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ABSTRACT: Recent studies have provided much needed data on the probability of seizure remission among adults with chronic intractable epilepsy treated medically. Here we provide an extended follow-up to our earlier study in order to provide a more comprehensive picture of long-term prognosis in this patient population during medical treatment. The prevalence cohort was followed for two outcomes-complete seizure remission for ≥ 12 months and subsequent seizure relapse among those attaining a seizure remission. The study outcomes were estimated using Kaplan-Meier analysis. We found that the probability of attaining a ≥ 12 months of complete seizure freedom to be approximately 3-4% per year through 8 years of follow-up. By year 5 since the start of seizure remission, the cumulative probability of seizure relapse was 81%, although only half of the patients with seizure relapse went on to experience their previous seizure frequency.
Epilepsy research 02/2011; 93(2-3):115-9. · 2.48 Impact Factor
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ABSTRACT: Dadd et al. [Hum Hered 2010;69:285-294] recently criticized our delta-centralization (DC) method of controlling for population stratification (PS) and concluded that DC does not work. To explore our method, the authors simulated data under the Balding-Nichols (BN) model, which is more general than the model we had used in our simulations. They determined that the DC method underestimated the PS parameter (δ) and inflated the type I error rates when applied to BN-simulated data, and from this they concluded that the DC method is invalid. However, we argue that this conclusion is premature. In this paper, we (1) show why δ is underestimated and type I error rates are inflated when BN-simulated data are used, and (2) present a simple adjustment to DC that works reasonably well for data from both kinds of simulations. We also show that the adjusted DC method has appropriate power under a range of scenarios.
Human Heredity 01/2011; 71(3):180-5. · 1.79 Impact Factor
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ABSTRACT: Patients with epilepsy are frequently confronted with complex treatment decisions. Communicating treatment risks is often difficult because patients may have difficulty with basic statistical concepts (i.e., low numeracy) or might misconceive the statistical information based on the way information is presented, a phenomenon known as "framing bias." We assessed numeracy and framing bias in 95 adults with chronic epilepsy and explored cognitive correlates of framing bias. Compared with normal controls, patients with epilepsy had significantly poorer performance on the Numeracy scale (P=0.02), despite a higher level of education than normal controls (P<0.001). Compared with patients with higher numeracy, patients with lower numeracy were significantly more likely to exhibit framing bias. Abstract problem solving performance correlated with the degree of framing bias (r=0.631, P<0.0001), suggesting a relationship between aspects of executive functioning and framing bias. Poor numeracy and susceptibility framing bias place patients with epilepsy at risk for uninformed decisions.
Epilepsy & Behavior 11/2010; 20(1):29-33. · 2.34 Impact Factor
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ABSTRACT: Depression is the most common comorbid condition in epilepsy. The cause of this comorbidity is unknown, and could involve psychosocial consequences of epilepsy, treatment side effects, seizure manifestations, or common neurobiologic mechanisms. One hypothesis of particular interest is a shared genetic susceptibility to epilepsy and depression. We tested this hypothesis by studying depressive symptoms in families with an identified genetic form of epilepsy: autosomal dominant partial epilepsy with auditory features caused by mutations in the leucine-rich, glioma inactivated 1 gene (LGI1).
A standardized depression screen was administered to 94 individuals from 11 families with mutations in LGI1, including 38 mutation carriers with epilepsy (AC), 11 clinically unaffected mutation carriers (UC), and 45 noncarriers (NC).
Current depressive symptom scores were significantly higher in AC than in NC, an association that remained after excluding depressive symptoms that appeared likely to be caused by antiepileptic medication use. However, scores did not differ between UC and NC.
Although LGI1 mutation carriers who were clinically affected with epilepsy had increased depressive symptoms, mutation carriers without epilepsy did not. These findings suggest that the increase in depressive symptoms in affected individuals from these families is related to epilepsy or its treatment rather than to LGI1 mutations per se.
