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1.
Epidemiol Infect ; 148: e20, 2020 02 05.
Article in English | MEDLINE | ID: mdl-32019616

ABSTRACT

Infectious diseases, such as Helicobacter pylori, which produce systemic inflammation may be one key factor in the onset of autoimmunity. The association between H. pylori and antinuclear antibodies (ANA), a marker of autoimmunity, has been understudied. Data from the 1999-2000 National Health and Nutrition Examination Survey were used to evaluate the cross-sectional association between H. pylori seroprevalence and ANA positivity in US adults aged ≥20 years. ANA was measured in a 1:80 dilution of sera by indirect immunofluorescence using HEp-2 cells (positive ⩾3). H. pylori immunoglobulin G enzyme-linked immunosorbent assays were used to categorise individuals as seropositive or seronegative. H. pylori seropositivity and ANA positivity were common in the adult US population, with estimated prevalences of 33.3% and 9.9%, respectively. Both were associated with increasing age. H. pylori seropositivity was associated with higher odds of ANA (prevalence odds ratio = 1.89, 95% confidence interval = 1.08-3.33), adjusted for age, sex, race/ethnicity, educational attainment and body mass index. H. pylori infection may be one key factor in the loss of self-tolerance, contributing to immune dysfunction.


Subject(s)
Antibodies, Antinuclear/blood , Antibodies, Bacterial/blood , Autoimmune Diseases/epidemiology , Helicobacter Infections/complications , Helicobacter Infections/epidemiology , Helicobacter pylori/immunology , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Nutrition Surveys , Seroepidemiologic Studies , United States/epidemiology , Young Adult
2.
Pediatr Obes ; 7(2): 101-9, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22434749

ABSTRACT

OBJECTIVE: To investigate the effect of birth weight and early weight gain on the timing of various measures of puberty in both girls and boys. METHODS: A total of 856 newborns enrolled in the North Carolina Infant Feeding Study were followed to age 5 years, with 600 children followed up at adolescence. Birth weight was obtained from medical records and children were weighed at study visits until age 5 years; gains in standardized weights were calculated over four early age intervals: 0-6 months, 6-12 months, 1-2 years and 2-5 years. Age at menarche in girls and age at advanced Tanner stages in both girls and boys were reported by adolescents and their parents. Survival models were used to analyse the effects of birth weight and early weight gain on these outcomes. RESULTS: Girls with higher birth weight and greater weight gains during the four early age intervals were younger when they reached menarche and advanced Tanner stages; boys with greater early weight gains also were younger when they reached advanced Tanner stages, but few of these effects were statistically significant. CONCLUSIONS: Higher birth weights and greater weight gains during infancy and early childhood can lead to earlier sexual maturation in girls.


Subject(s)
Birth Weight/physiology , Obesity/epidemiology , Obesity/physiopathology , Puberty/physiology , Weight Gain/physiology , Adolescent , Child , Child Development/physiology , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Longitudinal Studies , Male , Menarche/physiology , Pregnancy , Pregnancy Complications/epidemiology , Regression Analysis , Risk Factors , Surveys and Questionnaires
3.
Biometrics ; 56(4): 1068-75, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11129462

ABSTRACT

In some types of cancer chemoprevention experiments and short-term carcinogenicity bioassays, the data consist of the number of observed tumors per animal and the times at which these tumors were first detected. In such studies, there is interest in distinguishing between treatment effects on the number of tumors induced by a known carcinogen and treatment effects on the tumor growth rate. Since animals may die before all induced tumors reach a detectable size, separation of these effects can be difficult. This paper describes a flexible parametric model for data of this type. Under our model, the tumor detection times are realizations of a delayed Poisson process that is characterized by the age-specific tumor induction rate and a random latency interval between tumor induction and detection. The model accommodates distinct treatment and animal-specific effects on the number of induced tumors (multiplicity) and the time to tumor detection (growth rate). A Gibbs sampler is developed for estimation of the posterior distributions of the parameters. The methods are illustrated through application to data from a breast cancer chemoprevention experiment.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Drug Screening Assays, Antitumor/methods , Neoplasms, Experimental/pathology , Neoplasms, Experimental/prevention & control , Vitamin A/analogs & derivatives , 9,10-Dimethyl-1,2-benzanthracene , Animals , Biometry/methods , Canthaxanthin/therapeutic use , Diterpenes , Female , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/prevention & control , Models, Statistical , Rats , Rats, Sprague-Dawley , Retinyl Esters , Vitamin A/therapeutic use
4.
Toxicol Appl Pharmacol ; 168(2): 79-90, 2000 Oct 15.
Article in English | MEDLINE | ID: mdl-11032763

