David Kriebel

Prevalence odds ratio or prevalence ratio in the analysis of cross sectional data : what is to be done?

OBJECTIVES: To review the appropriateness of the prevalence odds ratio (POR) and the prevalence ratio (PR) as effect measures in the analysis of cross sectional data and to evaluate different models for the multivariate estimation of the PR. METHODS: A system of linear differential equations corresponding to a dynamic model of a cohort with a chronic disease was developed. At any point in time, a cross sectional analysis of the people then in the cohort provided a prevalence based measure of the effect of exposure on disease. This formed the basis for exploring the relations between the POR, the PR, and the incidence rate ratio (IRR). Examples illustrate relations for various IRRs, prevalences, and differential exodus rates. Multivariate point and interval estimation of the PR by logistic regression is illustrated and compared with the results from proportional hazards regression (PH) and generalised linear modelling (GLM). RESULTS: The POR is difficult to interpret without making restrictive assumptions and the POR and PR may lead to different conclusions with regard to confounding and effect modification. The PR is always conservative relative to the IRR and, if PR > 1, the POR is always > PR. In a fixed cohort and with an adverse exposure, the POR is always > or = IRR, but in a dynamic cohort with sufficient underlying follow up the POR may overestimate or underestimate the IRR, depending on the duration of follow up. Logistic regression models provide point and interval estimates of the PR (and POR) but may be intractable in the presence of many covariates. Proportional hazards and generalised linear models provide statistical methods directed specifically at the PR, but the interval estimation in the case of PH is conservative and the GLM procedure may require constrained estimation. CONCLUSIONS: The PR is conservative, consistent, and interpretable relative to the IRR and should be used in preference to the POR. Multivariate estimation of the PR should be executed by means of generalised linear models or, conservatively, by proportional hazards regression.

Bias in occupational epidemiology studies

The design of occupational epidemiology studies should be based on the need to minimise random and systematic error. The latter is the focus of this paper, and includes selection bias, information bias and confounding. Selection bias can be minimised by obtaining a high response rate (and by appropriate selection of the control group in a case-control study). In general, it is important to ensure that information bias is minimised and is also non-differential (for example, that the misclassification of exposure is not related to disease status) by collecting data in a standardised manner. A major concern in occupational epidemiology studies usually relates to confounding, because exposure has not been randomly allocated, and the groups under study may therefore have different baseline disease risks. For each of these types of bias, the goal should be to avoid the bias by appropriate study design and/or appropriate control in the analysis. However, it is also important to attempt to assess the likely direction and strength of biases that cannot be avoided or controlled.

The future of sustainability science: a solutions-oriented research agenda

Over the last decade, sustainability science has been at the leading edge of widespread efforts from the social and natural sciences to produce use-inspired research. Yet, how knowledge generated by sustainability science and allied fields will contribute to transitions toward sustainability remains a critical theoretical and empirical question for basic and applied research. This article explores the limitations of sustainability science research to move the field beyond the analysis of problems in coupled systems to interrogate the social, political and technological dimensions of linking knowledge and action. Over the next decade, sustainability science can strengthen its empirical, theoretical and practical contributions by developing along four research pathways focused on the role of values in science and decision-making for sustainability: how communities at various scales envision and pursue sustainable futures; how socio-technical change can be fostered at multiple scales; the promotion of social and institutional learning for sustainable development.

Effects of alcohol and tobacco on aerodigestive cancer risks: a meta-regression analysis

Objective: Meta-analysis was used to summarize the published evidence on the associations between alcohol and tobacco consumption and cancers of the oropharynx, pharynx, larynx, and esophagus. The objective was to produce summary risk estimates with uniform methods and on uniform exposure scales so that the magnitudes of the risks could be compared across tumor sites. Methods: Epidemiologic studies that estimated the effects of alcohol and tobacco consumption on the risk of cancers of the upper aero-digestive tract were identified from the MEDLINE database, 1966–2001. Alcohol and tobacco data were converted into common units (grams/week). For all studies meeting eligibility criteria, effect parameters (slopes) were estimated for both exposures. The exposure-risk slopes for each study were combined, site by site, using random effects meta-regression methods. Results: Fourteen studies met the final selection criteria. The carcinogenic effects of alcohol and tobacco were found to be multiplicative on the relative risk scale. Tobacco appeared to have a much stronger effect on the larynx than on any of the other aerodigestive sites, while alcohols effect was strongest on the pharynx. The weakest association was that of alcohol and adenocarcinoma of the esophagus – an order of magnitude weaker than that for tobacco and laryngeal cancer. Conclusions: Meta-analysis was used to combine the results from all available studies, providing a comprehensive summary of the combined effects of alcohol and tobacco on the upper aerodigestive cancers.

