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The author reflects on the procedures on how to make manuscripts for the development of the periodical "American Journal of Epidemiology." The author emphasized the advantages of the approach, including the taxing or sleeping-inducing method and strict fixed limit. He further explained the guidelines imposed by the National Institutes of Health regarding the epidemiologic papers.

In an effort to inform the ongoing discussion about the purpose, purview, theoretical orientation, and viability of epidemiology, this paper considers the contemporary epistemological foundations of the discipline by analyzing article citations. Two principal questions are the following: 1) What research do American Journal of Epidemiology (AJE) authors rely on to support, inform, and frame their investigations? and 2) to what extent do such authors use social scientific and statistical citations? The data used appear to be superior to those used in previous efforts because they contain complete citations for all articles published, along with complete within-article citations, for all AJE articles published from January 1981 to December 2002. The most frequent AJE citations are statistically oriented works. About 9% of citations are to AJE articles, 15% are to a larger set of eight epidemiologic journals, 15% are to a select set of eight medical journals, 3% are to (bio)statistics journals, and just 0.2% are to social science journals. Trend analysis reveals little change during the 22-year study period. The principal implication is that AJE authors are overlooking a vast literature that could inform their understanding of how exposures emerge and are maintained. [ABSTRACT FROM PUBLISHER]

In an accompanying paper (Am J Epidemiol 2002;155:1066–73), the authors describe the design of a large multicenter study being carried out in three West African countries for investigation of the roles of environmental and host-related factors in the development of tuberculosis. In this paper, the authors review some evidence that host genetic factors play a role in susceptibility to tuberculosis. They describe the three components of the study that are designed to investigate the effect of host genetic factors on the development of tuberculosis: case-control and family-based association studies of candidate genes and analysis of affected relative pairs to screen the human genome for areas of linkage to the disease. The authors also address a number of methodological issues that arise, such as the effects of consanguinity, half-siblings, and nonpaternity. Lastly, they review opportunities to assess gene-environment interaction in the framework of the study, in light of current methodological knowledge. Consideration of these issues may be useful in the design of other studies of genetic susceptibility to infectious diseases, particularly those to be carried out in developing countries. [ABSTRACT FROM PUBLISHER]

Arsenic in drinking water causes increased mortality from several cancers, ischemic heart disease, bronchiectasis, and other diseases. This paper presents the first evidence relating arsenic exposure to pulmonary tuberculosis, by estimating mortality rate ratios for Region II of Chile compared with Region V for the years 1958–2000. The authors compared mortality rate ratios with time patterns of arsenic exposure, which increased abruptly in 1958 in Region II and then declined starting in 1971. Tuberculosis mortality rate ratios in men started increasing in 1968, 10 years after high arsenic exposure commenced. The peak male 5-year mortality rate ratio occurred during 1982–1986 (rate ratio = 2.1, 95% confidence interval: 1.7, 2.6; P < 0.001) and subsequently declined. Mortality rates in women were also elevated but with fewer excess pulmonary tuberculosis deaths (359 among men and 95 among women). The clear rise and fall of tuberculosis mortality rate ratios in men following high arsenic exposure are consistent with a causal relation. The findings are biologically plausible in view of evidence that arsenic is an immunosuppressant and also a cause of chronic lung disease. Finding weaker associations in women is unsurprising, because this is true of most arsenic-caused health effects. Confirmatory evidence is needed from other arsenic-exposed populations. [ABSTRACT FROM PUBLISHER]

Discovering and understanding genetic risk factors for melanoma and their interactions with phenotype, sun exposure, and other risk factors could lead to new strategies for melanoma control. This paper describes the Australian Melanoma Family Study, which uses a multicenter, population-based, case-control-family design. From 2001 to 2005, the authors recruited 1,164 probands including 629 cases with histopathologically confirmed, first-primary cutaneous melanoma diagnosed before age 40 years, 240 population-based controls frequency matched for age, and 295 spouse/friend controls. Information on lifetime sun exposure, phenotype, and residence history was collected for probands and nearly 4,000 living relatives. More than 3,000 subjects donated a blood sample. Proxy-reported information was collected for childhood sun exposure and deceased relatives. Important features of this study include the population-based, family-based design; a focus on early onset disease; probands from 3 major cities differing substantially in solar ultraviolet exposure and melanoma incidence; a population at high risk because of high ultraviolet exposure and susceptible pigmentation phenotypes; population-based, spouse/friend, and sibling controls; systematic recruitment of relatives of case and control probands; self and parent reports of childhood sun exposure; and objective clinical skin examinations. The authors discuss methodological and analytical issues related to the study design and conduct, as well as the potentially novel insights the study can deliver. [ABSTRACT FROM PUBLISHER]

