Search

This paper discusses the application of estimating equations methods based on a quadratic exponential model [Prentice and Zhao, 1991] as a potential competitor with full likelihood approaches to estimating the effect of major genes in a segregation analysis [Elston, 1981] of continuous phenotypes, in the single allele problem. We show that while the estimating equations methods based on the quadratic exponential family cannot be used by themselves to estimate all parameters of interest, an iterative two-stage approach can be used, in which the population allele frequency is first considered to be a known parameter, which permits the estimating equations method to estimate the remaining parameters. At the second stage a "pseudo-profile" loglikelihood based only on the founders is used to estimate the allele frequency. After each maximization of the pseudo-profile loglikelihood at the second stage, the parameters in the first stage are reestimated using a new value of the allele frequency, and a new value of the second stage pseudo-profile loglikelihood is obtained. We used simulated pedigree data for illustrations.

The use of generalized estimating equations (GEE) [Liang and Zeger, 1986] is explored as a potential alternative to maximum likelihood methods for segregation analysis of continuous phenotypes. We discuss the number of sample moments required by GEE to estimate parameters in simple major gene models, and the computational burden of the GEE methods applied to large pedigrees.

An analysis of the proportion of cells with chromosome aberrations in cultured blood lymphocytes from A-bomb survivors in Hiroshima and Nagasaki reveals that the dose-response relationship using DS86 assigned dose is significantly steeper in the subsample of individuals who reported severe epilation after the bombings than in those who did not report severe epilation. This effect is due either to random errors in the DS86 dose assignments or to individual differences in sensitivity to radiation, or to both. In this paper, working within a class of dosimetry error models, we estimate the magnitude of random dosimetry errors which would be required to account for all of the difference in the observed dose response between people who did and did not report severe epilation under the assumption that random dosimetry error is the only cause of the effect. We conclude that random dosimetry errors in the range 45 to 50% of true dose are necessary to explain completely the difference in dose response between the two epilation groups. We discuss evidence that the contribution of individual differences in radiation sensitivity to the observed epilation effect is likely to be small, so that random dosimetry errors may be the major cause of this effect.

One hundred eighteen children with metastatic (Childrens Cancer Study Group [CCSG] stage IV), extensive regional (stage III), or stage II neuroblastoma with N-myc amplification received an intensive chemotherapeutic regimen of cis-platinum, etoposide, doxorubicin, and cyclophosphamide combined with persistent aggressive attempts at complete primary tumor resection. Fourteen patients were unevaluable and 42 left the study to be placed on bone marrow transplant protocols. The remaining 62 children were evaluated in detail. Complete excision was eventually accomplished in 39 patients (63%), 23 of whom are disease-free survivors after 8 to 47 months (median, 20 months). Twenty-three patients underwent partial excision or biopsy of their lesion and only 6 are alive without evidence of disease (P = .0011). Timing of surgery or site of tumor did not influence surgical outcome. N-myc oncogene expression could not predict which lesions would be completely resectable. Surgical complications occurred 21% of the time but the impact on the clinical course and chemotherapy administration was minimal. The ipsilateral kidney was removed with the tumor in 18 cases, 14 of which were during complete resection. Twelve of these children are disease-free survivors. With new intensive chemotherapy capable of eliciting an effective response from primary and metastatic neuroblastoma, aggressive surgical approaches for complete tumor resection are warranted and can be expected to improve patient outcome.