ABSTRACT

Toxic metals occur naturally at low concentrations throughout the environment, but are found in higher concentrations at many of the hazardous waste sites on the EPA Superfund list. As part of the Agency for Toxic Substances and Disease Registry (ATSDR) mandate to evaluate the toxicity of metals and mixtures, we chose four of the high-priority metal pollutants from ATSDR's HAZDAT list, including arsenic, cadmium, chromium, and lead, to test in a commercially developed assay system, CAT-Tox(L) (Xenometrix). This assay employs a battery of recombinant HepG2 cell lines to test the transcriptional activation capacity of xenobiotics in any of 13 different signal transduction pathways. Our specific aims were to identify metal-responsive promoters and determine whether the pattern of gene expression changed with a mixture of metals. Humic acid was used in all assays as a carrier to help solubilize the metals and, in all cases, the cells were exposed to the humic acid-metal mixture for 48 h. Humic acid alone, at 50-100 microM, showed moderate activation of the XRE promoter, but little other notable activity. As(V), at doses of 50-250 microM, produced a complex profile of activity showing significant dose-dependent induction of the hMTIIA, GST Ya, HSP70, FOS, XRE, NFkappaBRE, GADD153, p53RE, and CRE promoters. Pb(II) showed dose-related induction of the GST Ya, XRE, hMTIIA, GRP78, and CYP IA1 promoters at doses in the range of 12-100 microM. Cd(II), at 1.25-15 microM, yielded significant dose-dependent induction of hMTIIA, XRE, CYP IA1, GST Ya, HSP70, NFkappaBRE, and FOS. Whereas Cr(III) yielded small, though significant inductions of the CRE, FOS, GADD153, and XRE promoters only at the highest dose (750 microM), Cr(VI) produced significant dose-related inductions of the p53RE, FOS, NFkappaBRE, XRE, GADD45, HSP70, and CRE promoters at much lower doses, in the range of 5-10 microM. Assays testing serial dilutions of a mixture comprising 7.5 microM Cd(II), 750 microM Cr(III), and 100 microM Pb(II) (the combination of metals most frequently found at National Priority List sites) showed significant dose-dependent induction of the hMTIIA promoter, but failed to show dose-related induction of any other promoter and showed no evidence of synergistic activation of gene expression by the metals in this mixture. Our results thus show metal activation of gene expression through several previously unreported signal transduction pathways, including As(V) induction of GST Ya, FOS, XRE, NFkBRE, GADD153, p53RE, and CRE; Pb(II) induction of GST Ya, XRE, Cyp IA1, and GADD153; Cd(II) induction of NFkBRE, Cyp IA1, XRE, and GST Ya; and Cr(VI) induction of p53RE, XRE, GADD45, HSP70, and CRE promoters, and thus suggest new insights into the biochemical mechanisms of toxicity and carcinogenicity of metals. It is also an important finding that no evidence of synergistic activity was detected with the mixture of Cd(II), Cr(III), and Pb(II) tested in these assays.


