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Biomedical subjects

J M Friedman

Publications and source records attributed to J M Friedman.

At least 37 records · Page 2Linked to original sources
PubMed2004

Utility and limitations of genetic disease databases in clinical genetics research: a neurofibromatosis 1 database example.

Databases that collect clinical information on patients with particular genetic diseases can be used to investigate the clinical history of a disorder, its genetics, and genotype-phenotype correlations. A database can also serve as a valuable source of patients for studies of disease pathogenesis, variability, or treatment. We review the strengths and limitations of genetic disease databases in the context of our experience with the National Neurofibromatosis Foundation International Database (NNFFID). Genetic disease databases have been developed by individual investigators, scientific consortia, patient support organizations, and commercial enterprises. Databases vary from simple lists of affected individuals to comprehensive collections of detailed clinical and genetic information. Data may be obtained from people who volunteer to be included, systematic assessments of patients seen at participating medical centers, or population-based registries. Access to information may be highly restricted or widely available. These variables all affect the possible uses and usefulness of the data for research. Technical aspects of data entry, organization, storage, and retrieval, as well as issues related to data quality, confidentiality, and security, help determine how well a system actually functions. We discuss examples of research that have been accomplished with genetic disease databases and make recommendations regarding the organization and operation of these resources.

Biomedical Research↗
PubMed2003

Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes.

Studies have argued that genetic testing will provide limited information for predicting the probability of common diseases, because of the incomplete penetrance of genotypes and the low magnitude of associated risks for the general population. Such studies, however, have usually examined the effect of one gene at time. We argue that disease prediction for common multifactorial diseases is greatly improved by considering multiple predisposing genetic and environmental factors concurrently, provided that the model correctly reflects the underlying disease etiology. We show how likelihood ratios can be used to combine information from several genetic tests to compute the probability of developing a multifactorial disease. To show how concurrent use of multiple genetic tests improves the prediction of a multifactorial disease, we compute likelihood ratios by logistic regression with simulated case-control data for a hypothetical disease influenced by multiple genetic and environmental risk factors. As a practical example, we also apply this approach to venous thrombosis, a multifactorial disease influenced by multiple genetic and nongenetic risk factors. Under reasonable conditions, the concurrent use of multiple genetic tests markedly improves prediction of disease. For example, the concurrent use of a panel of three genetic tests (factor V Leiden, prothrombin variant G20210A, and protein C deficiency) increases the positive predictive value of testing for venous thrombosis at least eightfold. Multiplex genetic testing has the potential to improve the clinical validity of predictive testing for common multifactorial diseases.

Genetic Diseases, Inborn↗
PubMed2003

Exploring the "two-hit hypothesis" in NF2: tests of two-hit and three-hit models of vestibular schwannoma development.

Neurofibromatosis 2 (NF2) is a genetic disease that occurs in approximately 1 in 40,000 live births. Almost all affected individuals develop bilateral tumors of Schwann cells that surround the vestibular nerves; these tumors are known as vestibular schwannomas (VS). Evidence from molecular genetic studies suggests that at least two mutations are involved in formation of VS in patients with NF2. Several authors proposed probabilistic models for this process in other tumors, and showed that such models are consistent with incidence data. We evaluated two different probabilistic models for a "2-hit" hypothesis for VS development in NF2 patients, and we present results from fitting these models to incidence data. Molecular evidence does not exclude the possibility that additional hits are necessary for the development of VS, and we also assessed a "3-hit" model for tumor formation. The "3-hit" model fits the data marginally better than one of the "2-hit" models and much better than the other "2-hit" model. Our findings suggest that more than two mutations may be necessary for VS development in NF2 patients.

Humans↗
PubMed2003

Implications of research in male-mediated developmental toxicity to clinical counsellors, regulators, and occupational safety officers.

In closing, let me return to the somewhat irreverent question that I asked at the beginning: Apart from what we learn about fundamentally important biological processes, does male-mediated developmental toxicity make any practical difference? The answer is no, yes, and we don't know. No: The risk of serious birth defects in the future children of a man who is concerned about exposure to radiation or chemicals in the remote past does not appear to be measurably increased in comparison to the background. Yes: Male-mediated developmental toxicity may be of sufficient concern to restrict certain exposures in the population as a whole, but in order for male-mediated developmental toxicity to be determinative, these conditions will have to be otherwise non-toxic. To date, no exposures have been identified that produce substantial male-mediated developmental toxicity in the complete absence of other kinds of toxicity. We don't know how big a problem male-mediated developmental toxicity really is because we have not studied a large enough number and variety of exposures. We don't know if our perspective will change as we begin to understand the importance of individual susceptibility better. We don't know all of the mechanisms that may be involved in male-mediated developmental toxicity or their general biological importance. We don't know more than we do know about male-mediated developmental toxicity, and we are anxious to learn more.