Random errors in the DS86 radiation dose estimates used in the analysis of A-bomb survivor data are recognized to have an important impact upon estimates of the risk of late effects such as cancer. Little however is known for certain concerning the distribution of such random errors. This paper gives an overview of recent work at the Radiation Effects Research Foundation (RERF) using multivariate analysis of biological data, including acute effects of radiation exposure, late effects (eg leukemia mortality) and stable chromosome aberrations, for the purpose of evaluating the extent of random error in the estimation of individual doses using DS86. The emphasis here is on analyses of apparent association between biological endpoints, in light of a dosimetry error model framework proposed recently by Pierce et al. Analyses performed to date appear to be consistent with the view that lognormal random dosimetry errors with a standard deviation of 40% or greater of true dose may exist in DS86. Association between radiogenic outcomes in A-bomb survivors, after adjustment for DS86 estimated dose level, has been detected for such widely varying pairs of outcomes as mutant T-cell frequencies and chromosome aberrations, epilation and leukemia mortality, and epilation and chromosome aberrations. The motivation for examining association between pairs of biological endpoints has usually been to determine the extent to which radiation sensitivity varies between individual survivors. Recognizing, however, that random error in dose estimates results in apparent association between biological outcomes is crucial to interpreting studies, such as these, which use data on multiple biological endpoints. To go one step further, in situations where there is a prior knowledge about the biological plausibility of such associations in outcome data the amount of association between radiogenic outcomes (remaining after adjustment for estimated dose), to the extent that they are greater than that assumed to be reasonable, is an important potential source of information concerning the magnitude of random errors in the DS86 dose estimates.

Unless allowances are made, random errors in radiation dose estimates cause underestimation of linear risk estimates and distort the shape of dose-response curves. These errors also result in spurious associations between radiogenic endpoints, exaggerating possible variations in individual sensitivity to radiation. Statistical methods have been developed which reduce these biases, based on assumptions regarding the nature and magnitude of dose-estimation errors. Some understanding of the underlying statistical basis for these methods is necessary to both those interested in interpreting radiogenic effects and those interested in the dosimetry system. This paper discusses the basic statistical issues and their implications, presents some statistical methods to deal with the problem, and indicates the sensitivity of certain results to assumptions about the magnitude of the dose-estimation errors.

In an analysis of a follow-up study of a fixed population of 73,330 atomic bomb survivors in Hiroshima and Nagasaki, the slope of an estimated dose response between ionizing radiation and leukemia mortality was found to be steeper (P less than 0.002), by a factor of 2.4, among those who reported epilation within 60 days of the bombings, compared to those who did not experience this sign of acute radiation exposure. The strength of this empirical finding as evidence of biological association in individual radiosensitivity for these two end points is studied here. The major factor complicating the interpretation of this finding as evidence of such an association is the degree of imprecision of the radiation dosimetry system used in assignment of radiation doses to the A-bomb survivors. Using models recently suggested for dealing with dosimetry errors in epidemiological analysis of the A-bomb survivor data, the sensitivity of the apparent association between leukemia mortality and severe epilation to the assumed level of dosimetry error is investigated.

The presence of random errors in the individual radiation dose estimates for the A-bomb survivors causes underestimation of radiation effects in dose-response analyses, and also distorts the shape of dose-response curves. Statistical methods are presented which will adjust for these biases, provided that a valid statistical model for the dose estimation errors is used. Emphasis is on clarifying some rather subtle statistical issues. For most of this development the distinction between radiation dose and exposure is not critical. The proposed methods involve downward adjustment of dose estimates, but this does not imply that the dosimetry system is faulty. Rather, this is a part of the dose-response analysis required to remove biases in the risk estimates. The primary focus of this report is on linear dose-response models, but methods for linear-quadratic models are also considered briefly. Some plausible models for the dose estimation errors are considered, which have typical errors in a range of 30-40% of the true values, and sensitivity analysis of the resulting bias corrections is provided. It is found that for these error models the resulting estimates of excess cancer risk based on linear models are about 6-17% greater than estimates that make no allowance for dose estimation errors. This increase in risk estimates is reduced to about 4-11% if, as has often been done recently, survivors with dose estimates above 4 Gy are eliminated from the analysis.