Subject(s)
Arsenic/toxicity , Gene Expression Regulation/drug effects , Metals, Heavy/toxicity , Promoter Regions, Genetic/drug effects , Biomarkers , Cadmium/toxicity , Chloramphenicol O-Acetyltransferase/biosynthesis , Chloramphenicol O-Acetyltransferase/genetics , Chromium/toxicity , Dose-Response Relationship, Drug , Drug Interactions , Endoplasmic Reticulum Chaperone BiP , Gene Expression Regulation/genetics , Humans , Humic Substances/pharmacology , Lead/toxicity , Promoter Regions, Genetic/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Transcriptional Activation/drug effects , Tumor Cells, Cultured
5.
Cancer Causes Control ; 11(5): 441-9, 2000 May.
Article in English | MEDLINE | ID: mdl-10877337

ABSTRACT

OBJECTIVES: Jobs involving heavy asbestos exposure increase risk for lung cancer and mesothelioma substantially, and low-level exposures may carry some risk. At least one indicator of asbestos exposure, mesothelioma, has been increasing in the US for decades. We investigated the prevalence of another indicator, pleural thickening on x-ray, in a defined sample of the US population. METHODS: Certified physicians read 1060 x-rays from the second National Health and Nutrition Examination Survey (1976-1980) for pleural changes consistent with pneumoconiosis, which are a reasonably specific indicator of asbestos exposure. RESULTS: Prevalence estimates, in NHANES II, in the age group 35-74 years, are 6.4% (+/- 0.9%) among males, 1.7% (+/- 0.6%) among females, and 3.9% (+/- 0.6%) overall. These prevalences are approximately twice those estimated from NHANES I data (1971-1975). CONCLUSIONS: X-ray evidence of asbestos exposure was common in the late 1970s and increasing. The increase may be due to occupational asbestos exposure, but it is so large as to suggest some contribution from environmental, non-occupational asbestos exposure.


Subject(s)
Asbestos/adverse effects , Asbestosis/epidemiology , Lung Neoplasms/epidemiology , Pleural Diseases/diagnostic imaging , Precancerous Conditions/diagnostic imaging , Adult , Age Distribution , Aged , Asbestosis/diagnostic imaging , Environmental Exposure , Female , Humans , Lung Neoplasms/diagnostic imaging , Male , Middle Aged , Nutrition Surveys , Occupational Exposure , Prevalence , Radiography , United States/epidemiology
6.
Annu Rev Public Health ; 20: 173-209, 1999.
Article in English | MEDLINE | ID: mdl-10352856

ABSTRACT

To search for unexplained patterns in cancer incidence, we analyzed data from 1975 to 1994 that represent approximately 10% of the population of the United States. Our analysis focused on long-term time trends in incidence and on deviations from those trends attributable to birth cohorts or to calendar periods. On average, cancer incidence rose 0.8% annually in white women and 1.8% in white men. After removing several cancers related to smoking and increased screening, average annual increases fell to 0.1% in white women but persisted at 1.7% in white men. In particular, yearly increases in non-Hodgkin's lymphoma averaged 2.4% in white women and 4.7% in white men. Among men, incidence changes attributable to cohorts grew progressively larger from one cohort to the next. Cancer incidence patterns among black men and women were similar to those among whites despite smaller population sizes. Unexplained patterns of cancer incidence may signal changes in underlying risk factors and highlight the continuing need for research on cancer etiology and prevention.


Subject(s)
Neoplasms/epidemiology , Adult , Black or African American/statistics & numerical data , Age Distribution , Aged , Aged, 80 and over , Cohort Effect , Cohort Studies , Female , Humans , Incidence , Longitudinal Studies , Lymphoma, Non-Hodgkin/epidemiology , Male , Middle Aged , Neoplasms/ethnology , Sentinel Surveillance , Sex Distribution , United States/epidemiology , White People/statistics & numerical data
7.
Carcinogenesis ; 16(11): 2617-25, 1995 Nov.
Article in English | MEDLINE | ID: mdl-7586176

