Biomedical subjects

Richard D Todd

Publications and source records attributed to Richard D Todd.

At least 19 recordsLinked to original sources

PubMed2006

Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype.

BACKGROUND: In utero exposure to smoking and alcohol are common risk factors that have been associated with attention-deficit/hyperactivity disorder (ADHD) in human beings and animal models. Furthermore, molecular studies have focused on the association between ADHD and DNA polymorphisms in dopamine pathway-related genes. We examined the joint effects of genetic and prenatal substance exposures on DSM-IV and population-defined subtypes of ADHD. METHODS: Logistic regression was used to assess the relationship between ADHD subtypes, DAT1 and DRD4 polymorphisms, and prenatal substance exposures in a birth-record sample of male and female twin pairs, aged 7-19 years. RESULTS: Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with either the DSM-IV or population-defined ADHD combined subtypes. The odds of a diagnosis of DSM-IV combined subtype was 2.9 times greater in twins who had inherited the DAT1 440 allele and who were exposed, than in unexposed twins without the risk allele. The OR was 2.6 in the population-defined subtype. Odds ratios for the DRD4 seven-repeat allele were 3.0 (2.8) in the population-defined (DSM-IV) combined ADHD subtypes. The OR for exposed children with both alleles was 9.0 (95% confidence interval=2.0-41.5) for the population-defined combined subtypes. CONCLUSIONS: Results indicate that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.

Adolescent↗

PubMed2006

Does the Child Behavior Checklist juvenile bipolar disorder phenotype identify bipolar disorder?

BACKGROUND: A profile of Child Behavior Checklist(CBCL) T-scores>or=70 on the attention problems, aggression, and anxious/depressed subscales has been proposed to identify juvenile bipolar disorder(JBD). We tested this hypothesis in a population-based sample. METHODS: Data for this analysis come from a birth-records-based twin sample having semi-structured interview and CBCL data (N=1,346). We compared prevalence of DSM-IV psychiatric disorders and suicidal behaviors in CBCL-JBD and non-CBCL-JBD subjects. Twin modeling assessed genetic and environmental contributions to CBCL-JBD. Associations with DRD4 and DAT1 were examined using chi-square tests. RESULTS: The prevalence of CBCL-JBD was 2.5%. No subjects with CBCL-JBD met criteria for bipolar or other mood disorders. CBCL-JBD subjects had more oppositional defiant disorder (ODD), conduct disorder(CD), and attention deficit hyperactivity disorder(ADHD). The CBCL-JBD profile was uncommon in these disorders. CBCL-JBD subjects more frequently endorsed suicidal behaviors. The CBCL-JBD profile was heritable and associated with the number of DAT1 9-repeat 3' untranslated region alleles. CONCLUSIONS: The CBCL-JBD phenotype does not correspond with a semi-structured interview assessment of JBD. ADHD, CD, and ODD are common in children with CBCL-JBD but do not account for the profile. Increased suicidal behaviors indicate substantial impairment in CBCL-JBD subjects.

Adolescent↗

PubMed2006

Psychiatric comorbidity and progression in drug use in adult male twins: implications for the design of genetic association studies.

Psychiatric comorbidity with drug dependence has been widely documented. In the present study, we reanalyze DSM-III-R diagnostic data on middle-aged male twin pairs from the VETR study using latent class methods. We identify four subtypes based on 15 diagnostic categories. We then show that these subtypes are strongly associated with differential rates of transitions in drug use histories, with increased risks in relatives for depression, alcohol, drug and ASPD, as well as with a variety of non-normative and deviant behaviors in youth and in adulthood. We use the result of these analyses to show how the use of a particular drug disorder phenotype for selecting cases could impact final sample composition.

Adult↗

PubMed2006

Validation of population-based ADHD subtypes and identification of three clinically impaired subtypes.

