Biomedical subjects
Publications and source records attributed to M Vaeth.
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Although the lifetable methodology is a standard tool in epidemiology and risk assessment, there are a number of differences in the way it has been applied by various advisory committees that have attempted to estimate radiation risks. The most fundamental of these differences concerns the choice of parameter to be estimated: the "excess lifetime risk" is the difference in lifetime risks between exposed and unexposed populations; the "risk of exposure-induced death" is the lifetime risk of dying of a disease attributable to exposure. These two quantities are not the same, even at low doses. Although both quantities have some utility in risk assessment, the "risk of exposure-induced death" comes closer to capturing the total impact of exposure. Other differences between reported risk estimates include details of the calculations, the baseline rates and age distributions of the exposed population, the forms of the models for excess rates, handling of organ-specific doses, and the groupings of cancer sites. These issues are discussed theoretically and illustrated with comparisons of the BEIR V and UNSCEAR reports. Although the risk estimates from these two reports are similar for most cancer sites, it is shown that this happens to be the result of an approximate cancellation of a number of differences that could be quite large.
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 shape of the dose-response curve for cancer mortality in the A-bomb survivor data is analyzed in the context of linear-quadratic models. Results are given for all cancers except leukemia as a group, for leukemia, and for combined inferences assuming common curvature. Since there is substantial information aside from these data suggesting a dose-response curve with upward curvature, the emphasis here is not on estimating the best-fitting dose-response curve, but rather on assessing the maximum curvature under linear-quadratic models which is consistent with the data. The apparent shape of the dose-response curve is substantially affected by imprecision in the dose estimates, and methods are applied to correct for this. The extent of curvature can be expressed as the factor by which linear risk estimates from these data should be divided to arrive at appropriate estimates of risk at low doses. Influential committees have in the past recommended ranges of 1.5-4 and of 2-10 for such a factor. Results here suggest that values greater than about 2.0-2.5 are at least moderately inconsistent with these data, within the context of linear-quadratic models. It is emphasized, however, that there is little direct information in these data regarding risks following low doses; the inferences here depend strongly on the assumption of a linear-quadratic model.
This report has two aims: (1) to describe and analyze the age/time patterns of excess cancer risk in the atomic bomb survivor cohort followed up by the Radiation Effects Research Foundation (RERF), and (2) to describe statistical methods which are used in RERF's analyses of data on mortality and morbidity in the cohort. In contrast to previous analyses of the cohort cancer mortality data, substantial use is made of Japanese national cancer rates for the purpose of investigation of the age/time variations in excess risk. This analysis considers mortality from all cancers except leukemia as a group. Primary attention is given to description in terms of the age-specific excess relative risk, but the importance of appropriate descriptions of the absolute excess risk is also emphasized. When models for the excess risk allow variation with age and time, both constant relative and absolute excess risk models provide similar fits to the data. Previous reports have indicated that for a given age at exposure and sex, the excess age-specific relative risk is remarkably constant throughout the current follow-up period. Statistical analysis here indicates that for those less than about 35 years of age at exposure there is no departure from this pattern, beyond ordinary sampling variation. For those over about 35 years of age at exposure, there is modest evidence of an increasing trend in the excess relative risk, which could plausibly be attributed to effects related to minimal latent period. Some brief consideration is given to modeling the absolute excess risk as the product of an age-at-exposure and time-since-exposure effect. Interpretation of these results, particularly in regard to projections beyond the current follow-up, is discussed.
Regional cerebral blood flow in anaesthetized pigs is determined with the microsphere method. Five regions of cortical grey matter and three white subcortical areas in each hemisphere are examined together with anatomically classic structures. The validity of the biopsies was confirmed by freeze drying of the tissue. Three flow measurements in a group of six animals showed large interindividual variations whereas regions with the same structure in the particular animal showed a high degree of uniformity. Symmetrical regions in the two hemispheres were similar with a coefficient of variation between sides of less than 5%. The coefficient of variation of the particular flow measurements were 15%. The different brain structures have four discernible flow levels. White subcortical matter has three different flow values and forms together with medulla oblongata and hippocampus the low flow area. Flow in grey cortical matter is of the same magnitude as in unanaesthetized animals and constitutes together with thalamus, mesencephalon, pons and cerebellar hemispheres the intermediate flow level. The high flow areas are nucleus caudatus and lentiformis together with the cerebellar vermis. The choroid plexus, pituitary gland and pineal gland all have very high flow values and seem, in contrast to the rest of the brain, insensitive to the CO2-tension in arterial blood and global cerebral metabolism. Microsphere estimation of regional blood flow seems to be an appropriate technique for evaluating regional cerebral blood with a high degree of spatial resolution in repeated flow measurements.