Abnormalities, Radiation-Induced↗
PubMed2003

On the use of population attributable fraction to determine sample size for case-control studies of gene-environment interaction.

Most methods for calculating the sample size needed to detect gene-environment interactions use odds ratios to measure the effect size. We show that for any combination of susceptible genotype prevalence and exposure prevalence and their associated risks, the odds ratio measuring strength of interaction corresponds to a population attributable fraction (PAF) because of interaction and vice versa. Simultaneous consideration of odds ratio for interaction and the associated PAF attributable to interaction provides additional insight to investigators evaluating the feasibility and public health relevance of a proposed study. We considered gene-environment interactions on a multiplicative scale, and assumed a dichotomous environmental exposure variable and a single two-allele disease-susceptibility locus. Our results show, for example, that for studies of exposures and genotypes that are common in a population (30%-50%), the PAF for interaction is large (>27%) even if the odds ratio for interaction is only moderate (approximately 2). If simultaneous estimates of interaction odds ratio and PAF indicate that the PAF is so large as to be implausible, the investigator may decide to reevaluate the study design based on detecting a more reasonable PAF. In this case, the associated odds ratio for interaction will be weaker and a considerably larger sample size may be needed.

Case-Control Studies↗
PubMed2003

Population-based analyses of mortality in trisomy 13 and trisomy 18.

OBJECTIVE: Although trisomy 13 and trisomy 18 are generally considered to be lethal, long-term survival of patients has been reported. We sought to evaluate mortality in people with trisomy 13 or 18 using 2 population-based strategies. METHODS: In the first analysis, infants who had trisomy 13 or 18 and were born during 1968-1999 were identified using the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system. Dates of death were documented using hospital records, Georgia vital records, and the National Death Index. In the second analysis, we used the Multiple-Cause Mortality Files compiled from US death certificates from 1979 through 1997. Using these 2 analyses, we examined median survival time or median age at death, survival beyond 1 year of age, and factors associated with longer survival. RESULTS: Using Metropolitan Atlanta Congenital Defects Program, we identified 70 liveborn infants with trisomy 13 and 114 liveborn infants with trisomy 18. Median survival time was 7 days (95% confidence interval [CI]: 3-15) for people with trisomy 13 and 14.5 days (95% CI: 8-28) for people with trisomy 18. For each condition, 91% of infants died within the first year. Neither race nor gender affected survival for trisomy 13, but for trisomy 18, girls and infants of races other than white seemed to survive longer. The presence of a heart defect did not seem to affect survival for either condition. Using MCMF, we identified 5515 people with trisomy 13 and 8750 people with trisomy 18 listed on their death certificates. Median ages at death for people with trisomy 13 and trisomy 18 both were 10 days; 5.6% of people with trisomy 13 and 5.6% of people with trisomy 18 died at age 1 year or greater. Race and gender seemed to affect survival in both conditions, with girls and blacks showing higher median ages at death. CONCLUSIONS: Although survival is greatly affected by trisomy 13 and trisomy 18, 5% to 10% of people with these conditions survive beyond the first year of life. These population-based data are useful to clinicians who care for patients with these trisomies or counsel families with infants or fetuses who have a diagnosis of trisomy 13 or 18.

Black People↗
PubMed2002

Evaluation of clinical diagnostic criteria for neurofibromatosis 2.

BACKGROUND: Four sets of clinical diagnostic criteria for neurofibromatosis 2 (NF2) have been developed by groups of expert clinicians, but sensitivity has never been formally assessed. The sets of criteria differ for people without bilateral vestibular schwannomas, which are pathognomonic for NF2. OBJECTIVE: To empirically evaluate the four existing sets of clinical diagnostic criteria for NF2. METHODS: The study was based on 163 of 403 people in the United Kingdom NF2 registry (41%) who presented without bilateral vestibular schwannomas. The authors applied the sets of criteria to each person at initial assessment and at the most recent clinical evaluation (mean +/- SE length of follow-up, 13 +/- 1 years). RESULTS: In people with "definite NF2" and a negative family history of NF2, the 1987 US NIH and 1991 NIH criteria each identify 78% of people at the most recent clinical evaluation but 0% at initial assessment. The National Neurofibromatosis Foundation (NNFF) criteria and the Manchester criteria each identify higher proportions at both time points (NNFF criteria, 91% and 10%; Manchester criteria, 93% and 14%), but the proportions at initial assessment are still low. CONCLUSIONS: None of the existing sets of criteria are adequate at initial assessment for diagnosing people who present without bilateral vestibular schwannomas as having NF2, particularly people with a negative family history of NF2. The authors recommend that a single, revised set of diagnostic criteria be devised to replace all of the existing sets of criteria.