Epilepsia 09/2010; 51(9):1685-90. · 3.96 Impact Factor
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Human Heredity 04/2010; 69(4):295. · 1.79 Impact Factor
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ABSTRACT: Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia.
We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed.
Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found.
Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected.
Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.
The Lancet Neurology 05/2009; 8(5):441-6. · 23.46 Impact Factor
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ABSTRACT: There is comorbidity and a possible genetic connection between Bipolar disease (BP) and panic disorder (PD). Genes may exist that increase risk to both PD and BP. We explored this possibility using data from a linkage study of PD (120 multiplex families; 37 had > or =1 BP member). We calculated 2-point lodscores maximized over male and female recombination fractions by classifying individuals with PD and/or BP as affected (PD + BP). Additionally, to shed light on possible heterogeneity, we examine the pedigrees containing a bipolar member (BP+) separately from those that do not (BP-), using a Predivided-Sample Test (PST). Linkage evidence for common genes for PD + BP was obtained on chromosomes 2 (lodscore = 4.6) and chromosome 12 (lodscore = 3.6). These locations had already been implicated using a PD-only diagnosis, although at both locations this was larger when a joint PD + BP diagnosis was used. Examining the BP+ families and BP- families separately indicates that both BP+ and BP- pedigrees are contributing to the peaks on chromosomes 2 and 12. However, the PST indicates different evidence of linkage is obtained from BP+ and BP- pedigrees on chromosome 13. Our findings are consistent with risk loci for the combined PD + BP phenotype on chromosomes 2 and 12. We also obtained evidence of heterogeneity on chromosome 13. The regions on chromosomes 12 and 13 identified here have previously been implicated as regions of interest for multiple psychiatric disorders, including BP.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2009; 150B(8):1139-46. · 3.70 Impact Factor
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Human Heredity 01/2009; 67(2):145-6. · 1.79 Impact Factor
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Deborah Raymond MS,
MPH Rachel Saunders-Pullman MD,
PhD Patricia de Carvalho Aguiar MD,
Birgitt Schule MD,
Norman Kock MD,
Jennifer Friedman MD,
Juliette Harris PhD,
Blair Ford MD,
Steven Frucht MD,
Gary A. Heiman PhD, [......],
Danna Jennings,
Dana Doheny,
Mitchell F. Brin,
Deborah de Leon Brin,
Trisha Multhaupt‐Buell,
Anthony E. Lang,
Roger Kurlan,
Christine Klein,
Laurie Ozelius,
Susan Bressman
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ABSTRACT: Myoclonus-dystonia (M-D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys (P < 0.0097). We found no association between mutation type and phenotype. © 2007 Movement Disorder Society
Movement Disorders 03/2008; 23(4):588 - 592. · 4.51 Impact Factor
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ABSTRACT: Some twin studies suggest that substance initiation and dependence are part of a complex, two-stage process and that some genetic influences are stage-specific, acting on either the transition from abstinence to initiation, or on the transition from use to dependence. However, questions remain about the two-stage model, especially for illicit drugs. Using a familial aggregation design, we tested the hypothesized two-stage model of dependence on illicit substances and alcohol in a large, nationally representative sample. Family history of drug or alcohol problems is significantly associated with initiation that does not progress to dependence (i.e., conditional initiation). Furthermore, family history of drug or alcohol problems is significantly associated with dependence even after conditioning on factors influencing initiation (i.e., conditional dependence). These results suggest that substance initiation and dependence involve at least partially distinct familial factors. The possibility that different genetic factors affect initiation and dependence has important implications for control group selection in case-control genetic association studies, and may explain some inconsistent results for drug dependence. If some genetic factors are stage-specific (i.e., not common across initiation and dependence), inclusion of abstainers in the control group may mix the genetic effects for initiation with those for transition to dependence, providing unclear results. Depending on the specific question about the nature of the genetic effect (whether on initiation, on dependence, or both), investigators designing case-control genetic association studies should carefully consider inclusion and exclusion criteria of the control group.