When assessing the impact of radiation exposure it is common practice to present the final conclusions in terms of excess lifetime cancer risk in a population exposed to a given dose. The present investigation is mainly a methodological study focusing on some of the major issues and uncertainties involved in calculating such excess lifetime risks and related risk projection methods. The age-constant relative risk model used in the recent analyses of the cancer mortality that was observed in the follow-up of the cohort of A-bomb survivors in Hiroshima and Nagasaki is used to describe the effect of the exposure on the cancer mortality. In this type of model the excess relative risk is constant in age-at-risk, but depends on the age-at-exposure. Calculation of excess lifetime risks usually requires rather complicated life-table computations. In this paper we propose a simple approximation to the excess lifetime risk; the validity of the approximation for low levels of exposure is justified empirically as well as theoretically. This approximation provides important guidance in understanding the influence of the various factors involved in risk projections. Among the further topics considered are the influence of a latent period, the additional problems involved in calculations of site-specific excess lifetime cancer risks, the consequences of a leveling off or a plateau in the excess relative risk, and the uncertainties involved in transferring results from one population to another. The main part of this study relates to the situation with a single, instantaneous exposure, but a brief discussion is also given of the problem with a continuous exposure at a low-dose rate.
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.
We report a simple, reproducible, and low-invasive in vivo method for repeated examination of bladder well properties in mice. Over a period of 21 days transurethral bladder fillings were performed every second day on the same animal. Analysis of the bladder volume at an intravesical pressure of 10 and 20 mm. Hg and at the leakage point showed no trend during the 21 day study period with regard to changes in bladder volume. The model has been applied to a group of mice treated with a single fraction bladder irradiation dose of 20 Gy. These mice were investigated repeatedly during the following year. The end point selected for data evaluation in the irradiated group of mice was a 50% decrease in bladder volume at an intravesical pressure of 20 mm. Hg relative to the control value (bladder volume before irradiation). The results clearly demonstrate a biphasic change in the bladder reservoir function, in the form of an acute, reversible change, a period of normalization and then a late irreversible damage. The latter stage is consistent with the clinically found contracted bladder. In a control group there was no significant change in bladder volume during the study period of more than 200 days. The model thus appears feasible for future studies of bladder irradiation damage.
Forty-six newly diagnosed patients with T1 and T2 bladder tumors were treated with transurethral resection. During a 6-months period more than 50% of the tumors recurred. Subsequent progression of tumors was seen within 24 months in 35 and 28% of the patients with T1 and T2 tumors, respectively. Prognosis with regard to progression was significantly better in patients with Ta recurrence at first control than in patients with invasive recurrent tumors, irrespective of category of tumor at a later recurrence. It is concluded that the continued transurethral treatment of patients with early recurrent invasive tumors may have to be reconsidered.
This paper studies two classes of hazard-rate-based models for the mortality in a group of individuals taking normal life expectancy into account. In a multiplicative hazard model, the estimate for the relative mortality generalises the standardised mortality ratio, and the adequacy of a model with constant relative mortality can be tested using a type of total time on test statistic. In an additive hazard model, continuous-time generalisations of a "corrected" survival curve and a "normal" survival curve are obtained, and the adequacy of a model with constant excess mortality can again be tested using a type of total time on test statistic. A model including both the multiplicative hazard model and the additive hazard model is briefly considered. The use of the models is illustrated on a set of data concerning survival after operation for malignant melanoma.
In a multiphase material the structural components or phases are everywhere in contact with each other. The relative area of surface contact between various phases is an important aspect of the short-range ordering or organization of the structure. The stereological quantitation of such specific interfaces is a simple and well-known technique. The proper statistical definition of realistic models for the frequency of contact and the quantitative estimation of phase-specific affinities is studied. The meaningful interpretation of sets of estimated affinities poses a major problem of statistical inference which is dealt with in detail and illustrated by a worked-out biological example.