Adolescent↗
PubMed2002

Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1).

Children with neurofibromatosis 1 (NF1) often develop low-grade gliomas, but brain tumors are infrequently encountered in adults with NF1. The authors present evidence from two clinical series, one including patients known to have NF1 and another focusing on adults with new onset brain tumors, that suggests an association between NF1 and symptomatic gliomas in older individuals. They also summarize the clinical data on 17 adolescents or adults with NF1 and symptomatic gliomas. The findings suggest that individuals with NF1 are at increased risk of developing gliomas throughout their lives.

Adolescent↗
PubMed2002

Predictors of the risk of mortality in neurofibromatosis 2.

To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.

Adolescent↗
PubMed2002

Medical genetics: 1. Clinical teratology in the age of genomics.

Teratogenic exposures are those that can cause an embryo or fetus to develop abnormally. Several factors determine whether an agent is teratogenic, including the gestational timing of the exposure, as well as the dose, route and nature of the agent itself. We review the general concepts of teratogenesis, as well as known genetic susceptibilities to teratogenic effects, with a special focus on antiepileptic drugs. We discuss general principles of risk counselling and risk reduction, and we describe several long-known teratogens, as well as several exposures recognized only recently to have teratogenic potential.

Adult↗
PubMed2002

Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study.

BACKGROUND: Down's syndrome is the most frequently identified cause of mental retardation, but information about mortality and comorbidity in people with Down's syndrome is limited. METHODS: We used data from US death certificates from 1983 to 1997 to calculate median age at death and standardised mortality odds ratios (SMORs) for common medical disorders in people with Down's syndrome. FINDINGS: Of 17897 people reported to have Down's syndrome, median age at death increased from 25 years in 1983 to 49 years in 1997, an average increase of 1.7 years per year studied (p<0.0001). Median age at death was significantly lower in black people and people of other races than in white people with Down's syndrome. As expected, death certificates with a diagnosis of Down's syndrome were more likely to list congenital heart defects (SMOR 29.1, 95% CI 27.8-30.4), dementia (21.2, 19.6-22.7), hypothyroidism (20.3, 18.5-22.3), or leukaemia (1.6, 1.4-1.8) than were those that did not report Down's syndrome. By contrast, malignant neoplasms other than leukaemia were listed on death certificates of people with Down's syndrome less than one-tenth as often as expected (0.07, 0.06-0.08). A strikingly low SMOR for malignancy was associated with Down's syndrome at all ages, in both sexes, and for all common tumour types except leukaemia and testicular cancer. INTERPRETATION: Identification of factors responsible for the racial differences recorded could facilitate further improvement in survival of people with Down's syndrome. Reduced exposure to environmental factors that contribute to cancer risk, tumour-suppressor genes on chromosome 21, or a slower rate of replication or higher likelihood of apoptosis in Down's syndrome cells, could be possible reasons for paucity of cancer in people with Down's syndrome.

Adult↗
PubMed2002

Intrafamilial correlation of clinical manifestations in neurofibromatosis 2 (NF2).

Measuring correlation in clinical traits among relatives is important to our understanding of the causes of variable expressivity in Mendelian diseases. Random effects models are widely used to estimate intrafamilial correlations, but such models have limitations. We incorporated survival techniques into a random effects model so that it can be used to estimate intrafamilial correlations in continuous variables with right censoring, such as age at onset. We also describe a negative-binomial gamma mixture model to determine intrafamilial correlations of discrete (e.g., count) data. We demonstrate the utility of these methods by analyzing intrafamilial correlations among patients with neurofibromatosis 2 (NF2), an autosomal-dominant disease caused by mutations of the NF2 tumor-suppressor gene. We estimated intrafamilial correlations in age at first symptom of NF2, age at onset of hearing loss, and number of intracranial meningiomas in 390 NF2 nonprobands from 153 unrelated families. A significant intrafamilial correlation was observed for each of the three features: age at onset (0.35; 95% confidence interval (CI) 0.23-0.47), age at onset of hearing loss (0.51; 95% CI, 0.35-0.64), and number of meninginomas (0.29; 95% CI, 0.15-0.43). Significant correlations were also observed for age at first symptom within NF2 families with truncating mutations (0.41; 95% CI, 0.06-0.68) or splice-site mutations (0.29; 95% CI, 0.03-0.51), for age at onset of hearing loss within families with missense mutations (0.67; 95% CI, 0.18-0.89), and for number of meningiomas within families with splice-site mutations (0.39; 95% CI, 0.13-0.66). Our findings are consistent with effects of both allelic and nonallelic familial factors on the clinical variability of NF2.