ABSTRACT

Logistic regression analysis of age-specific prevalences for neoplastic and non-neoplastic liver lesions was used to examine treatment responses for B6C3F1 and B6D2F1 male mice continuously exposed to chlordane (55 p.p.m.) and to determine whether neoplasms were dependent on continuous exposure in the B6C3F1 mice. In order to determine if ras oncogene activation plays a role in the carcinogenicity of chlordane and whether the activation is dependent on genetic background, liver tumors from chlordane-treated B6C3F1 and B6D2F1 mice were analyzed for the presence of activating mutations in the ras oncogene. The overall liver tumor prevalence at terminal killing was nearly 100% for both strains; however, the age-specific prevalence increased more rapidly in B6C3F1 mice than in B6D2F1 mice. Tumor-bearing B6C3F1 mice had an average of two or more tumors per liver than B6D2F1 mice at their respective terminal killings (5.4 versus 3.3). When chlordane exposure was discontinued for a group of B6C3F1 mice ('stop' group) at 491 days of age, overall tumor multiplicity significantly decreased by 30% from an average of 4.4 per tumor-bearing-animal at 525 days to 3.1 at terminal killing (568 days). Over the same time period the prevalence of hepatocellular carcinomas significantly decreased from 80 to 54% and adenomas from 100 to 93% by terminal killing in B6C3F1 'stop-group' mice. Chlordane induced diffuse hepatocellular centrilobular hypertrophy, frequent multinucleate hepatocytes, toxic change and hepatoproliferative lesions composed predominantly of acidophilic hepatocytes in nearly 100% of both the B6C3F1 and B6D2F1 mice. The development of histological evidence of toxicity closely paralleled the temporal development of hepatocellular neoplasia and decreased in severity when the tumor burden was maximal. No H- or K-ras mutations were detected in the chlordane-induced hepatocellular tumors in B6C3F1 mice (15 adenomas and 15 carcinomas) or B6D2F1 mice (10 adenomas and 10 carcinomas). In conclusion, chlordane induced liver tumors in both B6C3F1 and B6D2F1 male mice by mechanisms independent of ras oncogene activation and 30% of both benign and malignant liver tumors in the B6C3F1 mice regressed after exposure was discontinued.


Subject(s)
Chlordan/toxicity , Genes, ras , Insecticides/toxicity , Liver Neoplasms, Experimental/chemically induced , Animals , Gene Expression Regulation , Hypertrophy , Liver/pathology , Liver Neoplasms, Experimental/genetics , Male , Mice , Mice, Inbred Strains , Mutation
8.
Stat Med ; 13(5-7): 689-708, 1994.
Article in English | MEDLINE | ID: mdl-8023043

ABSTRACT

Monte Carlo methods are used to evaluate the operating characteristics of several trend tests for comparing incidence rates of occult tumours. The candidate tests are applicable in long-term animal experiments that have just one sacrifice time and no information on cause of death. When survival decreases with dose and the tumour is lethal, the tests that do not adjust for survival or that assume tumours are non-lethal behave conservatively, whereas the test that assumes tumours are rapidly lethal rejects the hypothesis of equal incidence rates too frequently. The only test which consistently operates at the correct level is one that specifies a constant difference between the death rates for animals with and without the tumour. Surprisingly, the test that specifies a constant ratio of these death rates often is conservative. Finally, a test based on a simple modification of the unadjusted test, which accounts for differential mortality by scaling down the size of the risk set, performs reasonably well in many cases. Among the tests that operate at the proper level, the constant risk difference test consistently exhibits high power across a wide range of situations.


Subject(s)
Carcinogenicity Tests/statistics & numerical data , Incidence , Models, Statistical , Monte Carlo Method , Neoplasms, Experimental/mortality , Animals , Bias , Likelihood Functions , Neoplasms, Experimental/etiology , Neoplasms, Experimental/pathology , Proportional Hazards Models , Survival Analysis
9.
JAMA ; 271(6): 431-7, 1994 Feb 09.
Article in English | MEDLINE | ID: mdl-8295317