Disease can be caused by different mechanisms. A possible causal model proposed by Rothman is a complete causal mechanism or a so-called sufficient cause consisting of a set of component causes that can be illustrated in a pie chart. However, this model does not allow finding out what sufficient causes produce the majority of cases. The authors' objective was to extend Rothman's work by quantifying the proportion of disease that can be attributed to a class of sufficient causes. The underlying idea was to consider all combinations of a given set of known risk factors and to assign each combination to a class of sufficient causes. This assignment makes it possible to evaluate a class of sufficient causes by the population attributable fraction of the corresponding combination of risk factors. The approach presented was applied to sufficient causes of myocardial infarction by use of data on participants recruited between 1994 and 1998 into the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. As a result, 51.8% of cases were attributed to only four different classes of sufficient causes. In conclusion, the statistical method described in the paper may be beneficial for quantifying the importance of different sufficient causes and for improving the efficiency of public health programs. [ABSTRACT FROM AUTHOR]

The association between the response proportion in epidemiologic studies and nonresponse bias is complicated, because exposure prevalences and misclassification errors may vary by recruitment wave. In this paper, the authors illustrate the effect of varying degrees of wave-specific nondifferential exposure measurement error in a dichotomous exposure on the relative risk in a hypothetical cohort study of 5,000 participants, by recruitment wave. The field phase of the hypothetical cohort study consisted of five consecutive recruitment waves. The authors assigned response proportions to each wave (wave 1: 30%; wave 2: 10%; wave 3: 10%; wave 4: 30%; wave 5: 20%) and studied three different wave-specific patterns of true exposure prevalence: 1) the true exposure prevalence remains the same in all waves; 2) the true exposure prevalence increases by wave; and 3) the true exposure prevalence decreases by wave. The authors assumed three corresponding patterns of nondifferential misclassification error in exposure status across waves. If the nondifferential exposure misclassification increases by wave, the cumulative relative risk estimate is increasingly biased towards the null. This bias is intensified if the true exposure prevalence increases by wave. Studies with low response proportions may be less biased than studies with high response proportions if the nondifferential misclassification error in a dichotomous exposure increases by recruitment wave. [ABSTRACT FROM AUTHOR]

Dengue viruses are a major cause of morbidity in tropical and subtropical regions of the world. Knowledge about the epidemiology and host determinants of inapparent and severe dengue virus infections is limited. In this paper, the authors report findings from the first 3 years of a prospective study of dengue virus transmission and disease severity conducted in a cohort of 2,119 elementary school children in northern Thailand. A total of 717,106 person-school days were observed from 1998 to 2000. The incidence of inapparent and of symptomatic dengue virus infection was 4.3% and 3.6% in 1998, 3.2% and 3.3% in 1999, and 1.4% and 0.8% in 2000, respectively. Symptomatic dengue virus infection was responsible for 3.2%, 7.1%, and 1.1% of acute-illness school absences in 1998, 1999, and 2000, respectively. The early symptom complex of acute dengue virus infection is protean and difficult to distinguish from other causes of febrile childhood illnesses. The authors’ results illustrate the spatial and temporal diversity of dengue virus infection and the burden of dengue disease in schoolchildren in Thailand. Their findings increase understanding of dengue virus transmission and disease severity in a well-defined cohort population and offer a study design in which to test the efficacy of potential dengue vaccines. [ABSTRACT FROM PUBLISHER]

Host-related and environmental factors for tuberculosis have usually been investigated separately using different study designs. Joint investigation of the genetic, immunologic, and environmental factors at play in susceptibility to tuberculosis represents an innovative goal for obtaining a better understanding of the pathogenesis of the disease. In this paper, the authors describe methods being used to investigate these points in a West African study combining several designs. Patients with newly diagnosed smear-positive cases of tuberculosis are recruited. The effect of host-related factors is assessed by comparing each case with a healthy control from the case's household. The role of environmental factors is estimated by comparing cases with randomly selected community controls. The frequencies of candidate gene variants are compared between cases and community controls, and results are validated through family-based association studies. Members of the households of cases and community controls are being followed prospectively to determine the incidence of “secondary” tuberculosis and to evaluate the influence of geographic and genetic proximity to the index case. This type of design raises important methodological issues that may be useful to consider in studies investigating the natural history of infectious diseases and in attempts to disentangle the effects of environmental and genetic factors in response to infection. [ABSTRACT FROM PUBLISHER]

The etiology, particularly the genetic basis, of multifactorial late-onset diseases is the subject of many genetic epidemiologic studies. The authors' aim in this paper was to investigate the circumstances under which competing risks can lead to bias in studies of genetic susceptibility to late-onset diseases. The authors used a model built in an epidemiologic framework to show that when a genetic risk factor and an environmental risk factor interact to cause a frequent competing risk of death, the measure of the association between the disease under investigation and the genetic risk factor will be biased if the environmental risk factor is also associated with the latter disease and is omitted from the analysis. This is an example of confounding bias, and it is the consequence of an association between the genetic risk factor and the environmental risk factor that appears over time. Numerical examples show that under certain conditions this bias can be substantial. The authors present several patterns of association in favor of such a bias. Because competing risks of death are likely to be present in older subjects, researchers studying the etiology of late-onset diseases should be aware of the possibility of this bias. [ABSTRACT FROM PUBLISHER]