Drug and Alcohol Dependence 02/2008; 92(1-3):258-66. · 3.38 Impact Factor
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ABSTRACT: Recently, serious doubts have been cast on the usefulness of association studies as a means to genetically dissect complex diseases because most initial findings fail to replicate in subsequent studies. The reasons usually invoked are population stratification, genetic heterogeneity, and inflated Type I errors. In this article, we argue that, even when these problems are addressed, the scientific community usually has unreasonably high expectations on replication success, based on initial low P values, a phenomenon known as the replication fallacy. We present a modified formula that gives the replication power of a second association study based on the P value of an initial study. When both studies have similar sample sizes, this formula shows that: (1) a P value only slightly lower than the nominal alpha results in only approximately 50% replication power; (2) very low P values are required to achieve a replication power of at least 80% (e.g., at alpha = 0.05, a P value of <0.005 is required). Because many initially significant findings result in low replication power, replication failure should not be surprising or be interpreted as necessarily refuting the initial findings. We refer to replication failures for which the replication power is low as "pseudo-failures."
Genetics in Medicine 07/2007; 9(6):325-31. · 4.76 Impact Factor
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ABSTRACT: Prior studies suggest that obsessive-compulsive symptoms (OCS) and disorder (OCD) are co-morbid with dystonia. We tested if OCS/OCD is a clinical manifestation of the DYT1 dystonia mutation by interviewing members of families with an identified DYT1 mutation, and classifying by manifesting carriers (MC), non-manifesting carriers (NMC), and non-carriers (NC). We found that OCD/OCS are not increased in DYT1 mutation carriers compared with NC, nor is OCD associated with manifesting DYT1 dystonia.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2007; 144B(3):361-4. · 3.70 Impact Factor
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ABSTRACT: The HapMap project has given case-control association studies a unique opportunity to uncover the genetic basis of complex diseases. However, persistent issues in such studies remain the proper quantification of, testing for, and correction for population stratification (PS). In this paper, we present the first unified paradigm that addresses all three fundamental issues within one statistical framework. Our unified approach makes use of an omnibus quantity (delta), which can be estimated in a case-control study from suitable null loci. We show how this estimated value can be used to quantify PS, to statistically test for PS, and to correct for PS, all in the context of case-control studies. Moreover, we provide guidelines for interpreting values of delta in association studies (e.g., at alpha = 0.05, a delta of size 0.416 is small, a delta of size 0.653 is medium, and a delta of size 1.115 is large). A novel feature of our testing procedure is its ability to test for either strictly any PS or only 'practically important' PS. We also performed simulations to compare our correction procedure with Genomic Control (GC). Our results show that, unlike GC, it maintains good Type I error rates and power across all levels of PS.
Human Heredity 02/2007; 64(3):149-59. · 1.79 Impact Factor
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Abby J Fyer,
Steven P Hamilton,
Martina Durner,
Fatemeh Haghighi, Gary A Heiman,
Ramiro Costa,
Oleg Evgrafov,
Philip Adams,
Ada Baisre de Leon,
Nilda Taveras,
Donald F Klein,
Susan E Hodge,
Myrna M Weissman,
James A Knowles
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ABSTRACT: Panic disorder (PD) is a common illness with a definite but "complex" genetic contribution and estimated heritability of 30-46%.
We report a genome scan in 120 multiplex PD pedigrees consisting of 1591 individuals of whom 992 were genotyped with 371 markers at an average spacing of 9cM. Parametric two-point, multipoint, and nonparametric analyses were performed using three PD models (Broad, Intermediate, Narrow) and allowing for homogeneity or heterogeneity. The two-point analyses were also performed allowing for independent male and female recombination fractions (theta). Genome-wide significance was empirically evaluated using simulations of this dataset.
Evidence for linkage reached genome-wide significance in one region on chromosome 15q (near GABA-A receptor subunit genes) and was suggestive at loci on 2p, 2q and 9p using an averaged theta. Analyses allowing for sex-specific theta's were consistent except that support at one locus on 2q increased to genome-wide significance and an additional region of suggestive linkage on 12q was identified. However, differences in male and female recombination fractions predicted by the sex-specific approach were not consistent with current physical maps.