ABSTRACT

OBJECTIVE: Trends in cancer mortality, cardiovascular mortality, and cancer incidence are assessed among US whites to determine whether aging of the population and smoking patterns completely account for increased cancer rates from 1973 through 1987. DESIGN: For mortality, percentage changes in age-specific rates were calculated. For cancer incidence, trends in age-specific rates across time periods and birth cohorts were assessed for several sites. MAIN OUTCOME MEASURES: National US cardiovascular and cancer mortality rates and incidence rates for smoking-related cancer, breast cancer, and all other types of cancer in 10% of the US population covered by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program were analyzed. RESULTS: From 1973 through 1987, cardiovascular mortality decreased 42% in the age group 0 to 54 years and decreased 33% in the age group 55 to 84 years; concurrently, cancer mortality decreased 17% in the younger group but increased 12% in the older group. By 1987, even though proportionally fewer people in the older age groups died, relatively more of them died of cancer. Men born in the 1940s had twice as much cancer as those born in 1888 through 1897 and more than twice as much cancer not linked to smoking; women born during this period had 50% and 30% more of these same cancers, respectively. Rates of smoking-related cancers in recent cohorts of women were five to six times greater than in those born in 1888 through 1897, while rates in men declined. Recent cohorts of women also had more than twice as much breast cancer as those born in 1888 through 1897. CONCLUSIONS: In recent US birth cohorts, our model found that increases in cancer have occurred that are not solely linked to aging of the population and smoking patterns. In light of these results and similar findings in Sweden, changes in carcinogenic hazards in addition to smoking are likely to have occurred and need to be studied further.


Subject(s)
Cardiovascular Diseases/epidemiology , Neoplasms/epidemiology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Incidence , Infant , Male , Middle Aged , Mortality/trends , Population Surveillance , Smoking , Time Factors , United States/epidemiology , White People
10.
Biometrics ; 49(2): 399-407, 1993 Jun.
Article in English | MEDLINE | ID: mdl-8369376

ABSTRACT

Ideally, analyses of tumor incidence data from long-term animal experiments should allow the incidence rates to vary with age, without restricting tumor lethality, without requiring data on cause of death, and without assuming independence of competing risks. This article focuses on nonparametric methods that not only satisfy these conditions, but also accommodate studies having just one sacrifice time, by constraining the effects of age on one of the three functions used to characterize the likelihood. Several constrained analyses were evaluated using data on over 18,000 mice from the ED01 study. Of the five constraints considered, only the assumption of constant differences between the death rates for animals with and without the tumor of interest produced reasonable results across a wide range of tumor lethalities.


Subject(s)
Neoplasms/epidemiology , Neoplasms/veterinary , Rodent Diseases , Survival Analysis , Animals , Female , Incidence , Lymphoma/epidemiology , Lymphoma/mortality , Lymphoma/veterinary , Lymphoma, Large B-Cell, Diffuse/epidemiology , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/veterinary , Mathematics , Mice , Models, Statistical , Neoplasms/mortality , Polyps/epidemiology , Polyps/mortality , Polyps/veterinary , Probability , Uterine Neoplasms/epidemiology , Uterine Neoplasms/mortality , Uterine Neoplasms/veterinary
11.
Cancer Causes Control ; 3(5): 409-17, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1525321

ABSTRACT

We examined incidence time-trends for lung, stomach, intestinal, prostate, and breast cancer among Whites diagnosed in the United States between 1973 and 1987. For each sex and five-year age group, we modeled cancer incidence as a log-linear function of diagnosis-year to permit extrapolation over time and simple summarization of trends. Comparisons with nonparametric estimates show that, except for breast cancer, the model performs well. Plots of the annual percent change in incidence cf age illustrate the way in which time trends depend on age. Between 1973 and 1987, stomach cancer incidence decreased by about two percent per year. The annual change in lung cancer incidence progressed from a two to three percent decrease in persons under age 40 to an increase of two percent in men and eight percent in women by age 80. Intestinal cancer incidence decreased annually by as much as three percent in persons under age 50, remained constant in women aged 50 to 74, and otherwise increased about one percent per year. The annual increase in prostate cancer incidence declined from about six percent in men under age 40 to about two percent in men over age 80. After a surge in female breast-cancer diagnoses in 1974, the annual increase in incidence between 1980 and 1987 stabilized at four to six percent.