Statistically based classification methods have successfully refined ADHD into homogenous and heritable subtypes. External validity and impairment of these subtypes was examined using the Child Behavior Checklist (CBCL). We compared mean CBCL syndrome and competency t-scores across ADHD subtypes defined by latent class analysis in a sample of 1,346 individual twins from Missouri. The potential for comorbidity with conduct disorder (CD), oppositional defiant disorder (ODD), or major depression (MD) to increase impairment in specific ADHD subtypes was also examined. CBCL profiles confirm differences in severity, with more severe classes having increased syndrome scale and decreased competency scale CBCL scores. Clinically significant impairment was found for severe inattentive and combined subtypes and the mild combined subtype. Overall, the presence of comorbid CD, ODD, or MD did not result in increased ADHD subtype impairment. CBCL scores distinguish impairment in ADHD subtypes created through LCA. Comorbidity with CD, ODD, or MD does not significantly increase impairment among ADHD subtypes. The mild combined ADHD subtype represents a clinically significant but under-studied form of ADHD.

Adolescent↗

PubMed2006

ADHD medication use in a population-based sample of twins.

OBJECTIVE: To determine treatment patterns for youth attention-deficit/hyperactivity disorder (ADHD) symptoms in a general population sample of 1,610 twins. METHOD: Twin pairs ages 7 to 17 years and parents ascertained from birth records in the state of Missouri were interviewed using the Missouri Assessment of Genetics Interview for Children between 1996 and 2001. Multivariate logistic regression analyses were used to determine which factors were significant in answering three questions about treatment for ADHD. RESULTS: Of 302 boys, 177 (58.6%) and 26 of 57 girls (45.6%) who met full DSM-IV criteria for ADHD received stimulant medication in this sample. Of 314 youths, 111 (35.4%) who received stimulant medication did not meet DSM-IV criteria for ADHD. When controlling for comorbidity and other factors, the number of impairing ADHD symptoms and having a cotwin who was also brought to treatment for ADHD correlated with referral or treatment in youths without ADHD. Youths without ADHD who were treated had a large number of ADHD symptoms. CONCLUSION: As is shown in earlier studies, children with ADHD are being undertreated. Complex factors, including comorbid disorders and family history of ADHD treatment, affect treatment patterns in the general population.

Adolescent↗

PubMed2006

The Obsessive Compulsive Scale of the Child Behavior Checklist predicts obsessive-compulsive disorder: a receiver operating characteristic curve analysis.

BACKGROUND: The purpose of this study was to determine a score on the Obsessive Compulsive Scale (OCS) from the Child Behavior Checklist (CBCL) to screen for obsessive compulsive disorder (OCD) in children and to rigorously test the specificity and sensitivity of a single cutpoint. METHODS: A receiver operating characteristic (ROC) curve analysis was applied to data from 61 patients with clinically determined OCD, 64 clinical controls and 73 general population controls to determine the best sum score on the CBCL-OCS to predict confirmed OCD in children. Using the ROC-determined cutoff, this score was applied to a national sample of CBCL data from 2460 singleton children ages 4-18 and to 20,016 children ages 7-18 from three large general population twin samples to determine the estimated prevalence in the general population. RESULTS: Using a CBCL-OCS score of 5 demonstrated an area under the curve (AUC) of .88 with high sensitivity (92%) and moderate specificity (67%) compared to clinical controls. Compared to the general population controls, the AUC was .96 with high sensitivity (92%) and specificity (89%). In the twin samples, the number of participants with CBCL-OCS scores above this cutpoint was 2.3-7.1%. CONCLUSIONS: These findings suggest that the OCS of the CBCL may provide a highly effective way to screen for childhood OCD, and that the prevalence of childhood OCD may have been underestimated, thus prompting the need for further research into screening children for this condition.

Adolescent↗

PubMed2006

Autistic social impairment in the siblings of children with pervasive developmental disorders.

OBJECTIVE: Sibling recurrence risk in autism has been estimated to be approximately 10%. This study investigated subsyndromal autistic impairments among siblings of probands with pervasive developmental disorders. METHOD: The authors used the Social Responsiveness Scale to obtain quantitative assessments of autistic social impairment in three groups of proband-sibling pairs: 1) autistic children from multiple-incidence families and their closest in age nonautistic brothers (N=49 pairs); 2) children with any pervasive developmental disorder, including autism, and their closest-in-age brothers (N=100 pairs), and 3) children with psychopathology unrelated to autism and their closest-in-age brothers (N=45 pairs). RESULTS: Sibling Social Responsiveness Scale scores were continuously distributed and substantially elevated for both the autistic and pervasive developmental disorder groups. Highest scores (i.e., greatest impairment) were seen among siblings of autistic probands from multiple-incidence families, followed by siblings of probands with any pervasive developmental disorder, then siblings of probands with psychopathology unrelated to autism. CONCLUSIONS: Taken together with previous findings, these results support the notion that genetic susceptibility factors responsible for common, subsyndromal social impairments may be related to the causes of categorically defined pervasive developmental disorders.

