sex, and family members. All information of case and control families was collected by Questionnaire of Life and Health of Inhabitant. The data were analyzed with logistic regression model. Compared with the control families,it was shown that hobby for smoked food [2.10% (36/1711), 0.82% (14/1711); chi2 = 9.82, P = 0.00; OR = 2.61, 95% CI: 1.40 - 4.85], hobby for fried food [7.17% (66/921), 3.91% (35/894) ; chi2 = 9.13, P = 0.00; OR = 1.90, 95% CI: 1.24 -2.89], hobby for raw and hard food [13.36% (123/921), 8.95% (80/894); chi2 = 8.87, P =0.03; OR =1.57, 95% CI: 1.16 - 2.11], and hobby for hot food [20.05% (343/1711), 15.20% (260/1711); chi2 = 13.87, P= 0.00; OR= 1.40, 95% CI: 1.17 - 1.67], the history with mental stimulated [6.72% (115/1711), 3.10% (53/1711); chi2 = 24.06, P = 0.00; OR = 2.25, 95% CI: 1.62 -3.14], upper digestive symptom history [19.40% (332/1711), 12.74% (218/ 1711); chi2 = 28.15, P = 0.00; OR= 1.65, 95% CI: 1.37 - 1.99] entered the last model, and were responsible for the higher risk of EC. Eating fast was shown to be a protective factor [20.85% (192/921), 25.14% (225/895); chi2 = 4.73, P =0.03; OR = 0.78, 95% CI: 0.63 - 0.98]. EC is a kind of malignant tumor caused by multiple factors. Prevention and control of EC should be initiated from environmental factors, life style, genetic factors and social-psychological factors comprehensively.

Main Source of Drinking Water and Familial Aggregation of Kashin-Beck Disease: A Population Based on Case-Control Family Study

Kashin-Beck disease (KBD) is an osteoarthropathy affecting 2.5 million of 30 million residents of China's KBD-endemic regions. This study assesses the etiologic role of river water as a main source of drinking water, its impact on and interaction with KBD familial aggregation. From 2006-2007, we conducted a population-based case-control study of familial KBD in Linyou County, Shaanxi Province, China. Study subjects included 212 case families (1,951 individuals) and 212 control families (1,897 individuals). Using conditional logistic regression to analyze case-control data and second-order generalized estimating equation (GEE2) to examine family data, we adjusted for age and gender in all marginal regression analyses. The odds ratio (OR) for river water intake's association with KBD was 5.97 (95% confidence interval [CI]), 3.32-10.72). Compared with relatives of controls, proband relatives had a higher risk of disease, with a conditional OR = 2.35 (95% CI, 1.05-5.24). When river water was controlled in the analyses, association parameters among first- and second-degree relatives were no longer statistically significant. Collective river water intake among relatives was likely and predominantly responsible for familial KBD aggregation in southwestern China.

The Child Behavior Checklist-Pediatric Bipolar Disorder profile predicts a subsequent diagnosis of bipolar disorder and associated impairments in ADHD youth growing up: a longitudinal analysis.

To examine the predictive utility of the Child Behavior Checklist-Pediatric Bipolar Disorder (CBCL-PBD) profile to help identify children at risk for bipolar disorder. Subjects were ascertained from 2 identically designed longitudinal case-control family studies of subjects (males and females aged 6-18 years) with DSM-III-R attention-deficit/hyperactivity disorder (ADHD). Based on data from the baseline assessment, ADHD subjects without a lifetime diagnosis of bipolar disorder were stratified by the presence (CBCL-PBD positive, N=28) or absence (CBCL-PBD negative, N=176) of a CBCL-PBD score > or = 210 (total of attention, aggression, and anxious/depressed subscales). Subjects were comprehensively assessed at follow-up with structured psychiatric interviews. Data were collected from April 1988 to February 2003. Over a mean follow-up period of 7.4 years, a positive CBCL-PBD score predicted subsequent diagnoses of bipolar disorder, major depressive disorder, and conduct disorder, as well as impaired psychosocial functioning and higher risk for psychiatric hospitalization. This work suggests that a positive CBCL-PBD score based on elevations on the attention problems, aggressive behavior, and anxious/depressed subscales predicts subsequent pediatric bipolar disorder and associated syndrome-congruent impairments. If confirmed in other studies, the CBCL-PBD score has the potential to help identify children at high risk to develop bipolar disorder.

Parsing the Associations Between Prenatal Exposure to Nicotine and Offspring Psychopathology in a Nonreferred Sample

Purpose Several studies have suggested an association between maternal smoking during pregnancy and both attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) in the offspring of women who smoke during pregnancy. However, it is unclear whether one or both of the documented links are spurious, given the considerable comorbidity between these disorders. The main aim of this study was to disentangle the association between maternal smoking during pregnancy with psychopathological outcomes, adjusting for possible confounders. Methods Two large, identically designed, longitudinal, case-control family studies of male and female probands with and without ADHD were combined. We used data from the nonreferred siblings of the probands from both studies (n = 536). All subjects were blindly assessed with structured diagnostic interviews. Logistic regression analysis was used to determine the adjusted effect of exposure to maternal smoking during pregnancy. Results Among all siblings, maternal smoking during pregnancy was significantly associated with ADHD, independent of CD and other covariates. In contrast, maternal smoking during pregnancy was a risk factor for CD only in siblings of control probands, after adjusting for covariates. Conclusions These results support the hypothesis that maternal smoking during pregnancy is a risk factor for both ADHD and CD, independently of each other. However, the risk for CD appears to be conditional on family risk status.

The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions (“mimics”)

Background Epidemiological survey studies have suggested that a large fraction of the adult population, from five to more than 10%, have symptoms of Restless Legs Syndrome (RLS). Recently, however, it has become clear that the positive predictive value of many questionnaire screens for RLS may be fairly low and that many individuals who are identified by these screens have other conditions that can “mimic” the features of RLS by satisfying the four diagnostic criteria. We noted the presence of such confounders in a case-control family study and sought to develop methods to differentiate them from true RLS. Methods Family members from the case-control study were interviewed blindly by an RLS expert using the validated Hopkins telephone diagnostic interview (HTDI). Besides questions on the four key diagnostic features of RLS, the HTDI contains open-ended questions on symptom quality and relief strategies and other questions to probe the character of provocative situations and modes of relief. Based on the entire HDTI, a diagnosis of definite, probable or possible RLS or Not-RLS was made. Results Out of 1255 family members contacted, we diagnosed 1232: 402 (32.0%) had definite or probable RLS, 42 (3.3%) possible RLS, and 788 (62.8%) Not-RLS. Of the 788 family members who were determined not to have RLS, 126 could satisfy all four diagnostic criteria (16%). This finding indicates that the specificity of the four criteria was only 84%. Those with mimic conditions were found to have atypical presentations whose features could be used to assist in final diagnosis. Conclusion A variety of conditions, including cramps, positional discomfort, and local leg pathology can satisfy all four diagnostic criteria for RLS and thereby “mimic” RLS by satisfying the four diagnostic criteria. Definitive diagnosis of RLS, therefore, requires exclusion of these other conditions, which may be more common in the population than true RLS. Short of an extended clinical interview and workup, certain features of presentation help differentiate mimics from true RLS.