Methods of adjusting for bias in estimates due to mismeasured or missing covariates and outcomes through the use of validation sets have been developed in many types of health studies. These methods can be employed for the efficient design and analysis of vaccine studies as well. On the one hand, nonspecific case definitions can lead to attenuated efficacy and effectiveness estimates, but confirmation by culture or a quick test of the infectious agent is also expensive and difficult. On the other hand, data on exposure to infection can influence estimates of vaccine efficacy, but good data on exposure are difficult to obtain. In this paper, the authors show how use of small validation sets can correct the bias of the estimates obtained from a large main study while maintaining efficiency. They illustrate the approach for outcomes using the example of influenza vaccine efficacy and effectiveness trials and illustrate the approach for exposure to infection using the example of a human immunodeficiency virus vaccine trial. The authors discuss challenges posed by infectious diseases in the use of currently available methods. Development of these efficient designs and methods of analysis for vaccine field studies will improve estimation of vaccine efficacy for both susceptibility and infectiousness, as well as estimation of indirect and overall effects of vaccination in community trials. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to examine personal and health factors, both at the beginning of the study and thereafter, associated with participation in the GAZEL cohort, set up in 1989 in a large French company. The authors used logistic regression to analyze the associations between participation and data available for both participants (n = 20,093) and nonparticipants (n = 24,829). Higher participation was associated with male sex, marriage, children, managerial status, and residence in particular regions. Among men, lower participation was associated with sick leave in the year before recruitment and afterwards. During follow-up, participation was negatively associated with several groups of diseases, especially those associated with alcohol consumption. The risk of upper respiratory and digestive tract and lung cancer during follow-up was higher among nonparticipants. The same phenomenon occurred among women, but less markedly, for cancers of the breast and genital organs. During follow-up, mortality among men was higher among nonparticipants, especially for alcohol-related diseases. The association among women was less strong. Among men, but not among women, diseases caused by alcohol, smoking, or dangerous behavior were the primary reason for the health differences observed between participants and nonparticipants. Overall, the most important determinants of participation were cultural factors and lifestyle behaviors. [ABSTRACT FROM PUBLISHER]

Estimation of the genotype risk ratio can be an important part of studying the role of genetics in disease causation. For example, one might estimate risk among persons with genotype DD compared with risk among those with genotype Dd, where the candidate locus has alleles D and d, with D representing the disease susceptibility allele. In this paper, the authors propose a modified method of analysis for case-parental control studies that can improve efficiency. They show how investigators can use information from families in which both parents are observed to improve the estimator created by Sun et al., which applies when only one parent and an affected offspring have been observed. Since this information is not used by the conditional approach of Schaid and Sommer, the authors' approach allows for more complete use of available information, leading to a smaller mean squared error of the genotype risk ratio estimators. The authors also suggest a way to combine estimates from families in which one parent and one offspring are observed and estimates from families in which both parents and one offspring are observed. Am J Epidemiol 2001;154:259-63. [ABSTRACT FROM AUTHOR]

Preexisting computerized databases are potentially valuable sources of epidemiologic data. Since such databases are infrequently created specifically for etiologic research, data may be available for the exposure of interest and, through record linkage, for the endpoint of interest, but lacking for potential confounders. Because of the size of these databases, two-stage sampling is an efficient alternative to surveying the entire study population for confounder data. At stage 1, information on exposure and disease status is obtained for the entire study population. Confounder data are collected for probability-selected subsamples at stage 2. Logistic regression is performed on the stage 2 sample, with the parameter estimates and variances appropriately corrected to account for the stage 1 data. In this paper, the authors present methods for determining the required stage 2 sample size in the case of categorical exposure and confounding variables. Sample size tables, power curves, and a computer program have been produced to accommodate a binary exposure and a single binary confounder. With the increasing availability of preexisting yet incomplete databases, the potential for use of two-stage sampling will greatly increase in the future. This investigation provides a basis for estimating the number of participants to sample for the collection of confounder data at the second stage. [ABSTRACT FROM AUTHOR]

The article presents a commentary on a paper by Yue Chen et al. on the status of overweight and obesity as possible causes of asthma. It highlights the different risks for adult men and women that being overweight and their contributions to developing incident asthma. It also indicates the association of obesity with the development of asthma in women. In addition, the article stresses the need to implement health programs to diagnose asthma.

A response to commentaries on the article "Decomposing With a Lot of Supposing and Mediation" is presented. The authors explain the method they use to estimate risk differences. They argue in support of a commentary on the importance of temporal sequence in mediation analysis. They add that the methodology they used in their study notes the challenges associated with mediation analysis.