Subject(s)
Breast Neoplasms/epidemiology , Intestinal Neoplasms/epidemiology , Lung Neoplasms/epidemiology , Prostatic Neoplasms/epidemiology , Stomach Neoplasms/epidemiology , Adult , Aged , Aged, 80 and over , Female , Humans , Incidence , Male , Middle Aged , Models, Statistical , Time Factors , United States/epidemiology
12.
Biometrics ; 47(2): 681-700, 1991 Jun.
Article in English | MEDLINE | ID: mdl-1912267

ABSTRACT

In a typical tumorigenicity study, most tumors are not observable in live animals and only a single (terminal) sacrifice is performed. This paper proposes a nonparametric, survival-adjusted analysis for these data that focuses on tumor incidence and yet does not require data on cause of death or assumptions about the tumor's lethality. The tumor onset/death process is most naturally characterized in terms of the tumor incidence rate and the death rates for tumor-free and tumor-bearing animals. The proposed approach, however, reparameterizes the problem in terms of the incidence rate, the death rate for tumor-free animals, and the difference between the death rates for tumor-free and tumor-bearing animals (i.e., the risk difference). The advantage of this alternative formulation is that a full likelihood analysis is possible with as few as one sacrifice time if the risk difference is assumed to be constant with respect to time. Data from the large ED01 study suggest that reasonable results can be obtained under the assumption of constant risk differences.


Subject(s)
Biometry , Carcinogenicity Tests/statistics & numerical data , Algorithms , Animals , Carcinogens/administration & dosage , Data Interpretation, Statistical , Likelihood Functions , Neoplasms, Experimental/chemically induced , Regression Analysis , Risk Factors , Survival Analysis
13.
Environ Health Perspect ; 87: 123-9, 1990 Jul.
Article in English | MEDLINE | ID: mdl-2269215

ABSTRACT

In this paper we combine Japanese data on radiation exposure and cancer mortality with U.S. data on cancer incidence and lethality to estimate the effects of ionizing radiation on cancer incidence. The analysis is based on the mathematical relationship between the mortality rate and the incidence and lethality rates, as well as on statistical models that relate Japanese incidence rates to U.S. incidence rates and radiation risk factors. Our approach assumes that the risk of death from causes other than the cancer does not depend on whether or not the cancer is present, and among individuals with the cancer, the risk of death attributable to the cancer is the same in Japan and the U.S. and is not affected by radiation exposure. In particular, we focus on the incidence of breast cancer in Japanese women and how this incidence is affected by radiation risk factors. The analysis uses Japanese exposure and mortality data from the Radiation Effects Research Foundation study of atomic bomb survivors and U.S. incidence and lethality data from the Surveillance, Epidemiology, and End Results Registry. Even without Japanese incidence data, we obtain reasonable estimates of the incidence of breast cancer in unexposed Japanese women and identify the radiation risk factors that affect this incidence. Our analysis demonstrates that the age at exposure is an important risk factor, but that the incidence of breast cancer is not affected by the city of residence (Nagasaki versus Hiroshima) or the time since exposure.


Subject(s)
Breast Neoplasms/mortality , Neoplasms, Radiation-Induced/mortality , Age Factors , Breast Neoplasms/epidemiology , Breast Neoplasms/etiology , Cohort Studies , Female , Humans , Japan/epidemiology , Likelihood Functions , Neoplasms, Radiation-Induced/epidemiology , Nuclear Warfare , Risk Factors , United States/epidemiology
14.
Biometrics ; 44(2): 405-15, 1988 Jun.
Article in English | MEDLINE | ID: mdl-3390506

ABSTRACT

Tumor incidence is the primary measure of carcinogenesis. This article focuses on estimating time-dependent incidence rates in animal experiments with few sacrifices. When the context of observation is known for none or all of the animals dying with the tumor of interest, previous results are obtained under relaxed assumptions. The link with existing semiparametric and nonparametric procedures based on latent failure times is exploited by using these methods to compute maximum likelihood estimates of the incidence rates without introducing latent random variables. Nonparametric estimators that are appropriate when all contexts of observation are known are generalized to the case in which the contexts of observation are unknown for a subset of the tumor-bearing animals.


Subject(s)
Biometry/methods , Neoplasms, Experimental/epidemiology , Animals , Carcinogens , Models, Theoretical , Neoplasms, Experimental/chemically induced
15.
Biometrics ; 43(1): 107-14, 1987 Mar.
Article in English | MEDLINE | ID: mdl-3567301

ABSTRACT

This paper addresses the problem of comparing treatment groups with respect to the rate of tumor development for animals in a survival experiment with some serial sacrifices. The analysis specifies a parametric model for the tumor incidence function, but places no parametric restrictions on the death rates. The procedure is feasible with as few as two sacrifice times and requires no individual data on cause of death. Other diseases need not act independently of the tumor of interest, nor are any restrictions imposed on tumor lethality or the relationship between the onset and death times for tumor-bearing animals. The proposed methods are illustrated with some survival/sacrifice data.