Autistic Disorder↗

PubMed2006

The latent class structure of ADHD is stable across informants.

Previous studies have looked at the structure of attention-deficit/hyperactivity disorder (ADHD) using latent class analysis (LCA) of Child Behavior Checklist (CBCL) or Diagnostic and Statistical Manual of Mental Disorders (DSM) symptom structure. These studies have identified distinct classes of children with inattentive, hyperactive, or combined subtypes and have used these classes to refine genetic analyses. The objective of the current report is to determine if the latent class structure of ADHD subtypes is consistent across informant using the Conners' Rating Scales (CRS). LCA was applied to CRS forms from mother, father, and teacher reports of 1837, 1329 and 1048 latency aged Dutch twins, respectively. The optimal solution for boys was a 5-class solution for mothers, a 3-class solution for fathers, and a 4-class solution for teachers. For girls, a 4-class solution for mothers and a 3-class for fathers and teachers was optimal. Children placed into a class by one informant had markedly increased odds ratio of being placed into the same or similar class by the other informants. Results from LCA using Dutch twins with the CRS show stability across informants suggesting that more stable phenotypes may be accessible for genotyping using a multi-informant approach.

Adult↗

PubMed2006

Genetic influences on free and cued recall in long-term memory tasks.

Long-term memory (LTM) problems are associated with many psychiatric and neurological illnesses and are commonly measured using free and cued recall tasks. Although LTM has been linked with biologic mechanisms, the etiology of distinct LTM tasks is unknown. We studied LTM in 95 healthy female twin pairs identified through birth records in the state of Missouri. Performance on tasks of free recall of unrelated words, free and cued recall of categorized words, and the vocabulary section of the Wechsler Adult Intelligence Scale (WAIS-R) were examined using structural equation modeling. Additive genetic and unique environmental factors influenced LTM and intelligence. Free recall of unrelated and categorized words, and cued recall of categorized words, were moderately heritable (55%, 38%, and 37%). WAIS-R vocabulary score was highly heritable (77%). Controlling for verbal intelligence in multivariate analyses of recall, two components of genetic influence on LTM were found; one for all three recall scores and one for free and cued categorized word recall. Recall of unrelated and categorized words is influenced by different genetic and environmental factors indicating heterogeneity in LTM. Verbal intelligence is etiologically different from LTM indicating that these two abilities utilize different brain functions.

Adult↗

PubMed2005

Intergenerational transmission of subthreshold autistic traits in the general population.

BACKGROUND: Autistic disorder (AD) is a disabling oligogenic condition characterized by severe social impairment. Subthreshold autistic social impairments are known to aggregate in the family members of autistic probands; therefore, we conducted this study to examine the intergenerational transmission of such traits in the general population. METHODS: The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was completed on 285 pairs of twins (by maternal report) and on their parents (by spouse report). RESULTS: Correlation for social impairment or competence between parents and their children and between spouses was on the order of .4. In families in which both parents scored in the upper quartile for social impairment on the SRS, mean SRS score of offspring was significantly elevated (effect size 1.5). Estimated assortative mating explained approximately 30% of the variation in parent SRS scores. CONCLUSIONS: Children from families in which both parents manifest subthreshold autistic traits exhibit a substantial shift in the distribution of their scores for impairment in reciprocal social behavior, toward the pathological end. As has been previously demonstrated in children, heritable subthreshold autistic impairments are measurable in adults and appear continuously distributed in the general population.

Adolescent↗

PubMed2005

Brief report: autistic traits in twins vs. non-twins--a preliminary study.