It is a commonly held belief that most complex diseases (e.g., diabetes, asthma, cancer) are affected in part by interactions between genes and environmental factors. However, investigators conducting genome-wide association studies typically test for only the marginal effects of each genetic marker on disease. In this paper, the authors propose an efficient and easily implemented 2-step analysis of genome-wide association study data aimed at identifying genes involved in a gene-environment interaction. The procedure complements screening for marginal genetic effects and thus has the potential to uncover new genetic signals that have not been identified previously. [ABSTRACT FROM AUTHOR]

The authors respond to a commentary by Stephen C. Redd and Ali H. Mokdad on their paper about the status of overweight and obesity as possible causes of asthma. They commend Redd and Mokdad for their perspective on the relation between obesity and asthma incidence in women in Canada. They recognize the importance of establishing the link between obesity and asthma to the prevention and control of both diseases. In addition, the authors note a higher risk of asthma among women who lost or gained weight.

For dichotomous outcomes, the authors discuss when the standard approaches to mediation analysis used in epidemiology and the social sciences are valid, and they provide alternative mediation analysis techniques when the standard approaches will not work. They extend definitions of controlled direct effects and natural direct and indirect effects from the risk difference scale to the odds ratio scale. A simple technique to estimate direct and indirect effect odds ratios by combining logistic and linear regressions is described that applies when the outcome is rare and the mediator continuous. Further discussion is given as to how this mediation analysis technique can be extended to settings in which data come from a case-control study design. For the standard mediation analysis techniques used in the epidemiologic and social science literatures to be valid, an assumption of no interaction between the effects of the exposure and the mediator on the outcome is needed. The approach presented here, however, will apply even when there are interactions between the effect of the exposure and the mediator on the outcome. [ABSTRACT FROM PUBLISHER]

Observational epidemiology has made outstanding contributions to the discovery and elucidation of relations between lifestyle factors and common complex diseases such as type 2 diabetes. Recent major advances in the understanding of the human genetics of this disease have inspired studies that seek to determine whether the risk conveyed by bona fide risk loci might be modified by lifestyle factors such as diet composition and physical activity levels. A major challenge is to determine which of the reported findings are likely to represent causal interactions and which might be explained by other factors. The authors of this commentary use the Bradford-Hill criteria, a set of tried-and-tested guidelines for causal inference, to evaluate the findings of a recent study on interaction between variation at the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) locus and total energy intake with respect to prevalent metabolic syndrome and hemoglobin A1c levels in a cohort of 313 Japanese men. The current authors conclude that the study, while useful for hypothesis generation, does not provide overwhelming evidence of causal interactions. They overview ways in which future studies of gene × lifestyle interactions might overcome the limitations that motivated this conclusion. [ABSTRACT FROM PUBLISHER]

Sufficient cause interactions concern cases in which there is a particular causal mechanism for some outcome that requires the presence of 2 or more specific causes to operate. Empirical conditions have been derived to test for sufficient cause interactions. However, when regression outcome models are used to control for confounding variables in tests for sufficient cause interactions, the outcome models impose restrictions on the relation between the confounding variables and certain unidentified background causes within the sufficient cause framework; often, these assumptions are implausible. By using marginal structural models, rather than outcome regression models, to test for sufficient cause interactions, modeling assumptions are instead made on the relation between the causes of interest and the confounding variables; these assumptions will often be more plausible. The use of marginal structural models also allows for testing for sufficient cause interactions in the presence of time-dependent confounding. Such time-dependent confounding may arise in cases in which one factor of interest affects both the second factor of interest and the outcome. It is furthermore shown that marginal structural models can be used not only to test for sufficient cause interactions but also to give lower bounds on the prevalence of such sufficient cause interactions. [ABSTRACT FROM PUBLISHER]

The authors examined the relation between occupation and lung cancer in the large, population-based Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study. In 2002–2005 in the Lombardy region of northern Italy, 2,100 incident lung cancer cases and 2,120 randomly selected population controls were enrolled. Lifetime occupational histories (industry and job title) were coded by using standard international classifications and were translated into occupations known (list A) or suspected (list B) to be associated with lung cancer. Smoking-adjusted odds ratios and 95% confidence intervals were calculated with logistic regression. For men, an increased risk was found for list A (177 exposed cases and 100 controls; odds ratio = 1.74, 95% confidence interval: 1.27, 2.38) and most occupations therein. No overall excess was found for list B with the exception of filling station attendants and bus and truck drivers (men) and launderers and dry cleaners (women). The authors estimated that 4.9% (95% confidence interval: 2.0, 7.8) of lung cancers in men were attributable to occupation. Among those in other occupations, risk excesses were found for metal workers, barbers and hairdressers, and other motor vehicle drivers. These results indicate that past exposure to occupational carcinogens remains an important determinant of lung cancer occurrence. [ABSTRACT FROM PUBLISHER]