This report presents a reanalysis of the Hiroshima and Nagasaki data on severe epilation as an acute radiation effect using both the new DS86 and the old T65D dosimetries. The focus of the report is on several aspects of the data which have previously been examined by Jablon et al (ABCC TR 12-70, 1970) and Gilbert and Ohara [Radiat. Res. 100, 124-138 (1984)]. The report examines the uniformity of epilation response across shielding category, across sex and age, and in terms of interactions between city, sex, age, and shielding category; it also investigates the apparent relative biological effectiveness (RBE) of neutrons in the DS86 dose compared with the T65D dose, using both within- and between-city information. In addition the report discusses evidence for nonlinearity in epilation response. The epilation response function exhibits nonlinearity in terms of both a marked increase in slope at about 0.75 Gy, and then, beginning at about 2.5 Gy, a leveling off and eventual decrease in response. The principal conclusions of the report are as follows. The use of the DS86 dosimetry rather than T65D increases the apparent RBE of neutrons compared with gamma dose from approximately 5 to 10. At these values of RBE the slope of the dose response, in a middle range from 0.75-2.5 Gy, is about 165% greater using DS86 than T65D. With respect to the interactions of sex, city, and shielding method, the size and significance of virtually all nonuniformities in epilation response seem using T65D are also evident with DS86. Additionally it seems difficult to find any evidence that DS86 is an improved predictor of epilation response over T65D. Finally, the fact that the nonlinearity in dose response and apparent actual downturn in epilation occurrence rate at the high end of dose is more striking with DS86 than with T65D is found to be due primarily to the common practice of truncating all T65D doses to 600 rad.

Results are presented from a second cross-sectional assessment of the association of air pollution with chronic respiratory health of children participating in the Six Cities Study of Air Pollution and Health. Air pollution measurements collected at quality-controlled monitoring stations included total suspended particulates (TSP), particulate matter less than 15 microns (PM15) and 2.5 microns (PM2.5) aerodynamic diameter, fine fraction aerosol sulfate (FSO4), SO2, O3, and No2. Reported rates of chronic cough, bronchitis, and chest illness during the 1980-1981 school year were positively associated with all measures of particulate pollution (TSP, PM15, PM2.5, and FSO4) and positively but less strongly associated with concentrations of two of the gases (SO2 and NO2). Frequency of earache also tended to be associated with particulate concentrations, but no associations were found with asthma, persistent wheeze, hay fever, or nonrespiratory illness. No associations were found between pollutant concentrations and any of the pulmonary function measures considered (FVC, FEV1, FEV0.75, and MMEF). Children with a history of wheeze or asthma had a much higher prevalence of respiratory symptoms, and there was some evidence that the association between air pollutant concentrations and symptom rates was stronger among children with these markers for hyperreactive airways. These data provide further evidence that rates of respiratory illnesses and symptoms are elevated among children living in cities with high particulate pollution. They also suggest that children with hyperreactive airways may be particularly susceptible to other respiratory symptoms when exposed to these pollutants.(ABSTRACT TRUNCATED AT 250 WORDS)

Reported here are the results from an ongoing study of outdoor air pollution and respiratory health of children living in six cities in the eastern and midwestern United States. The study enrolled 10,106 white preadolescent children between 1974 and 1977 in 3 successive annual visits to each city. Each child received a spirometric examination, and a parent completed a standard questionnaire. Of this cohort, 8,380 children were seen for a second examination 1 yr later. An air pollution monitoring program was begun in each community at about the time of the first examination. For this report, measurements of total suspended particulates (TSP), the sulfate fraction of TSP (TSO4), and sulfur dioxide (SO2) concentrations at study-affiliated outdoor stations were combined with measurements at other public and private monitoring sites to create a record of TSP, TSO4, and SO2 concentrations in each of 9 air pollution regions during the 1-yr period preceding each examination and, for TSP, during each child's lifetime up to the time of testing. Across the 6 cities, frequency of cough was significantly associated with the average of 24-h mean concentrations of all 3 air pollutants during the year preceding the health examination (p less than 0.01). Rates of bronchitis and a composite measure of lower respiratory illness were significantly associated with average particulate concentrations (p less than 0.05). In analyses restricted to lifetime residents, these outcomes were significantly associated with measures of lifetime mean TSP concentration. Within the cities, however, temporal and spatial variation in air pollutant concentrations and illness and symptom rates were not positively associated.(ABSTRACT TRUNCATED AT 250 WORDS)