Biomedical subjects

R Ottman

Publications and source records attributed to R Ottman.

At least 73 records · Page 4Linked to original sources

PubMed1994

Carcinogen-DNA adducts and gene mutation in foundry workers with low-level exposure to polycyclic aromatic hydrocarbons.

Carcinogen-DNA adducts and somatic gene mutation at the hypoxanthine guanine phosphoribosyl transferase (HPRT) locus were evaluated in peripheral leukocytes of workers in an iron foundry with exposure to benzo[a]pyrene (B[a]P) and other polycyclic aromatic hydrocarbons (PAHs). During the two year study period, B[a]P exposure declined by approximately 40%, from a maximum of 60 ng/m3 in the first year to < 36 ng/m3 1 year later. A total of 64 persons were sampled in November/December of the two successive study years; 24 of them gave two samples one year apart. The biomarkers included carcinogen-DNA adducts in leukocytes (PAH-DNA measured by an immunoassay, aromatic-DNA by the 32P-postlabeling method) and HPRT mutation in lymphocytes. After adjusting for smoking, levels of PAH-DNA, aromatic-DNA and HPRT mutation frequency (Mf) increased with exposure among the 64 workers sampled during the 2 year period (P < or = 0.05). However, the markers showed a differential response to the change in exposure, consistent with their individual biology. For example, among the 24 workers sampled in both years, carcinogen-DNA adducts (which have a half-life on the order of several months) were markedly reduced from the first to the second year (PAH-DNA, 6.2 versus 2.3/10(8); aromatic-DNA, 2.5 versus 1.4/(8); P < 0.01). HPRT Mf (a longer-lived marker) was somewhat less affected by the decline in exposure (1.3 versus 0.8, P < or = 0.05). Moreover, in the second year several long-term workers had low levels of adducts, but elevated HPRT Mf. Thus, PAH-DNA and HPRT Mf were highly correlated in the first year (n = 17; r = 0.67; P < 0.01), but not in the second year or in the two years combined. However, when analysis was restricted to workers with detectable levels of adducts (who included the more highly exposed workers) the correlation was significant between PAH-DNA and HPRT (n = 17; r = 0.65; P = 0.005). In contrast, aromatic-DNA adducts and HPRT were not correlated in either year. These results suggest a molecular link between somatic gene mutation and PAHs; and they highlight the need in such molecular epidemiologic studies to consider the varying lifetimes of the individual markers.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1994

Familial aggregation of amyotrophic lateral sclerosis, dementia, and Parkinson's disease: evidence of shared genetic susceptibility.

Clinicians have long suspected an association of classic amyotrophic lateral sclerosis (ALS) with Parkinson's disease (PD), dementia, or both. If proven, this would raise the possibility of a shared genetic susceptibility to the three disorders. To investigate this hypothesis, we compared 151 newly diagnosed ALS patients (seven familial) with 140 controls in terms of cumulative incidence of ALS, PD, and dementia in parents, siblings, and grandparents. We used Cox proportional hazards analysis to compute rate ratios (RRs) for ALS, dementia, and PD in relatives of ALS patients versus relatives of controls. The risk for dementia was significantly higher in relatives of ALS patients than in those of controls (RR = 1.9; 95% CI 1.1-3.1) and was similar for relatives of patients with sporadic and familial ALS. The risk of PD was higher in relatives of patients with familial ALS (RR = 5.6; 95% CI 0.6-50.3) than in relatives of patients with sporadic ALS (RR = 1.8; 95% CI 0.5-6.0), but these differences were not statistically significant, probably due to insufficient statistical power with the available sample size. These findings indicate that ALS and dementia, and perhaps also PD, co-occur within families more often than expected by chance, suggesting that there may be a shared genetic susceptibility to these disorders.

Adult↗

PubMed1994

Comorbidity of migraine and epilepsy.

