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Biomedical subjects

W Navidi

Publications and source records attributed to W Navidi.

16 recordsLinked to original sources
PubMed2000

Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate.

An increasing number of human diseases and syndromes are being found to result from micro-duplications or microdeletions arising from meiotic recombination between homologous repeats on the same chromosome. The first microduplication syndrome delineated, Charcot-Marie-Tooth disease type 1A (CMT1A), results from unequal crossing over between two >98% identical 24 kb repeats (CMT1A-REPs) on chromosome 17. In addition to its medical significance, the CMT1A region has features that make it a unique resource for detailed analysis of human unequal recombination. Previous studies of CMT1A patients showed that the majority of unequal crossovers occurred within a small region (<1 kb) of the REPs suggesting the presence of a recombination hot-spot. We directly measured the frequency of unequal recombination in the hot-spot region using sperm from four normal individuals. Surprisingly, unequal recombination between the REPs occurs at a rate no greater than the average rate for the male genome (approximately 1 cM/Mb) and is the same as that expected for equally aligned REPs. This conclusion extends to humans the findings in yeast that recombination between repeated sequences far apart on the same chromosome may occur at similar frequencies to allelic recombination. Finally, the CMT1A hot-spot stands in sharp contrast to the human MS32 mini-satellite-associated hot-spot that exhibits highly enhanced recombination initiation in addition to positional specificity. One possibility is that the CMT1A hot-spot may consist of a region with genome average recombination potential embedded within a recombination cold-spot.

Adult↗
PubMed1999

A study of twelve Southern California communities with differing levels and types of air pollution. I. Prevalence of respiratory morbidity.

To study possible chronic respiratory effects of air pollutants, we initiated a 10-yr prospective cohort study of Southern California children, with a study design focused on four pollutants: ozone, particulate matter, acids, and nitrogen dioxide (NO2). Twelve demographically similar communities were selected on the basis of historic monitoring information to represent extremes of exposure to one or more pollutants. In each community, about 150 public school students in grade 4, 75 in grade 7, and 75 in grade 10 were enrolled through their classrooms. Informed consent and written responses to surveys about students' lifetime residential histories, historic and current health status, residential characteristics, and physical activity were obtained with the help of the parents. In the first testing season, 3,676 students returned questionnaires. We confirmed associations previously reported between respiratory morbidity prevalence and the presence of personal, demographic, and residential risk factors. Rates of respiratory illness were higher for males, those living in houses with pets, pests, mildew, and water damage, those whose parents had asthma, and those living in houses with smokers. Wheeze prevalence was positively associated with levels of both acid (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.14-1.83) and NO2 (OR = 1.54; 95% CI, 1.08-2.19) in boys. We conclude, based on this cross-sectional assessment of questionnaire responses, that current levels of ambient air pollution in Southern California may be associated with effects on schoolchildren's respiratory morbidity as assessed by questionnaire.

Acids↗
PubMed1999

A study of twelve Southern California communities with differing levels and types of air pollution. II. Effects on pulmonary function.

To study the possible chronic respiratory effects of air pollutants, we designed and initiated a 10-yr prospective study of Southern California public schoolchildren living in 12 communities with different levels and profiles of air pollution. The design of the study, exposure assessment methods, and survey methods and results related to respiratory symptoms and conditions are described in the accompanying paper. Pulmonary function tests were completed on 3,293 subjects. We evaluated cross-sectionally the effects of air pollution exposures based on data collected in 1986-1990 by existing monitoring stations and data collected by our study team in 1994. Expected relationships were seen between demographic, physical, and other environmental factors and pulmonary function values. When the data were stratified by sex, an association was seen between pollution levels and lower pulmonary function in female subjects, with the associations being stronger for the 1994 exposure data than the 1986-1990 data. After adjustment, PM10, PM2.5, and NO2 were each significantly associated with lower FVC, FEV1, and maximal midexpiratory flow (MMEF); acid vapor with lower FVC, FEV1, peak expiratory flow rate (PEFR), and MMEF; and O3 with lower PEFR and MMEF. Effects were generally larger in those girls spending more time outdoors. Stepwise regression of adjusted pulmonary function values for girls in the 12 communities showed that NO2 was most strongly associated with lower FVC (r = -0.74, p < 0.01), PM2.5 with FEV1 (r = -0.72, p < 0.01), O3 with PEFR (r = -0.75, p < 0.005), and PM2.5 with MMEF (r = -0.80, p < 0.005). There was a statistically significant association between ozone exposure and decreased FVC and FEV1 in girls with asthma. For boys, significant associations were seen between peak O3 exposures and lower FVC and FEV1, but only in those spending more time outdoors. These findings underline the importance of follow-up of this cohort.

Acids↗
PubMed1999

Statistical methods for epidemiologic studies of the health effects of air pollution.