Subject(s)
Carcinogens , Drug Evaluation, Preclinical/methods , Neoplasms, Experimental/chemically induced , Toxicology/methods , Animals , Benzidines/toxicity , Female , Liver Neoplasms, Experimental/chemically induced , Male , Mice , Risk , Sex Factors , Species Specificity , Statistics as Topic
16.
Fundam Appl Toxicol ; 6(1): 44-52, 1986 Jan.
Article in English | MEDLINE | ID: mdl-3710027

ABSTRACT

Survival differences can have a substantial impact on the statistical comparison of tumor development in control and treated animals and thus should be taken into account routinely in the analysis of carcinogenicity data from laboratory experiments. However, the appropriate survival adjustment depends on whether the tumor of interest is fatal or incidental. The usual analysis of incidental tumors, which adjusts for survival by stratifying the animals according to age at death, has various shortcomings. Alternatively, logistic regression methods allow a continuous survival adjustment and furnish a convenient framework for solving many of the problems associated with the age-stratified approach of grouping the data into time intervals. Logistic regression substitutes modeling the prevalence function for the arbitrary choice of time intervals, providing a survival adjustment (when the model holds) even when differential mortality might increase the bias or decrease the sensitivity of interval-based methods. The logistic analysis also can incorporate covariables which, if ignored, might confound the interpretation of the data. Several examples illustrate these potential advantages of basing the analysis of incidental tumors on logistic regression techniques.


Subject(s)
Carcinogens , Neoplasms, Experimental/chemically induced , Aging , Animals , Body Weight/drug effects , Male , Models, Biological , Rats , Rats, Inbred F344 , Regression Analysis
17.
Biometrics ; 41(3): 751-70, 1985 Sep.
Article in English | MEDLINE | ID: mdl-4074825

ABSTRACT

In the analysis of animal carcinogenicity studies, the standard survival-adjusted test for a dose-related trend in the prevalence of nonlethal tumors is the Hoel-Walburg test, which stratifies on age at death by grouping survival times into intervals. An alternative analysis assesses trend on the basis of the likelihood score test under a logistic model for the prevalence function, which adjusts for survival by including age at death as a continuous regression variable. Extensive simulations demonstrate that the test based on modeling the prevalence log-odds as a linear function of age is more powerful than the Hoel-Walburg test, regardless of the intervals used by the latter to stratify the data. Without incorporating a continuity correction, the size of each test often exceeds the nominal level, especially when the mortality patterns differ across dose groups. Corrected versions of the tests operate at conservative levels, where the degree of conservatism varies with the distribution of the data. When the mortality patterns for the dose groups are similar, both tests have essentially the same power to detect a trend in tumor prevalence rates. However, when mortality varies with dose, the logistic regression test with a linear age term is more powerful than the Hoel-Walburg test, and this gain in power increases as the dose-specific mortality patterns become more disparate.


Subject(s)
Neoplasms/epidemiology , Aging , Animals , Biometry , Humans , Neoplasms/mortality , Neoplasms, Experimental/pathology , Time Factors
18.
Br J Ind Med ; 42(8): 507-16, 1985 Aug.
Article in English | MEDLINE | ID: mdl-4016002

ABSTRACT

To evaluate critical exposure levels and the reversibility of lead neurotoxicity a group of lead exposed foundry workers and an unexposed reference population were followed up for three years. During this period, tests designed to monitor neurobehavioural function and lead dose were administered. Evaluations of 160 workers during the first year showed dose dependent decrements in mood, visual/motor performance, memory, and verbal concept formation. Subsequently, an improvement in the hygienic conditions at the plant resulted in striking reductions in blood lead concentrations over the following two years. Attendant improvement in indices of tension (20% reduction), anger (18%), depression (26%), fatigue (27%), and confusion (13%) was observed. Performance on neurobehavioural testing generally correlated best with integrated dose estimates derived from blood lead concentrations measured periodically over the study period; zinc protoporphyrin levels were less well correlated with function. This investigation confirms the importance of compliance with workplace standards designed to lower exposures to ensure that individual blood lead concentrations remain below 50 micrograms/dl.