Previous studies have suggested that among affected sib pairs with autism there is an increase in the frequency of twins over what would be expected in comparison to the prevalence of twins in the general population. In this study we sought to determine whether sub-threshold autistic traits were more pronounced in twins than in non-twins. The Social Responsiveness Scale (SRS) was administered in an epidemiologic twin sample (n=802) and in a separate population-based sample of non-twins ascertained from a local school district (n=255). For males (but not females), the mean SRS score was significantly higher among twins than among non-twins. As has been suggested for autism, twin status may incur increased liability to subthreshold autistic symptomatology, particularly in males.

Adolescent↗

PubMed2005

Genetic advances in autism hinge on the method of measuring symptoms.

Advances in genotyping and related technologies and the study of families with two or more autistic siblings have allowed the reporting of various genetic linkage and candidate gene association studies for autism. Despite this significant research effort, there still is no general agreement on the role of particular genes that predispose to the risk of autism. One source of general debate is whether core symptoms studied in research on the heredity of autism include single or multiple independent genetic domains. In this review, it is argued that failure to control for co-existing dimensions of psychopathology and lack of assessment of parents may lead to misinterpretation of genetic findings from pedigrees involving multiple affected family members.

Adolescent↗

PubMed2005

Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study.

BACKGROUND: Genetic influences have been shown to play a major role in determining the risk of attention-deficit hyperactivity disorder (ADHD). In addition, prenatal exposure to nicotine and/or alcohol has also been suggested to increase risk of the disorder. Little attention, however, has been directed to investigating the roles of genetic transmission and prenatal exposure simultaneously. METHOD: Diagnostic telephone interview data from parents of Missouri adolescent female twin pairs born during 1975-1985 were analyzed. Logistic regression models were fitted to interview data from a total of 1936 twin pairs (1091 MZ and 845 DZ pairs) to determine the relative contributions of parental smoking and drinking behavior (both during and outside of pregnancy) as risk factors for DSM-IV ADHD. Structural equation models were fitted to determine the extent of residual genetic and environmental influences on ADHD risk while controlling for effects of prenatal and parental predictors on risk. RESULTS: ADHD was more likely to be diagnosed in girls whose mothers or fathers were alcohol dependent, whose mothers reported heavy alcohol use during pregnancy, and in those with low birth weight. Controlling for other risk factors, risk was not significantly increased in those whose mothers smoked during pregnancy. After allowing for effects of prenatal and childhood predictors, 86% of the residual variance in ADHD risk was attributable to genetic effects and 14% to non-shared environmental influences. CONCLUSIONS: Prenatal and parental risk factors may not be important mediators of influences on risk with much of the association between these variables and ADHD appearing to be indirect.

Adolescent↗

PubMed2005

A systematic evaluation of ADHD and comorbid psychopathology in a population-based twin sample.

OBJECTIVE: Clinical and population samples demonstrate that attention-deficit/hyperactivity disorder (ADHD) occurs with other disorders. Comorbid disorder clustering within ADHD subtypes is not well studied. METHOD: Latent class analysis (LCA) examined the co-occurrence of DSM-IV ADHD, oppositional defiant disorder (ODD), conduct disorder (CD), and depression symptoms in a population twin sample. The authors fit separate models for ADHD and comorbid disorder symptoms. Twin concordance ratios (monozygotic versus dizygotic) were compared examining genetic influence on class membership. RESULTS: LCA of ADHD symptoms resulted in seven classes including inattentive, combined, and hyperactive subtypes in 1,616 subjects. The few ADHD symptoms (53.4%) and severe inattentive (12.3%) classes were most frequent. LCA of ODD, CD, and depression symptoms in 1,587 subjects revealed five classes including ODD (19.4%), depression (14.5%), and two composite classes: ODD/CD (6.9%) and ODD/CD/depression (7.2%). Internalizing and externalizing comorbid disorders were present across all ADHD subtypes. Odds ratios (ORs) for twin concordance indicate genetic influence on severe inattentive (OR = 4.18; 95% confidence interval [CI], 1.52-11.53) and combined (OR = 5.25; 95% CI, 1.32-20.78) ADHD classes and ODD (OR = 1.49; 95% CI, 0.70-3.17), ODD/CD (OR = 3.32; 95% CI, 0.57-19.28), and ODD/CD/depression (OR = 1.20; 95% CI, 0.30-4.77) classes. CONCLUSIONS: Internalizing and externalizing disorders did not cluster differentially within ADHD subtypes. LCA may provide a more precise characterization of comorbidity with ADHD.