We describe two statistical designs that can provide efficient estimates of the health effects of exposure to air pollutants in epidemiologic studies. We also evaluate the effects of measurement error in exposure assessment on the accuracy of estimated health effects. The bidirectional case-crossover design is a variant of a method proposed by Maclure (1991). Our version of the method takes advantage of the fact that in epidemiologic studies involving environmental exposure, accurate information about past exposure is more readily available, and that levels of exposure are generally unaffected by the response of the subject. It differs from other case-crossover methods in that control information is assessed both before and after failure, thus avoiding confounding due to time trends in exposure. The multilevel analytic design provides a method of combining estimates of health effects made on the individual level with those made at the group level. It has great potential value in situations where variations in exposure within groups may not be great enough to provide adequate power to detect health effects, as is often the case in air pollution studies where exposure levels are similar within a geographic community. Measurement errors in exposure assessment can have substantial impact on the accuracy of estimated health effects. When the microenvironmental approach is used to estimate exposure, a standard error of 30% in estimating indoor/outdoor ratios can increase the standard error of a relative risk estimate by 50%, and introduce bias as well. Similar results hold when exposure is estimated with personal samplers. When the microenvironmental approach is used, errors in estimating indoor/outdoor ratios have more influence on the accuracy of risk estimation than do errors in estimating the time spent in microenvironments.

Absenteeism↗
PubMed1998

Bidirectional case-crossover designs for exposures with time trends.

In the case-crossover design (Maclure, 1991, American Journal of Epidemiology 133, 144-153), only cases are sampled, and risk estimates are based on within-subject comparisons of exposures at failure times with exposures at times prior to failure, using matched case-control methods. While the design provides considerable advantages, unidirectional retrospective control sampling (selecting control times only prior to failure) can cause risk estimates to be confounded by time trends in exposure. However, when subsequent exposures are not influenced by failures, as in studies of environmental exposures such as air pollutants, it is possible to determine at times postfailure what a subject's level of exposure would have been had the subject not failed. We describe a bidirectional case-crossover design in which exposures at failure are compared with exposures both before and after failure. Simulation analyses show that relative risk estimates are resistant to confounding by time trend. We also extend the method to studies involving multiple failure times.

Absenteeism↗
PubMed1996

Los Angeles study of residential magnetic fields and childhood brain tumors.

A measurement study of residential magnetic fields and brain tumors in children that was added onto an ongoing case-control interview study in Los Angeles County, California, include 298 children under age 20 years with a primary brain tumor diagnosed from 1984 to 1991 and 298 control children identified by random digit dialing. Magnetic fields were determined for all Los Angeles homes where these 596 children lived from conception to diagnosis (1,131 homes) by mapping and coding the wiring configurations outside the home and by taking a series of exterior spot and profile measurements. In addition, for a subset of subjects (35%; 211 homes) 24-hour measurements were taken in the child's room and one other room. Although measured fields are consistently highest in the highest of the five wire code categories, fields in homes in this category are much lower in Los Angeles than in Denver, where the code originated. Brain tumor risk appears not to relate to measured fields inside (p for trend for child's room = 0.98) or outside (p for trend for front wall = 0.82) the home. An apparent increase in risk among children living at diagnosis in homes with underground wiring appears to be an artifact introduced by using current controls for historical cases because this apparent excess risk disappeared in an analysis restricted to the later years of the study when cases and controls were accrued concurrently. Our study does not show an overall association of pediatric brain tumors with measured fields, with "very high" wiring configurations, or with any of several other potential sources of exposure, such as use of various electrical appliances, but the prevalence of high fields (> 2 mG) and very high fields (> 3 mG) in Los Angeles homes was too low to detect a moderate effect of the magnitude reported in other studies.

Adolescent↗
PubMed1996

Somatic microsatellite mutations as molecular tumor clocks.

Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one-month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tumorigenesis provides direct estimates of tumor ages, with up to thousands of cell divisions and high death rates necessary to yield the observed diversities. MS molecular tumor clocks have the unique potential to systematically reconstruct the early and occult evolution of individual human mutator phenotype tumors.

Adenocarcinoma↗
PubMed1996

The mutation rate of the human mtDNA deletion mtDNA4977.

The human mitochondrial mutation mtDNA4977 is a 4,977-bp deletion that originates between two 13-bp direct repeats. We grew 220 colonies of cells, each from a single human cell. For each colony, we counted the number of cells and amplified the DNA by PCR to test for the presence of a deletion. To estimate the mutation fate, we used a model that describes the relationship between the mutation rate and the probability that a colony of a given size will contain no mutants, taking into account such factors as possible mitochondrial turnover and mistyping due to PCR error. We estimate that the mutation rate for mtDNA4977 in cultured human cells is 5.95 x 10(-8) per mitochondrial genome replication. This method can be applied to specific chromosomal, as well as mitochondrial, mutations.

Adult↗
PubMed1996

Individual variation in recombination among human males.

Studies of recombination between the markers D6S291 and D6S109 in individuals by sperm typing provide direct evidence for significant variation in recombination among humans. A statistically significant difference in the recombination fraction (range 5.1%-11.2%) was detected among five donors. This variation could reflect polymorphisms in genes affecting recombination or in chromosome structure. Ignoring this variability in studies designed to examine the relationship between physical and genetic distances could lead to incorrect inferences. Individual variation in recombination makes it difficult to predict the recombination fraction for an interval in any particular individual. This could be important in certain genetic counseling situations.