Extremely low frequency magnetic fields (ELF-MFs) have been classified as possibly carcinogenic to humans by the International Agency for Research on Cancer. The authors investigated, in a population-based case-control study in Germany, if children whose parents were exposed preconceptionally at work to ELF-MFs had an increased risk of developing cancer. Cases aged 0–14 years were ascertained from the German Childhood Cancer Registry. Controls were selected from local resident registration offices. The parental occupational history was recorded in questionnaires and telephone interviews, and preconceptional magnetic field exposure was estimated according to a job-exposure matrix. The analysis included 2,382 controls and 2,049 cases (846 children with acute leukemia, 159 children with non-Hodgkin's lymphoma, 444 children with central nervous system tumors, and 600 children with other solid tumors). Frequency-matched conditional logistic regression models revealed no increased cancer risks in children whose fathers were occupationally exposed to magnetic fields above 0.2 μT. Additionally, there was no evidence for a risk increase at magnetic field levels exceeding 1 μT. Based on much smaller numbers, maternal occupational exposure was also not related to increased cancer risks. In this large case-control study, the risk of childhood cancer was not linked to preconceptional parental ELF-MF exposure. [ABSTRACT FROM PUBLISHER]

The assessment of indirect effects is an important tool for epidemiologists interested in exploring the mechanisms of exposure-disease relations. A standard way of expressing an indirect effect is in terms of the “proportion explained”; this is the proportion of the total effect that is explained by a particular mediator (or set of mediators). There are several ways to calculate the proportion explained, based on both additive and multiplicative models. However, these standard methods (particularly those based on multiplicative models) have been criticized for lacking a causal interpretation. To address this issue, the author uses a framework of potential outcomes to define the indirect effects of interest (natural effects) and assess the correspondence between the natural effects and standard measures. The author finds that standard additive measures represent an unbiased weighted average of the effects of interest; standard multiplicative measures, on the other hand, yield a biased weighted average of these effects. If the investigator is primarily interested in whether or not an indirect effect exists, standard measures for mediation will often yield the correct answer. In contrast, if valid quantification of the indirect effect is desired, counterfactual-based methods should be used. [ABSTRACT FROM PUBLISHER]

In the 1950s, case-control studies of smoking and lung cancer established a paradigm for epidemiologic studies of risk factors for chronic diseases. Since then, thousands of case-control studies have examined possible associations of countless risk factors with numerous diseases, rarely finding associations as strong or consistent as that of smoking with lung cancer. Recently, researchers have applied advances in molecular genetics to conduct candidate gene and genome-wide association studies of lung cancer. Skeptics among both epidemiologists and geneticists have argued that genomic research adds little value when most cases of disease can be attributed to a preventable exposure; however, well-conducted studies of gene-environment interactions that draw on data from more than 50 years of research in toxicology, pathophysiology, and behavioral science offer important models for the development of more comprehensive approaches to understanding the etiology of chronic diseases. [ABSTRACT FROM PUBLISHER]

According to the authors, time-modified confounding occurs when the causal relation between a time-fixed or time-varying confounder and the treatment or outcome changes over time. A key difference between previously described time-varying confounding and the proposed time-modified confounding is that, in the former, the values of the confounding variable change over time while, in the latter, the effects of the confounder change over time. Using marginal structural models, the authors propose an approach to account for time-modified confounding when the relation between the confounder and treatment is modified over time. An illustrative example and simulation show that, when time-modified confounding is present, a marginal structural model with inverse probability-of-treatment weights specified to account for time-modified confounding remains approximately unbiased with appropriate confidence limit coverage, while models that do not account for time-modified confounding are biased. Correct specification of the treatment model, including accounting for potential variation over time in confounding, is an important assumption of marginal structural models. When the effect of confounders on either the treatment or outcome changes over time, time-modified confounding should be considered. [ABSTRACT FROM PUBLISHER]

Fertility status may predict later mortality, but no studies have examined the effect of semen quality on subsequent mortality. Men referred to the Copenhagen Sperm Analysis Laboratory by general practitioners and urologists from 1963 to 2001 were, through a unique personal identification number, linked to the Danish central registers that hold information on all cases of cancer, causes of death, and number of children in the Danish population. The men were followed until December 31, 2001, death, or censoring, whichever occurred first, and the total mortality and cause-specific mortality of the cohort were compared with those of all age-standardized Danish men or according to semen characteristics. Among 43,277 men without azospermia referred for infertility problems, mortality decreased as the sperm concentration increased up to a threshold of 40 million/mL. As the percentages of motile and morphologically normal spermatozoa and semen volume increased, mortality decreased in a dose-response manner (Ptrend < 0.05). The decrease in mortality among men with good semen quality was due to a decrease in a wide range of diseases and was found among men both with and without children; therefore, the decrease in mortality could not be attributed solely to lifestyle and/or social factors. Semen quality may therefore be a fundamental biomarker of overall male health. [ABSTRACT FROM PUBLISHER]