Subject(s)
Behavior/drug effects , Brain/drug effects , Lead Poisoning/psychology , Occupational Diseases/psychology , Dose-Response Relationship, Drug , Emotions/drug effects , Humans , Lead/blood , Lead Poisoning/blood , Male , Prospective Studies
19.
Cancer ; 55(1): 26-40, 1985 Jan 01.
Article in English | MEDLINE | ID: mdl-3917352

ABSTRACT

The combinations of triethylenethiophosphoramide and methotrexate (TM) and cyclophosphamide, Adriamycin (doxorubicin), and 5-fluorouracil (CAF) were compared, both as sequential and fixed rotational treatments for advanced ovarian cancer, with L-phenylalanine mustard (L-PAM). Treatment with CAF produced a higher response rate (25% complete responses plus 31% partial responses) than treatment with L-PAM (15% complete responses plus 18% partial responses). A fixed rotation of TM and CAF resulted in longer survival (median of 15 months and 75th percentile of 27 months) than sequential treatment with TM initially, followed by CAF upon failure (median of 12 months and 75th percentile of 22 months). The fixed rotation of TM and CAF also increased progression-free survival (median of 12 months and 75th percentile of 24 months) over that achieved by initial treatment with TM (median of 6 months and 75th percentile of 15 months) or L-PAM (median of 9 months and 75th percentile of 21 months). Most patients (96%) on the fixed rotation were treated with both TM and CAF. Fewer patients (62%) on the sequential schedule with TM actually received both combination regimens, and even fewer patients (37%) beginning on CAF ever crossed over to TM. Patient age of 50 years or younger was a favorable prognostic factor for response, survival, and time to first treatment failure (progression-free survival). Disease Stage IIIA or IIIB, surgery including a bilateral salpingo-oophorectomy plus hysterectomy, and treatment within 6 months of initial diagnosis were favorable predictors for both survival and time to first treatment failure. Ambulatory performance status and well-differentiated disease were favorable prognostic factors for survival. Patients with unevaluable disease failed later than those with evaluable disease who, in turn, failed later than patients with measurable disease.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ovarian Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Clinical Trials as Topic , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Melphalan/administration & dosage , Methotrexate/administration & dosage , Middle Aged , Prospective Studies , Random Allocation , Thiotepa/administration & dosage
20.
Br J Ind Med ; 41(3): 352-61, 1984 Aug.
Article in English | MEDLINE | ID: mdl-6743583

ABSTRACT

To evaluate the effects of chronic lead exposure on the nervous system in adults, a set of neurobehavioural and electrophysiological tests was administered to 99 lead exposed foundry employees and 61 unexposed workers. Current and past blood lead concentrations were used to estimate the degree of lead absorption; all previous blood lead concentrations had been less than or equal to 90 micrograms/100 ml. Characteristic signs (such as wrist extensor weakness) or symptoms (such as colic) of lead poisoning were not seen. Sensory conduction in the sural nerve was not affected. By contrast, various neurobehavioural functions deteriorated with increasing lead burden. Workers with blood lead concentrations between 40 and 60 micrograms/100 ml showed impaired performance on tests of verbal concept formation, visual/motor performance, memory, and mood. Thus impairment in central nervous system function in lead exposed adults occurred in the absence of peripheral nervous system derangement and increased in severity with increasing lead dose.


Subject(s)
Lead Poisoning/physiopathology , Neural Conduction , Occupational Diseases/physiopathology , Psychological Tests , Adolescent , Adult , Chronic Disease , Depression/etiology , Emotions , Humans , Lead/blood , Lead Poisoning/blood , Lead Poisoning/psychology , Middle Aged , Occupational Diseases/blood , Occupational Diseases/psychology
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