We investigated comorbidity of migraine and epilepsy by using information from structured telephone interviews with 1,948 adult probands with epilepsy and 1,411 of their parents and siblings. Epilepsy was defined as a lifetime history of two or more unprovoked seizures, and migraine as severe headaches with two or more of the following symptoms: unilateral pain, throbbing pain, visual aura, or nausea. Cumulative incidence of migraine to age 40 was 24% in probands with epilepsy, 23% in relatives with epilepsy, and 12% in relatives without epilepsy. Using Cox proportional hazards analysis to control for years at risk and gender, the rate ratio for migraine was 2.4 (95% CI, 2.02 to 2.89) among probands and 2.4 (1.58 to 3.79) among relatives with epilepsy in comparison with relatives without epilepsy. Migraine risk was highest in probands with epilepsy due to head trauma, but it was significantly higher in every subgroup of probands than in unaffected relatives when probands were stratified by seizure type, age at onset, etiology of epilepsy, and history of epilepsy in first-degree relatives. Age-specific incidence of migraine among probands was increased to a greater extent after onset of epilepsy than before, but it was also significantly increased more than 5 years before onset and 1 to 5 years before onset. These results indicate that migraine and epilepsy are strongly associated, independent of seizure type, etiology, age at onset, or family history of epilepsy.

Adolescent↗

PubMed1994

Multivariate survival analysis using piecewise gamma frailty.

In this note we propose a frailty model called piecewise gamma frailty for correlated survival data with random effects having a nested structure. In frailty models, a dependence function defined as a hazard ratio of one member given the failure time of another member in a unit is determined by the distributional assumptions on frailty. In the piecewise gamma frailty model, the nested structure of random effects or frailty allows the dependence function to vary over the time periods. This model includes existing models such as the piecewise exponential model (Breslow, 1974, Biometrics 30, 89-100) and the gamma frailty model (Clayton, 1978, Biometrika 65, 141-151; Oakes, 1982, Journal of the Royal Statistical Society, Series B 44, 414-428) as special cases. A study of familial aggregation of epilepsy is used to illustrate the proposed method.

Adult↗

PubMed1994

Comorbidity of migraine: the connection between migraine and epilepsy.

Although an association between migraine and epilepsy has long been discussed, it has rarely been studied systematically. According to the evidence from the large epidemiologic study reviewed in this article, individuals with epilepsy are 2.4 times more likely to develop migraine than their relatives without epilepsy. Risk of migraine is elevated in patients with partial-onset and generalized-onset seizures. The comorbidity of migraine and epilepsy may be explained by a state of neuronal hyperexcitability that increases the risk of both disorders. Clinical and EEG features useful in the differential diagnosis of migraine and epilepsy as well as in the diagnosis of both conditions when they occur concurrently are reviewed. When migraine and epilepsy occur together, therapy with agents effective for both conditions should be considered.

Adult↗

PubMed1993

Genetic susceptibility and head injury as risk factors for Alzheimer's disease among community-dwelling elderly persons and their first-degree relatives.

We performed a community-based study to investigate the relationship of genetic susceptibility and head injury to Alzheimer's disease (AD) in 138 patients with AD and 193 healthy elderly control subjects. Data concerning presence or absence of dementia and certain exposures were also obtained from 799 first-degree relatives of the patients and 1,238 first-degree relatives of the control subjects. Adjusting for age, gender, and other risk factors, the odds ratio for AD associated with head injury was 3.7 (95% confidence interval [CI], 1.4-9.7). The association was highest for head injuries that occurred after age 70. The risk of AD was higher in first-degree relatives of patients with onset prior to age 70 than in relatives of control subjects (risk ratio [RR] = 2.5; 95% CI, 1.1-5.6). The risk was not increased for relatives of patients with onset of AD at age 70 or older. Compared with relatives without head injury, the risk of AD was increased among both head-injured relatives of patients (RR = 5.9; 95% CI, 2.3-14.8) and head-injured relatives of control subjects (RR = 6.9; 95% CI, 2.5-18.9). Our results are consistent with the hypothesis that severe head injury and genetic susceptibility are associated with AD. Both associations concur with current concepts regarding the role of amyloid in AD. Although we regard head injury, like genetic susceptibility, to be a putative risk factor for AD, the temporal relationship between head injury and AD warrants further investigation.

Age Factors↗

PubMed1993

The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease.

Apolipoprotein E (APO-E) binds to the beta-amyloid peptide and is present in senile neuritic plaques in Alzheimer's disease (AD). The epsilon 4 isoform of APO-E has been associated with both sporadic and familial late-onset AD, implying a causal role. Among patients and control subjects similar in age, gender, and ethnic group from the New York City community of Washington Heights-Inwood, we found that the odds ratio (OR) for AD associated with homozygosity for APO-epsilon 4 was 17.9 (95% confidence interval [CI], 4.6-69.8) and that associated with heterozygosity for APO-epsilon 4 was 4.2 (95% CI, 1.8-9.5) compared with persons with other APO-E genotypes. The association was stronger among patients with sporadic disease (OR = 10.3; 95% CI, 3.4-31.1) than among those with a family history of dementia in a first-degree relative (OR = 0.9; 95% CI, 0.1-13.5). The association between APO-epsilon 4 and AD did not differ according to age at onset (< 65 vs > or = 65), but appeared to vary across the 3 ethnic groups investigated (black, Hispanic, and white). Our data confirm the association between AD and APO-epsilon 4 and support the hypothesis that the APO-epsilon 4 allele either confers genetic susceptibility to AD or may be in linkage disequilibrium with another susceptibility locus. Ethnic variability in the allelic frequency of APO-epsilon 4 in the elderly warrants further investigation.