Potent and Selective Inhibitors of the Inositol-requiring Enzyme 1 Endoribonuclease

Inositol-requiring enzyme 1 (IRE1) is the most highly conserved signaling node of the unfolded protein response (UPR) and represents a potential therapeutic target for a number of diseases associated with endoplasmic reticulum stress. IRE1 activates the XBP-1 transcription factor by site-specific cleavage of two hairpin loops within its mRNA to facilitate its nonconventional splicing and alternative translation. We screened for inhibitors using a construct containing the unique cytosolic kinase and endoribonuclease domains of human IRE1α (hIRE1α-cyto) and a mini-XBP-1 stem-loop RNA as the substrate. One class compounds was salicylaldehyde analogs from the hydrolyzed product of salicylaldimines in the library. Salicylaldehyde analogs were active in inhibiting the site-specific cleavage of several mini-XBP-1 stem-loop RNAs in a dose-dependent manner. Salicyaldehyde analogs were also active in inhibiting yeast Ire1 but had little activity inhibiting RNase L or the unrelated RNases A and T1. Kinetic analysis revealed that one potent salicylaldehyde analog, 3-ethoxy-5,6-dibromosalicylaldehyde, is a non-competitive inhibitor with respect to the XBP-1 RNA substrate. Surface plasmon resonance studies confirmed this compound bound to IRE1 in a specific, reversible and dose-dependent manner. Salicylaldehydes inhibited XBP-1 splicing induced pharmacologically in human cells. These compounds also blocked transcriptional up-regulation of known XBP-1 targets as well as mRNAs targeted for degradation by IRE1. Finally, the salicylaldehyde analog 3-methoxy-6-bromosalicylaldehyde strongly inhibited XBP-1 splicing in an in vivo model of acute endoplasmic reticulum stress. To our knowledge, salicylaldehyde analogs are the first reported specific IRE1 endoribonuclease inhibitors.

Reenergizing Public Health Through Precaution

The precautionary principle has provoked a spirited debate among environmentalists worldwide, but it is equally relevant to public health and shares much with primary prevention. Its central components are (1) taking preventive action in the face of uncertainty; (2) shifting the burden of proof to the proponents of an activity; (3) exploring a wide range of alternatives to possibly harmful actions; and (4) increasing public participation in decision making. Precaution is relevant to public health, because it can help to prevent unintended consequences of well-intentioned public health interventions by ensuring a more thorough assessment of the problems and proposed solutions. It can also be a positive force for change. Three aspects are stressed: promoting the search for safer technologies, encouraging greater democracy and openness in public health policy, and stimulating reevaluation of the methods of public health science.

RESPIRATORY HEALTH OF AUTOMOBILE WORKERS EXPOSED TO METAL-WORKING FLUID AEROSOLS: RESPIRATORY SYMPTOMS

A total of 1,811 automobile workers at three General Motors facilities were evaluated by questionnaire for possible respiratory effects resulting from airborne exposures to metal-working fluids (MWF): 1,042 currently worked as machinists and were exposed to one of three types of MWF aerosols (straight mineral oils, soluble oil emulsions, or water-based synthetic fluids that contained no oils); 769 assembly workers, without direct exposure, served as an internal reference group (of these, 239 had never worked as machinists). Symptoms of usual cough, usual phlegm, wheezing, chest tightness, and breathlessness, as well as physician-diagnosed asthma, and chronic bronchitis were the primary outcomes examined. Machinists as a whole had higher prevalence of cough, phlegm, wheezing, and breathlessness than that of assembly workers. Adjusting for confounding, phlegm and wheeze were associated with increasing levels of current exposure to straight oils; cough, phlegm, wheeze, chest tightness, and chronic bronchitis were associated with increasing levels of current exposure to synthetics. In models that included both past and current exposure, only current exposures to straight and synthetic fluids were associated with current symptoms.