A few epidemiologic studies have shown an increased risk of death from external causes among men with hypertension. Previous studies were limited by small numbers of events, however, and none assessed the association of blood pressure with specific types of “accidental” death. The authors examined data obtained from baseline interviews and 25 years of mortality follow-up (1973−1999) for 347,978 men screened for the US Multiple Risk Factor Intervention Trial. Proportional hazards regression analyses were used to quantify associations of blood pressure with all external causes of death and individual causes. There were 3,910 deaths from external causes, including 2,313 unintentional injuries, 1,248 suicides, and 349 homicides. Compared with those for men whose blood pressure status was “normal” according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the multivariate-adjusted hazard ratios and 95% confidence intervals for death from external causes among men with prehypertension, stage 1 hypertension, and stage 2 hypertension were 0.91 (95% confidence interval (CI): 0.83, 1.00), 1.06 (95% CI: 0.96, 1.16), and 1.44 (95% CI: 1.28, 1.62), respectively. Men with stage 2 hypertension had multivariate-adjusted hazard ratios of 1.90 for falls (95% CI: 1.32, 2.74), 1.45 for motor vehicle injuries (95% CI: 1.14, 1.85), 1.33 for other “accidents” (95% CI: 1.06, 1.66), 1.40 for suicide (95% CI: 1.13, 1.73), and 1.35 for homicide (95% CI: 0.92, 1.97). For men, hypertension may signal an increased risk of death from external causes. [ABSTRACT FROM AUTHOR]

Familial aggregation of non-Hodgkin's lymphoma, and the co-occurrence of non-Hodgkin's lymphoma and other hematologic malignancies within families, provide evidence for genetic or common environmental etiologies for these conditions. The authors analyzed the association between non-Hodgkin's lymphoma risk and family history of hematologic malignancy using a case-control study based in the United Kingdom. The study recruited patients diagnosed with lymphoma during 1998–2001. Results indicated an increased risk of non-Hodgkin's lymphoma for persons with a positive family history of any hematologic malignancy (odds ratio = 1.70, 95% confidence interval: 1.08, 2.69) and particularly of any lymphoma (odds ratio = 2.43, 95% confidence interval: 1.14, 5.19). The authors compared the number of hematologic malignancies among relatives reported by the cases and controls with that expected from the national rates of hematologic malignancy registered in the United Kingdom. Through these comparisons, the authors raise questions about the validity of self-reported family history of hematologic malignancy, especially regarding identification of specific types of hematologic malignancies. Given these reservations, they consider how future epidemiologic studies may contribute to further understanding the role of familial susceptibility in non-Hodgkin's lymphoma. [ABSTRACT FROM AUTHOR]

Many studies have identified urban-rural differences in schizophrenia risk. Hypothetical underlying cause(s) may include toxic exposures, diet, infections, and selective migration. The authors investigated whether the underlying cause(s) responsible for the urban-rural differences were rooted in families or in individuals. Linking data from the Danish Civil Registration System and the Danish Psychiatric Central Register, a population-based cohort of 711,897 people aged 15 years or more was established. Overall, 2,720 persons developed schizophrenia during the period 1970–2001. The authors evaluated whether the nearest older sibling's place of birth had an independent effect on schizophrenia risk. If the cause(s) responsible for the urban-rural differences are rooted in individuals only, the nearest older sibling's place of birth should have no independent effect. In this analysis, the nearest older sibling's place of birth had an independent effect; among persons who lived in a rural area during their first 15 years of life, the relative risk was 1.59 (95% confidence interval: 1.10, 2.30) if their nearest older sibling had been born in the capital area as compared with a rural area. Some of the cause(s) responsible for the urban-rural differences in schizophrenia risk are rooted in families, but some might also be rooted in individuals. [ABSTRACT FROM AUTHOR]

Some reports suggest that bacteria, including Chlamydophila pneumoniae, could be involved in the etiology of multiple sclerosis. If that is true, persons who used antibiotics active against these bacteria, compared with nonusers, might be at lower risk of multiple sclerosis. Using a 1993–2000 case-control study nested in the United Kingdom–based General Practice Research Database cohort, the authors identified 163 multiple sclerosis cases who were followed up for at least 3 years before their first symptoms (the index date). Up to 10 controls matched to the cases by age, sex, general practice, and time in the cohort were selected. Exposure to antibiotics was assessed through computerized medical records. Overall antibiotic use or use of antibiotics against C. pneumoniae was not associated with multiple sclerosis risk. However, use of penicillins in the 3 years before the index date decreased the risk of developing a first attack of multiple sclerosis (odds ratio = 0.5, 95% confidence interval: 0.3, 0.9 for those who used penicillins for ≥15 days compared with no use). In conclusion, use of antibiotics active against C. pneumoniae was not associated with a decreased risk of short-term multiple sclerosis. The observed lower risk of multiple sclerosis for penicillin users needs to be confirmed in other populations. [ABSTRACT FROM AUTHOR]