These data provide evidence for chromosomal regions on 15q and 2q that may be important in genetic susceptibility to panic disorder. Although we are encouraged by the findings of analyses using sex-specific recombination fractions, we also note that further understanding of this analytic strategy will be important.
Biological Psychiatry 09/2006; 60(4):388-401. · 8.28 Impact Factor
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ABSTRACT: We present a new method, the delta-centralization (DC) method, to correct for population stratification (PS) in case-control association studies. DC works well even when there is a lot of confounding due to PS. The latter causes overdispersion in the usual chi-square statistics which then have non-central chi-square distributions. Other methods approach the noncentrality indirectly, but we deal with it directly, by estimating the non-centrality parameter tau itself. Specifically: (1) We define a quantity delta, a function of the relevant subpopulation parameters. We show that, for relatively large samples, delta exactly predicts the elevation of the false positive rate due to PS, when there is no true association between marker genotype and disease. (This quantity delta is quite different from Wright's F(ST) and can be large even when F(ST) is small.) (2) We show how to estimate delta, using a panel of unlinked "neutral" loci. (3) We then show that delta2 corresponds to tau the noncentrality parameter of the chi-square distribution. Thus, we can centralize the chi-square using our estimate of 6; this is the DC method. (4) We demonstrate, via computer simulations, that DC works well with as few as 25-30 unlinked markers, where the markers are chosen to have allele frequencies reasonably close (within +/- .1) to those at the test locus. (5) We compare DC with genomic control and show that where as the latter becomes overconservative when there is considerable confounding due to PS (i.e. when delta is large), DC performs well for all values of delta.
Genetic Epidemiology 06/2006; 30(4):277-89. · 3.44 Impact Factor
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Cancer Epidemiology Biomarkers & Prevention 07/2005; 14(6):1579-80; author reply 1580-1. · 4.12 Impact Factor
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ABSTRACT: Recently, testing for anticipation has received renewed interest. It is well known that standard statistical methods are inappropriate for this purpose due to problems of sampling bias. Few statistical tests have been proposed for comparing mean age of onset in affected parents with mean age of onset in affected children. All of them are difficult to compute and lack software to perform the tests. In this report, we formulate the problem in terms of symmetry tests. We propose a simple generalized paired t-test and a Wilcoxon signed rank test to adjust for the bias caused by the right truncation of both the parent's and child's ages at onset. We also extend the generalized paired t-test to a random effects model that enables analysis of correlated data from nuclear families, and could be further extended to larger family structures. We illustrate the approaches with an example of panic disorder.
Genetic Epidemiology 05/2005; 28(3):256-60. · 3.44 Impact Factor
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ABSTRACT: Clinical and animal studies suggest a role for pathways regulated by cyclic-AMP in anxiety. Mouse gene deletion studies, our own linkage findings on chromosome 10, and a recently published genetic association study by Domschke et al. [2003: Am J Med Genet 117B:70-78] suggest that the cAMP responsive element modulator (CREM) may be involved in panic disorder. We have employed a family-based design to investigate the role of DNA sequence variations in the gene for CREM in panic disorder. We have genotyped 613 individuals in 70 panic disorder pedigrees, as well as 42 parent/offspring triads. Subjects were genotyped at two informative single nucleotide polymorphisms (SNPs) and three polymorphic microsatellites in the CREM genomic region; and the data were analyzed for genetic association and linkage. Linkage analysis employing several diagnostic/genetic models produced a maximum lod score of 0.63 for SNP-1, located in the 5' UTR of CREM, under a dominant model with a broad diagnostic definition of panic disorder. Non-parametric analysis, using the NPL statistic or FBAT, also did not support any linkage or association between the markers and panic disorder. All five markers (spanning 77 kb) used in the study showed modest, but significant linkage disequilibrium. Analysis of 2-, 3-, 4-, or 5-marker haplotypes using TRANSMIT failed to find any globally significant results; however, individual haplotypes containing a single allele of MS-3 were nominally associated with panic disorder. These findings provide little additional evidence for a susceptibility locus for panic disorder either within the CREM gene or in a nearby region of chromosome 10p11 in our sample.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2004; 126B(1):111-5. · 3.70 Impact Factor
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ABSTRACT: Evidence from a genetic linkage study had suggested a possible syndrome in some families with panic disorder (PD). This syndrome includes bladder problems (possibly urinary interstitial cystitis [IC]), thyroid disorders, chronic headaches/migraine, and/or mitral valve prolapse. In 19 multiplex families with PD, one marker (D13S779) on chromosome 13 gave a logarithm of odds score of more than 4 when individuals with any of the syndrome conditions were analyzed as affected. Families with the bladder problems yielded the highest logarithm of odds scores. These findings were replicated in an extended sample of 60 families. Whereas PD had been well characterized by direct interview, the urologic problems had been found only via medical history checklists and records. A case review by a board-certified urologist suggested they could be IC.