Adolescent↗
PubMed2002

Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1).

The relationship of genetic factors to variable expressivity in neurofibromatosis 1 (NF1) is poorly understood. We examined familial aggregation of NF1 features among different classes of affected relatives. Clinical information was obtained from the National NF Foundation International Database on 904 affected individuals in 373 families with 2 or more members with NF1. We used multivariate probit regression to measure the associations between various classes of relatives for each of 10 clinical features of NF1, while simultaneously adjusting for covariates including related features, age, and gender. Two distinct patterns were observed when we compared associations between first- and second-degree relatives, sibs, and parent-child pairs: Lisch nodules and café-au-lait spots had greater associations between first-degree relatives than between second-degree relatives, while subcutaneous neurofibromas, plexiform neurofibromas, café-au-lait spots, and intertriginous freckling had greater associations between sibs than between parents and children. In addition, Lisch nodules, subcutaneous neurofibromas, and cutaneous neurofibromas had greater associations between affected fathers and children than between affected mothers and children. These familial patterns suggest that unlinked modifying genes and the normal NF1 allele may both be involved in the development of particular clinical features of NF1, but that the relative contributions vary for different features.

Female↗
PubMed2002

Update on new developments in the study of human teratogens.

BACKGROUND AND METHODS: The purpose of this annual article is to highlight and briefly review new and significant information on agents that may be teratogenic in pregnant women. Various sources of on-line and printed information are given. RESULTS: The following topics have been discussed: 1) lithium medication: decreased estimate of risk; 2) cigarette smoking and genotype as contributors to oral-facial clefts and clubfoot; 3) trimethoprim; 4) methimazole syndrome?; 5) glucocorticoids and oral-facial clefts; 6) binge drinking; 7) fetal valproate syndrome; and 8) carbamazepine. CONCLUSIONS: We have highlighted several maternal exposures during pregnancy that are associated with small but increased rates of birth defects, generally only a few cases per 1,000 infants. These exposures include cigarette smoking, and treatment with lithium, trimethoprim, methimazole, or corticosteroids. This weak teratogenic effect was usually identified by the linkage of an uncommon treatment with an unusual birth defect outcome. The use of modern epidemiologic techniques, especially prospective multicenter studies that provide increased numbers, has helped to strengthen the evidence for these associations. We discuss how teratogenic risks that are small in comparison to the background risk can be presented to at-risk women and their doctors. We have briefly listed some elements that might be used in prioritizing further studies of suspected teratogenic exposures. Various existing methods for expressing the strength of evidence for human teratogenicity are also given.

Abnormalities, Drug-Induced↗
PubMed2002

Teratogenicity of recently introduced medications in human pregnancy.

OBJECTIVE: To determine how long it takes after a new drug is marketed to establish whether or not its use by pregnant women is likely to pose a substantial teratogenic risk. METHODS: We used standard clinical teratology resources to assess the teratogenic risks in human pregnancy of therapeutic treatment with 468 drugs approved by the US Food and Drug Administration between 1980 and 2000. The teratogenic risk of each treatment was classified using the current online version of TERIS into one of three categories: 1) no risk, minimal risk, or unlikely to produce an increased risk; 2) associated with a small, moderate, or high risk; or 3) risk undetermined. RESULTS: We found that the teratogenic risk in human pregnancy was still undetermined for 91.2% of drug treatments approved in the United States between 1980 and 2000. The proportion of treatments classified as having an "undetermined" teratogenic risk was more than 80% for drugs approved for marketing 0-4, 5-9, 10-14, or 15-20 years ago, but the highest proportion of drugs with an "undetermined" teratogenic risk was found among those approved 15-20 years ago. The agreement between TERIS risk ratings and Food and Drug Administration Use-in-Pregnancy Categories for 163 drugs that had been assessed by both systems was poor (kappa +/- standard error = 0.082 +/- 0.042). CONCLUSION: We conclude that inadequate information is available for pregnant women and their physicians to determine whether the benefits exceed the teratogenic risks for most drug treatments introduced in the past 20 years.

Abnormalities, Drug-Induced↗