Information suggesting that infection may be an underlying cause of childhood leukemia and lymphoma includes the occasional appearance of cases in time-space clusters within communities and increased incidence after communities experience marked population influxes (population mixing). Among 50 clusters involving cases of childhood leukemia and lymphoma investigated in the United States in 1961–1977, eight showed suggestive evidence of underlying infectious causation. In seven of the eight communities, case occurrence was associated with the attendance of patients or their siblings at particular schools or with family participation in particular church groups. In five, rapid population growth had occurred. Other findings included the possible association of cases with unusual patterns of infectious disease (rheumatic illness in one community, chickenpox in another) and with other childhood diseases, including other forms of childhood cancer. In one community, two cases of Burkitt's lymphoma occurred at the same time, and a third case arose 3 years later in boys living in a newly developing neighborhood. Such community observations support the need for continued biologic research regarding the possible role of infectious agents in childhood leukemia and lymphoma. [ABSTRACT FROM AUTHOR]

Musculoskeletal disorders of the back and spine are a leading cause of disability in working-age populations. There is limited information on the potential consequences of childhood socioeconomic and health status on the risk of incident back pain in early adulthood. The authors describe factors associated with having had a first episode of back pain during the past year in the Ontario Child Health Study, a prospective cohort study of children who were aged 4–16 years at the time of enrollment in 1983 and were resurveyed in 2001. Respondents reporting a first episode of back pain (n = 143) were compared with respondents who had never experienced back pain (n = 896). The annual incidence of a first episode of back pain in this sample of young adults was 74.7/1,000. Following adjustment for age, sex, childhood conditions, childhood health status, and measures of early adult health, behavior, socioeconomic status, and work environment, the risk of incident back pain was associated with both low (odds ratio (OR) = 1.86, 95% confidence interval (CI): 1.14, 3.03) and moderate/high (OR = 1.85, 95% CI: 1.07, 3.02) levels of psychological distress, current heavy smoking (OR = 1.85, 95% CI: 1.10, 3.10), lower levels of parental education in childhood (OR = 1.72, 95% CI: 1.06, 2.80), and emotional or behavioral disorders in childhood (OR = 1.87, 95% CI: 1.02, 3.41). The associations of low childhood socioeconomic status and childhood emotional and behavioral disorders with risk of incident back pain in early adulthood are important findings with implications for better understanding the etiology of soft-tissue disorders. [ABSTRACT FROM AUTHOR]

Modern microarray genotyping now permits simultaneous analysis of tens of thousands of polymorphisms, and this technology is being widely used to associate the role of genes with the etiology of complex disease. Genome-wide hypothesis-free mapping will also increasingly generate candidate genes that require further testing in association studies. At the same time, genetic effects are increasingly observed to be buffered by a wide array of biologic mechanisms that evolved to protect the genome from environmental insult and that serve to obscure observation of direct effects of polymorphisms on a disease phenotype. These two forces combine to make replication of genomic epidemiology extraordinarily difficult. Traditional research synthesis of emerging bodies of genomic epidemiology is problematic and often quickly outdated. The author proposes that electronic evidence-based methodology, perhaps modeled after that used by the Cochrane Collaboration in clinical medicine, would facilitate the systematic preparation and frequent updating of systematic reviews, which is essential for identifying valid and replicable gene-disease associations. [ABSTRACT FROM AUTHOR]

Studying associations between sibship characteristics and allergic diseases in detail may contribute clues to their etiology. The authors studied associations between sibship characteristics and risk of self-reported allergic rhinitis and asthma among 31,145 pregnant women participating in a nationwide study in Denmark during 1997–2000. Increasing sibship size was associated with a decreased risk of allergic rhinitis and asthma with allergic rhinitis but not with asthma without allergic rhinitis. The protective effect of having older siblings was stronger than the protective effect of having younger siblings for both allergic rhinitis and asthma with allergic rhinitis. There was no association between interval to closest older or younger sibling and risk of allergic rhinitis or asthma with allergic rhinitis, while the risk of asthma without allergic rhinitis increased with intervals of 2 or more years compared with less than 2 years to the nearest older sibling. The protective effect of having siblings on the risk of asthma with allergic rhinitis could be explained by a protective effect of siblings on the risk of allergic rhinitis alone. In conclusion, our findings suggest that different etiologic mechanisms are involved for allergic rhinitis and asthma with respect to the effect of sibship characteristics. Furthermore, the findings that allergic rhinitis was associated with the number of younger siblings but not with the age interval to younger siblings support the hypothesis of an influence of postnatal mechanisms and suggest that these mechanisms may not necessarily be operating only in early life. [ABSTRACT FROM AUTHOR]