Aged↗

PubMed1993

HPRT and glycophorin A mutations in foundry workers: relationship to PAH exposure and to PAH-DNA adducts.

Mutations were evaluated in workers in an iron foundry with exposure to polycyclic aromatic hydrocarbons (PAHs), measured by personal and area monitoring, ranging from < 5 to 60 ng/m3 of benzo[a]pyrene (B[a]P). Mutation at the hypoxanthine guanine phosphoribosyl transferase (HPRT) and glycophorin A (GPA) loci (measures of molecular effect in lymphocytes and erythrocytes respectively) were assessed to demonstrate their relationship to external exposure at lower levels than previously analyzed in foundry workers at this plant (< 50-200 ng/m3). The relationship between mutations and PAH-DNA adducts measured by immunoassay (as a measure of the biologically effective dose) was also investigated. The markers were analyzed for dose-response and interindividual variability. Workers were classified into three exposure categories (low, medium and high). PAH-DNA adduct values for the low, medium and high exposure groups were 5.19, 6.10 and 9.57 x 10(-8) nucleotides respectively (r = 0.28; P = 0.08). HPRT mutant frequencies (adjusted for age and cloning efficiency) for the low, medium and high exposure groups were 1.04, 1.13 and 1.82 x 10(-6) cells respectively and demonstrated an upward trend with increasing exposure that was of borderline significance (r = 0.46, P = 0.06). In contrast, HPRT mutations were highly correlated with PAH-DNA adducts (r = 0.67; P = 0.004). Interindividual variability in mutant frequencies ranged from 1.5- to 4.5-fold within the three exposure categories. With respect to GPA variants, NN frequency (Vf) in erythrocytes (which reflects chromosomal loss and duplication, recombination or gene conversion) was not positively correlated with PAH exposure. The level of N0 Vf (arising from small-scale structural mutations in the GPA gene or from larger-scale chromosomal rearrangements or deletions) increased slightly, but not significantly, over the three exposure groups from 8.2 to 10.7 to 11.8/10(6) cells (P = 0.32). Interindividual variation in GPA NN Vf ranged from 2- to 18-fold and in GPA N0 from 4- to 5-fold. NN and N0 Vf were highly correlated (P = 0.001) but no correlation was seen between GPA and HPRT or between GPA and PAH-DNA adducts. Thus, the most interesting and novel finding is that, even at relatively low exposures to PAH, HPRT mutations were increased in parallel with PAH-DNA adducts. The observed association between PAH-DNA adducts and HPRT gene mutation in humans is consistent with experimental data for PAHs. These results support the use of both biomonitoring and personal ambient monitoring in further molecular epidemiology studies.

Adult↗

PubMed1993

Validity of family history data on severe headache and migraine.

This study evaluated the validity of family history data on severe headache and migraine obtained from adult probands with epilepsy in a family study of seizure disorders. We compared the probands' reports of severe headaches and migraines in their parents and full siblings with symptom-based diagnoses based on self-reports. Overall sensitivity was 48% for severe headache and 44% for migraine. When we used reports of severe headaches to screen for migraine headaches in the relatives, sensitivity was 56%. These results indicate that severe headache and migraine are underreported in family history interviews with first-degree relatives. To obtain accurate information on headaches in families for clinical practice and genetic research, direct interviews with each relative may be required.

Adult↗

PubMed1993

Reliability of seizure classification using a semistructured interview.