Adolescent↗

PubMed2005

Collaborative analysis of DRD4 and DAT genotypes in population-defined ADHD subtypes.

BACKGROUND: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by latent class analysis help resolve issues of variable findings across individual gene association studies. METHODS: Three studies which had previously reported no associations between polymorphisms of the DRD4 and DAT genes and DSM-IV defined ADHD were reanalyzed using population-based and DSM-IV defined ADHD subtypes. RESULTS: Across studies no significant associations were found for either DRD4 or DAT polymorphisms using DSM-IV ADHD subtypes. In contrast, a significant association was found between the combined data set for the 440 base pair 3' DAT VNTR polymorphism and population-defined severe combined ADHD (OR=1.25, p=.01). A marginally significant association was also found between the 7 repeat DRD4 allele and population-defined severe combined ADHD. CONCLUSION: Use of alternative population-based defined ADHD subtypes may help resolve some of the variable results presented for candidate gene association studies in ADHD.

Adolescent↗

PubMed2005

Estimation of prevalence of DSM-IV and latent class-defined ADHD subtypes in a population-based sample of child and adolescent twins.

The goal of this study is to determine the prevalence and age of onset of Diagnostic and Statistical Manual of Mental Disorders and latent class-derived attention deficit/hyperactivity disorder (ADHD) subtypes in a population-based twin sample of boys and girls. Missouri birth records identified families with a twin pair 7 to 18 years of age. Telephone screening interviews for ADHD symptoms were completed for 5007 families. Diagnostic assessments were administered to 564 families with at least one twin meeting screening criteria, plus 183 control families. Prevalence and age of onset for both ADHD nosologies were calculated by sex and zygosity from parent report data. The prevalence of any DSM-IV ADHD was 6.2% overall, 7.4% in boys and 3.9% in girls. The inattentive subtype was most common in boys; the combined subtype was most common in girls. The mean age of onset of symptoms in children with any DSM-IV ADHD was 3.5 years, with no significant differences between boys and girls. Prevalences of latent class defined ADHD subtypes also varied by sex with the severe inattentive and combined classes more common in boys than girls. The age of onset of symptoms did not differ between boys and girls but were higher than in the DSM-IV subtypes. Findings in this twin sample showed that clinically significant ADHD, defined by either DSM-IV or latent class criterion, has an early age of onset and is more common in boys than girls. As clinical samples are most commonly composed of male combined subtypes, the inattentive subtype of both sexes in the general population is an under-treated segment of the general population.

Adolescent↗

PubMed2005

Comorbidity between ADHD and symptoms of bipolar disorder in a community sample of children and adolescents.

The prevalence and frequency of comorbidity of possible bipolar disorder was examined with attention-deficit hyperactivity disorder (ADHD) in a nonreferred population of twins. Children and adolescents aged 7 to 18 years with a history of manic symptoms were identified from a population-based twin sample obtained from state birth records (n = 1610). The sample was enriched for ADHD; however, there was also a random control sample (n = 466), which allowed a look at the population prevalence of the disorder. Juveniles with threshold or below threshold manic episodes were further assessed for comorbidity with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) and population-defined ADHD subtypes (from latent class analysis) using Fisher's exact test. Nine juveniles who exhibited DSM-IV manic (n = 1), hypomanic (n = 2) or below threshold episodes (n = 6) were identified. The population prevalence of broadly defined mania in the random sample was 0.2%. The possible manic episodes showed significant comorbidity with population-defined severe combined and talkative ADHD subtypes. It can be concluded that there is a significant association of bipolar symptoms with two population-defined subtypes of ADHD. Episodes of possible bipolar disorders as defined by DSM-IV are uncommon in this nonreferred sample. Children and adolescents with ADHD appear to be only modestly at increased risk for bipolar disorders.

Adolescent↗

PubMed2004

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.

Attention Deficit Disorder with Hyperactivity↗