Endotoxin exposure-response in a fiberglass manufacturing facility

Peak expiratory flow (PEF) and workplace exposure to endotoxin, phenolic resin, and formaldehyde were measured to investigate asthma symptoms and medication use among employees in a fiberglass wool manufacturing plant. Self-recorded PEF was obtained from 37 workers, for a total of 181 days off work and 187 days at work with concurrent personal exposure monitoring. Pre- and post-shift spirometry were obtained on at least 2 days. The 8 hr time-weighted average personal exposure ranges were endotoxin; 0.4-759 ng/m3; phenolic resin, 5.7-327 micrograms/m3; and formaldehyde, 1.2-265 micrograms/m3. Amplitude percent mean peak flow was associated with years since starting regular work in the highest endotoxin exposure area, although current assignment in that area was associated with reduced amplitude--evidence for a healthy worker effect. Exposure-response was analyzed by regression of lung function change on exposure using generalized estimating equations with robust variance estimates. Endotoxin exposure above 4 ng/m3 (8 hr time-weighted average) was associated with a decline in lung function across the work shift, and with drops in lung function 16-20 hr after exposure. Phenolic resin exposure was not consistently associated with decrements, and formaldehyde was not associated with decrements in lung function.

The effect of temperature on the formation of mutagens in heated beef stock and cooked ground beef.

Abstract The microsome-activatable mutagens (chromatographically distinguishable from benzo[ a ]pyrene and from the mutagens produced from pyrolysed amino acids and proteins) previously found in beef extract and in bacterial nutrients which contain beef extract are produced when beef stock is heated. Reflux boiling of beef stock at 100°C results in a linear increase in mutagenic activity toward Salmonella strain TA1538. The rate of production of mutagenic activity at temperatures between 68°C and 98°C conforms closely to the Arrhenius equation, yielding an activation energy of 23 738 calories per mole. Extrapolation from these data predicts a sharp rise in the rate of mutagen formation between 140 and 180°C. This expectation is confirmed when ground beef patties (hamburgers) are prepared in various conventional electrically-heated appliances which operate at different cooking temperatures within this range. The mutagenic activity of hamburger cooked at high temperatures is limited to the surface layers; the temperature of the inside of the hamburger does not exceed 100°C during cooking. No mutagenic activity is found in comparable samples of uncooked meat. The results indicated that the mutagens may be formed as a result of the temperatures encountered in certain conventional cooking procedures.

A multicenter case-control study in Italy on hematolymphopoietic neoplasms and occupation

We conducted a population-based, case-control study on hematolymphopoietic malignancies in 12 areas in Italy to investigate associations between different hematolymphopoietic malignancies and exposure to solvents and pesticides. We collected all incident cases 20–74 years of age from 12 areas, with a combined population of approximately 7 million residents. The control group was formed by a random sample of the study population. Data presented in this paper refer to 2,737 interviewed cases of 3,357 eligible cases and to 1,779 of 2,391 eligible controls. We analyzed risks associated with occupation using job-title information to evaluate disease pattern according to job category. An earlier publication presented results for women; here, we report the findings for men and discuss the overall patterns in both genders. The most consistent overall finding was an approximate doubling in relative risk for all four types of malignancies among male managers and related occupations. Several additional occupations were associated with elevated risk of one or more malignancies among men. These included cooks, waiters, and bartenders, and building caretakers and cleaners, for non-Hodgkin’s lymphoma; textile workers and machinery fitters for Hodgkin’s lymphoma; metal processors, material handlers, rubber workers, and painters for leukemia; and hairdressers, metal processors, tailors, electrical workers, and plumbers for multiple myeloma. The finding of increased risk of non-Hodgkin’s lymphoma among both male and female cooks, waiters, and bartenders has not been previously reported; nor has the elevated risk of leukemia among material handlers. Among people engaged in agriculture, those employed as tractor drivers and as “orchard, vineyard, and related tree and shrub workers” appeared to be at increased risk for hematolymphopoietic malignancies.