Methods for standardized classification of epileptic seizures are important for both clinical practice and epidemiologic research. In this study, we developed a strategy for standardized classification using a semistructured telephone interview and operational diagnostic criteria. We interviewed 1,957 adults with epilepsy ascertained from voluntary organizations. To confirm and expand the seizure history, we also interviewed a first-degree relative for 67% of subjects and obtained medical records for 59%. Three lay reviewers used all available information to classify seizures. To assess reliability, each reviewer classified a sample of subjects assigned to the others. In addition, an expert physician classified a sample of subjects assigned to two of the reviewers. Agreement was "moderate-substantial" for generalized-onset seizures, both for the comparisons between pairs of lay reviewers and for the neurologist versus lay reviewers. Agreement was "substantial-almost perfect" for partial-onset seizures, both for pairs of lay reviewers and for the neurologist versus lay reviewers. These results suggest that seizures can be reliably classified by lay reviewers, using operational criteria applied to symptoms ascertained in a semistructured telephone interview.

Adolescent↗

PubMed1992

Data collection strategies in genetic epidemiology: The Epilepsy Family Study of Columbia University.

A large-scale study of genetic influences on seizure disorders is described here as a primer of tested methods for collection of family history data. 1957 adult probands with epilepsy were ascertained from voluntary organizations. Personal and family history data were obtained from probands in semistructured telephone interviews. To increase sensitivity, an independent family history was obtained from a second family informant in a similar interview. To increase specificity and diagnostic detail, family members reported to be affected were interviewed, and medical records of probands and affected relatives were collected. Participation rates for probands were 84-90%. Interviews were completed with second informants in 67% of families, and with 51% of eligible affected relatives. The main reasons for non-interview were lack of permission from probands and difficulties in locating relatives. Although 90% of probands gave verbal permission for medical record review, only 75% of these signed and returned consent forms for this purpose. Physicians returned 87% of the records requested. The resulting proportion of probands with medical records was 59%. These findings illustrate the complexity involved in assembling useful databases in genetic epidemiology.

Adult↗

PubMed1992

Genetic and developmental influences on susceptibility to epilepsy: evidence from twins.

This study evaluated genetic and developmental contributions to epilepsy, using data on epilepsy and multiple births in the sibships of 1981 probands with epilepsy. Prevalence of a history of epilepsy was much higher in monozygotic (MZ) than in dizygotic (DZ) co-twins of probands (35.0% vs. 3.7%), but prevalence was not significantly higher in DZ co-twins than in singleton siblings. The proportion of individuals who were MZ twins was higher among probands with epilepsy than among their non-co-twin siblings without epilepsy (odds ratio 2.5, 95% CI 1.31-4.85). However, the proportion who were DZ twins was similar among probands and unaffected siblings (odds ratio 1.0, 95% CI 0.67-1.60). These findings suggest that the increased prevalence of epilepsy in MZ co-twins of probands may be partly explained by developmental factors related to MZ twinning, rather than by their genetic identity with the probands.

Disease Susceptibility↗

PubMed1991

Control for environmental risk factors in assessing genetic effects on disease familial aggregation.

A probabilistic model was developed to assess the impact of two independent dichotomous familial risk factors on familial aggregation of a disorder in pairs of relatives where one member was ascertained as a proband or index subject (i.e., a case or control). Under this model, one risk factor is of primary interest (i.e., a susceptibility gene), while the effect of the other is to be controlled (i.e., an environmental risk factor). Familial aggregation was examined within strata defined by the status of proband and relative with respect to the environmental factor. The findings suggest that for proband-relative pairs, under both the additive and multiplicative models, an environmental factor can be controlled in the analysis based solely on the status of the proband. If the relation between the genetic and environmental factors is neither additive nor multiplicative, however, the analysis must take account of environmental risk factors in both proband and relative.

Bias↗

PubMed1991

Familial aggregation of Paget's disease of bone.

This epidemiologic study of Paget's disease of bone used data from 788 cases and 387 spouse controls to investigate the following: (1) the extent to which this disorder aggregates in families; (2) the cumulative incidence of the disease in first-degree relatives of patients throughout life; and (3) the influence of age at diagnosis (less than 55 versus 55+ years) and presence of bone deformity in the case on risk of Paget's disease in relatives. A positive family history in parents or siblings was reported by 12.3% of cases and 2.1% of controls. The rate of Paget's disease was approximately seven times as high in relatives of cases as in relatives of controls, and this increased rate did not differ according to gender of case or control or gender of relatives. Cumulative incidence of Paget's disease to age 90 was much higher in relatives of cases (8.9 +/- 1.0% SEM) than in relatives of controls (1.8 +/- 0.9% SEM). Among relatives of cases, cumulative risk was highest when the case had both early age at diagnosis and bone deformity (20.7 +/- 3.6% SEM) compared with risk when the case had early age at diagnosis but not bone deformity (10.8 +/- 3.2% SEM), bone deformity but not early age at diagnosis (5.8 +/- 1.3% SEM), or neither bone deformity nor early age at diagnosis (3.6 +/- 0.8% SEM). Risk in siblings of cases was higher when a parent was affected (22.1 +/- 8.0% SEM) than when both parents were unaffected (6.7 +/- 1.1% SEM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

An epidemiologic approach to gene-environment interaction.