To determine whether patients diagnosed as having IC by urodynamics and/or cystoscopy and their first-degree relatives (FDRs) have increased rates of the syndrome conditions, thus validating that the bladder problems observed in the linkage study could be IC and providing further support for the panic syndrome.
Case-control and family history study.
Two metropolitan urology clinics.
One hundred forty-six probands (67 with IC and 79 with other urologic disorders) and 815 FDRs.
Lifetime rates of syndrome conditions in probands and FDRs who were blind to urologic or psychiatric diagnoses in the proband.
Compared with patients without IC, patients with IC had a significantly higher lifetime prevalence of PD (controlling for age and sex) (odds ratio, 4.05; 95% confidence interval, 1.22-13.40; P =.02) and a higher lifetime prevalence of any of the syndrome disorders (controlling for age and sex) (odds ratio, 2.22; 95% confidence interval, 0.89-5.54; P =.09). First-degree relatives of probands with (vs without) IC were significantly more likely to have PD, thyroid disorder, urologic problems, and any of the syndrome disorders (controlling for age and sex of the relative and sex of the proband) (adjusted odds ratio, 1.95; 95% confidence interval, 1.13-3.38; P =.02). These results in relatives were not influenced by PD in probands, and did not change substantially when controlling for the proband-relative relationship, modeling age as a categorical (vs continuous) variable, or excluding FDRs with PD. There were no interactions between proband IC status and sex of the relative.
The increased frequency of seemingly disparate disorders in patients with IC and their FDRs is consistent with the genetic linkage findings in families with PD. These findings suggest that the bladder problems observed in the linkage study may be IC. The hypothesis that there is a familial, possibly pleiotropic, syndrome that may include IC, PD, thyroid disorders, and other disorders of possible autonomic or neuromuscular control deserves further investigation.
Archives of General Psychiatry 04/2004; 61(3):273-9. · 12.02 Impact Factor
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ABSTRACT: Data from clinical and behavioral pharmacological studies have implicated adenosine in anxiety behaviors, while genetic studies have suggested that adenosine receptors may be associated with panic disorder. We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees. Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association. Linkage analysis revealed elevated LOD scores for a silent substitution (1083C/T, SNP-4) in the second coding exon. This SNP has been previously reported to be associated with panic disorder. We observed a maximal heterogeneity LOD score of 2.98 (theta=0) under a recessive genetic model and narrow diagnostic model. Other SNPs showed no evidence for linkage. Association tests were not significant for any of the five ADORA2A SNPs. When SNP haplotypes were assessed in the triads with TRANSMIT, one 3-marker haplotype (SNPs 1, 4, 5) was nominally significantly associated with panic disorder (p=0.029). Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus. Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A. Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder.
Neuropsychopharmacology 04/2004; 29(3):558-65. · 7.99 Impact Factor