The impact of microalbuminuria on mortality as well as other risk factors was investigated in a 10-year follow-up study of 503 predominantly non-insulin-dependent diabetic patients of whom 265 had died. Using Cox's regression analysis the prognostic influence of age, sex, age at diagnosis, known diabetes duration, blood pressure, fasting plasma glucose, relative weight, serum creatinine, retinopathy, and treatment was evaluated as well as morning urine albumin concentration (UAC) in four categories, i.e. UAC less than or equal to 15 micrograms/ml (normal), 15 micrograms/ml less than UAC less than or equal to 40 micrograms/ml, 40 micrograms/ml less than UAC less than or equal to 200 micrograms/ml and UAC greater than 200 micrograms/ml. Age, UAC, known duration, and serum creatinine were the only significant risk factors. After correction for the other three independent risk factors, the hazard ratios in the elevated UAC categories relative to the group with UAC less than or equal to 15 micrograms/ml were 1.53 (p = 0.007), 2.28 (p = 0.000002), and 1.82 (p = 0.02). The statistically significant correlations with UAC were: age (r = 0.09, p less than 0.05), duration (r = 0.14, p less than 0.01), systolic blood pressure (r = 0.12, p less than 0.01), serum creatinine (r = 0.33, p less than 0.001), and fasting plasma glucose (r = 0.12, p less than 0.01). Increased UAC was associated also with retinopathy (p = 0.01). Fifty-eight per cent of the deaths were caused by cardiovascular disease or stroke; only 3% died from uraemia. A reinvestigation including blood pressure, fasting plasma glucose, and UAC was made on 208 survivors.
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A total of 122 patients (mean age: 55 years, range 20-75 years) were alive 30 days after isolated aortic valve replacement (AVR) performed in 1965-73 for aortic valve stenosis (AS). Cold chemical Bretschneider cardioplegia was used in all operations. The maximum follow-up was 17 years, mean 9 years. The 10-year cumulative survival +/- SE was 63 +/- 4%. Twenty-one preoperative clinical, invasive and valve-related variables were entered into a Cox regression analysis. Variables with independent predictive value regarding long-term survival were: Left ventricular failure (regression coefficient: b = 1.078, p less than 0.0002), age (b = 0.749, p less than 0.009), pulse pressure (b = -0.663, p less than 0.02) and cardio-thoracic index (CTI) (b = 0.603, p less than 0.04). Based on these variables, a prognostic index with 16 different risk groups was made. In the "best" group (n = 8), the observed 10-year survival +/- SE was 88 +/- 11%, compared to 13 +/- 12% for the "worst" group (n = 8). Multivariate analysis of complication-free survival showed that the total valve-related complication-rate (VRC) (4.2/100 pat.-yrs) was influenced by valve type (Starr-Edwards ball valves, n = 118, versus Lillehei-Kaster and Smeelof-Cutter valves, n = 4) and CTI. The valve- and heart-related events (VRC together with late myocardial infarctions and pacemaker implantations, 6.5/100 pat.-yrs) depended on CTI and previous myocardial infarction. No predictors of thromboembolism (1.6/100 pat.-yrs) or coumarin-related hemorrhage (1.8/100 pat.-yrs) could be identified.(ABSTRACT TRUNCATED AT 250 WORDS)
92 patients with acute myeloid leukemia were classified according to the FAB classification (M1 n = 20, M2 n = 43, M3 n = 1, M4 n = 19, M5a n = 2, M5b n = 2, and M6 n = 5 patients). Serum measurements of lactoferrin (LF), myeloperoxidase (MPO) and lysozyme (LYS) were performed before the start of treatment. LF was significantly lower in M1 when compared with M2 but not as compared to M4, MPO was significantly higher in M2 and M4 than in M1, but comparable MPO levels were found in M2 and M4. LYS was significantly elevated in M2 in comparison with M1, and in M4 when compared to both M1 and M2. Polymorphonuclear granulocytes (PMNs) in M1 were significantly reduced when compared with M2 and M4, whereas mononuclear cells were significantly increased in M4 in comparison with both M1 and M2. FAB classification did not generate any prognostic information. When the patients were, instead, subdivided according to LF levels were found prognostically significant differences. Of patients below 100 micrograms/l, 44% went into remission as compared to 77% with LF from 101 to 400 micrograms/l. In patients with LF levels above 400 micrograms/l the remission frequency was only 14%. Multivariate statistical analysis on the data further suggested that lactoferrin may be used as an independent prognostic indicator. We conclude that although determination of the serum-levels of lactoferrin, lysozyme and myeloperoxidase in certain cases may be valuable as a supplement to the morphological examination of acute myeloid leukemia, it is evident that none of the three determinations can be used alone to distinguish between the FAB groups.
Forty-six newly diagnosed patients with T1 and T2 bladder tumours were treated with radical transurethral resection. During a six-month period more than 50% of the tumours recurred. Subsequently progression of tumours was seen within 24 months in 30 and 50% of the patients with T1 and T2 tumours, respectively. Prognosis with regard to the progression was significantly better in patients with Ta recurrence at first TUR control than in patients with invasive recurrent tumours.