This paper illustrates how epidemiologic principles can be used to investigate relationships between genetic susceptibility and other risk factors for disease. Five plausible models are described for relationships between genetic and environmental effects, and an example of a simple mendelian disorder that fits each model is given. Each model leads to a different set of predictions about disease risk in individuals with the genetic susceptibility alone, the risk factor alone, both, or neither. The risk predictions for the different models are described, and research designs for testing them are discussed.

Case-Control Studies↗

PubMed1988

Voluntary health agencies as target populations for epidemiologic research.

The ability of two voluntary health agencies to provide suitable target populations for epidemiologic research was explored in a pilot study of epilepsy. The results suggest that, properly approached, voluntary agencies offer advantage for this purpose. In the first agency (Group A), subjects were recruited by mail, producing a response rate of 15%. In the second agency (Group B), subjects were recruited by telephone, producing a response rate of 87%. A structured, precoded telephone interview about personal and family history of seizure disorders was administered to both groups of subjects. Subjects in Group A gave permission to contact a higher proportion of their eligible relatives than did those in Group B (73 vs 57%). Permission was obtained more often for relatives reported to have had seizures (Group A 86%, Group B 78%) than for other relatives. 89% of relatives contacted directly agreed to be interviewed. Consent forms for medical record review were signed and returned by 95% of Group A and 77% of Group B subjects. Diagnoses of etiology and seizure type of epilepsy based on the interview data agreed with diagnosis based on the medical records in most cases. In first-degree relatives of subjects with epilepsy, reported rates of epilepsy did not appear to be seriously biased.

Adult↗

PubMed1988

Higher risk of seizures in offspring of mothers than of fathers with epilepsy.

Seizure risk has consistently been found to be higher in offspring of mothers than of fathers with epilepsy. This pattern cannot be explained by any simple genetic model. The present study examined the possibility that the pattern arises from differences between affected mothers and fathers in the characteristics of their epilepsy that influence offspring seizure risk. The study population comprised 687 offspring of parents with epilepsy from the Rochester-Olmsted County Record Linkage Project. Cumulative incidences of unprovoked seizures to age 25 were 8.7% and 2.4% in offspring of affected mothers and fathers, respectively. Cox proportional hazards analysis was used to calculate rate ratios (RRs) for unprovoked seizures in offspring. In the univariate analysis, risk of unprovoked seizures was higher if the affected parent was the mother (RR = 2.8, 95% confidence interval [ci] 1.1-7.2) or if the parent's onset was before age 20 (RR = 2.5, 95% ci 1.1-5.9), but there was no effect on offspring risk of either parent's etiology (idiopathic vs. remote symptomatic) or parent's seizure type (generalized vs. partial). These findings were not substantially changed in the multivariate analysis. Thus, differences between affected mothers and fathers in these characteristics did not account for the higher risk in offspring of affected mothers. Anticonvulsant use during pregnancy was not associated with increased offspring seizure risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1987

Simple test of the Multifactorial-Polygenic Model with sex dependent thresholds.

Under the Multifactorial-Polygenic Model, a sex difference in population incidence implies higher risk in relatives of low risk sex probands than in those of high risk sex probands. The relationship between sex ratio in population incidence and expected relative risk (RR) to first-degree relatives of probands of the low risk sex vs the high risk sex under the Multifactorial-Polygenic Model was examined. Five observations were made from this analysis: as the sex ratio increases, the expected RR increases for each combination of incidence and r, the liability correlation between relatives, RRs are higher for low risk sex relatives than for high risk sex relatives at each combination of incidence, r, and sex ratio, the expected RR increases as r increases at each incidence and sex ratio, and variation in population incidence has little effect on RR at a given sex ratio and r, and the expected RRs are small, rarely exceeding two-fold. The quantitative relationship between sex ratio and RR provides the basis for a simple test of the Multifactorial-Polygenic Model when two different sex or severity thresholds can be identified.

Epidemiologic Methods↗