Adult↗
PubMed1994

Design and analysis of multilevel analytic studies with applications to a study of air pollution.

We discuss a hybrid epidemiologic design that aims to combine two approaches to studying exposure-disease associations. The analytic approach is based on comparisons between individuals, e.g., case-control and cohort studies, and the ecologic approach is based on comparisons between groups. The analytic approach generally provides a stronger basis for inference, in part because of freedom from between-group confounding and better quality data, but the ecologic approach is less susceptible to attenuation bias from measurement error and may provide greater variability in exposure. The design we propose entails selection of a number of groups and enrollment of individuals within each group. Exposures, outcomes, confounders, and modifiers would be assessed on each individual; but additional exposure data might be available on the groups. The analysis would then combine the individual-level and the group-level comparisons, with appropriate adjustments for exposure measurement errors, and would test for compatibility between the two levels of analysis, e.g., to determine whether the associations at the individual level can account for the differences in disease rates between groups. Trade-offs between numbers of groups, numbers of individuals, and the extent of the individual and group measurement protocols are discussed in terms of design efficiency. These issues are illustrated in the context of an on-going study of the health effects of air pollution in southern California, in which 12 communities with different levels and types of pollution have been selected and 3500 school children are being enrolled in a ten-year cohort study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Whole genome amplification from a single cell: implications for genetic analysis.

We have developed an in vitro method for amplifying a large fraction of the DNA sequences present in a single haploid cell by repeated primer extensions using a mixture of 15-base random oligonucleotides. We studied 12 genetic loci and estimate that the probability of amplifying any sequence in the genome to a minimum of 30 copies is not less than 0.78 (95% confidence). Whole genome amplification beginning with a single cell, or other samples with very small amounts of DNA, has significant implications for multipoint mapping by sperm or oocyte typing and possibly for genetic disease diagnosis, forensics, and the analysis of ancient DNA samples.

Base Sequence↗
PubMed1992

Gene-centromere linkage mapping by PCR analysis of individual oocytes.

We describe a general method of determining the recombination fraction between a polymorphic locus and the centromere in any species where single oocytes can be obtained. After removal of the first polar body, each oocyte is analyzed by PCR. The frequency of oocytes heterozygous at the polymorphic locus is used to estimate the recombination fraction. We estimate a recombination fraction of 0.15 between the mouse major histocompatibility complex (H-2) and the centromere of chromosome 17.

Animals↗
PubMed1992

A multiple-tubes approach for accurate genotyping of very small DNA samples by using PCR: statistical considerations.

A multiple-tubes procedure is described for using PCR to determine the genotype of a very small DNA sample. The procedure involves dividing the sample among several tubes, then amplifying and typing the contents of each tube separately. The results are analyzed by a statistical procedure which determines whether a genotype can be conclusively assigned to the DNA sample. Simulation studies show that this procedure usually gives correct results even when the number of double-stranded fragments in the sample is as small as 30. The procedure remains effective even in the presence of small amounts of laboratory contamination. We find that the multiple-tubes procedure is superior to the standard one-tube procedure, either when the sample is small or when laboratory contamination is a potential problem; and we recommend its use in these situations. Because the procedure is statistical, it allows the degree of certainty in the result to be quantified and may be useful in other PCR applications as well.

DNA↗
PubMed1991

Using PCR in preimplantation genetic disease diagnosis.

Preimplantation diagnosis of genetic disease can be accomplished by embryo biopsy or polar body analysis using in-vitro gene amplification (PCR). PCR analysis of single cells is subject to a number of errors which decrease the reliability of the diagnosis. Using realistic assumptions about error rates based on experimental data, we analyse some of the practical consequences to be faced by whose wishing to use this diagnostic procedure. We considered both autosomal dominant and recessive diseases. We calculate the probability of making mistakes in the diagnosis, assuming a realistic range in the magnitude of PCR efficiency, cell transfer, and contamination errors. We conclude that, in general, analysing blastomeres is subject to less mis-diagnosis than polar body analysis, except in the case of dominant diseases which are caused by genes which lie extremely close to the centromere. We also show that typing multiple blastomeres from a single embryo or combining polar body typing with blastomere analysis results in significantly lower levels of mis-diagnosis with unacceptable consequences. The preimplantation diagnosis of X-linked diseases based upon Y chromosome sequence analysis is also discussed.

Blastomeres↗
PubMedDate not supplied

Measurement error in air pollution exposure assessment.

The exposure of an individual to an air pollutant can be assessed indirectly, with a "microenvironmental" approach, or directly with a personal sampler. Both methods of assessment are subject to measurement error, which can cause considerable bias in estimates of health effects. If the exposure estimates are unbiased and the measurement error is nondifferential, the bias in a linear model can be corrected when the variance of the measurement error is known. Unless the measurement error is quite large, estimates of health effects based on individual exposures appear to be more accurate than those based on ambient levels.

Air Pollutants↗