Smoking-attributable mortality (SAM) is the number of deaths in a population caused by smoking. In this study, the authors examined and empirically quantified the effects of methodological problems in the estimation of SAM through population attributable fraction methods. In addition to exploring common concerns regarding generalizability and residual confounding in relative risks, the authors considered errors in measuring estimates of risk exposure prevalence and mortality in target populations and estimates of relative risks from etiologic studies. They also considered errors resulting from combining these three sources of data. By modifying SAM estimates calculated using smoking prevalence obtained from the 2000–2001 Canadian Community Health Survey, a population-based survey of 131,535 Canadian households, the authors observed the following effects of potential errors on estimated national SAM (and the range of effects on 87 regional SAMs): 1) using a slightly biased, mismatched definition of former smoking: 5.3% (range, 1.8% to 11.6%); 2) using age-collapsed prevalence and relative risks: 6.9% (range, 1.1% to 15.5%) and −15.4% (range, −7.9% to −21.0%), respectively; 3) using relative risks derived from the same cohort but with a shorter follow-up period: 8.7% (range, 4.5% to 11.8%); 4) using relative risks for all diseases with age-collapsed prevalence: 49.7% (range, 24.1% to 82.2%); and 5) using prevalence estimates unadjusted for exposure-outcome lag: −14.5% (range, −20.8% to 42.6%) to −1.4% (range, −0.8% to −2.7%), depending on the method of adjustment. Applications of the SAM estimation method should consider these sources of potential error. [ABSTRACT FROM PUBLISHER]

Osteoporosis (OMIM166710) is a common skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with increased susceptibility to fracture. Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease in which genetic determinants are modulated by hormonal, environmental, and nutritional factors. Estrogens are known to play an important role in regulating bone homeostasis and preventing postmenopausal bone loss. They act through binding to two different estrogen receptors (ERs), ERα (OMIM133430) and ERβ (OMIM601663), which are members of the nuclear receptor superfamily of ligand-activated transcription factors. Different polymorphisms have been described in both the ER α and ER β genes. Although a large number of association studies have been performed, the individual contribution of these polymorphisms to the pathogenesis of osteoporosis remains to be universally confirmed. Moreover, an important aim in future work will be to define their functional molecular consequences and their interaction with the environment in the causation of the osteoporotic phenotype. A further promising application of these polymorphisms comes from their pharmacogenomic implications, with the possibility of providing better guidance for therapeutic regimens, such as estrogen replacement therapy and selective ER modulators. At the moment, no recommendations for population-based screening can be made. [ABSTRACT FROM PUBLISHER]

Observational longitudinal research is particularly useful for assessing etiology and prognosis and for providing evidence for clinical decision making. However, there are no structured reporting requirements for studies of this design to assist authors, editors, and readers. The authors developed and tested a checklist of criteria related to threats to the internal and external validity of observational longitudinal studies. The checklist criteria concerned recruitment, data collection, biases, and data analysis and descriptive issues relevant to study rationale, study population, and generalizability. Two raters independently assessed 49 randomly selected articles describing stroke research published from 1999 to 2003 in six journals: American Journal of Epidemiology, Journal of Epidemiology and Community Health, Stroke, Annals of Neurology, Archives of Physical Medicine and Rehabilitation, and American Journal of Physical Medicine and Rehabilitation. On average, 17 of the 33 checklist criteria were reported. Criteria describing the study design were better reported than those related to internal validity. No relation was found between study type (etiologic or prognostic) or word count and quality of reporting. A flow diagram for summarizing participant flow through a study was developed. Editors and authors should consider using a checklist and flow diagram when reporting on observational longitudinal research. [ABSTRACT FROM PUBLISHER]

A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person’s genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure. Plotting the log odds ratio of genotype-disease against the mean genotype-phenotype difference may help investigators detect departures from the assumptions underlying Mendelian randomization. Testing for differences between studies reporting on only the genotype-phenotype or genotype-disease association and those reporting on both associations may help in detecting reporting bias. This integrated approach to the meta-analysis of genotype-phenotype and genotype-disease studies is illustrated here using the example of the methylenetetrahydrofolate reductase (MTHFR) gene, homocysteine level, and coronary heart disease. An integrated meta-analytical approach may increase the precision of this estimate and provide information on the assumptions underlying Mendelian randomization. Serious biases may arise if the assumptions behind the analysis based on Mendelian randomization are not met. [ABSTRACT FROM AUTHOR]

The role of dietary fat in the etiology of type 2 diabetes remains uncertain. The authors investigated the association between dietary fat composition and risk of clinical type 2 diabetes in the European Prospective Investigation of Cancer-Norfolk study and identified food consumption patterns associated with dietary fat composition. Diet was assessed at baseline (1993-1997) using a semiquantitative food frequency questionnaire. From multiple sources of information, 414 incident cases of diabetes were identified among 23,631 men and women aged 40-78 years during 3-7 years of follow-up. The capture-recapture ascertainment level was 99%. The energy-adjusted dietary polyunsaturated:saturated fat ratio was inversely associated with the risk of diabetes (odds ratio (OR) = 0.84 per standard deviation change, 95% confidence interval (CI): 0.75, 0.94). Adjustment for age, sex, family history of diabetes, smoking, physical activity, total fat, protein, and alcohol attenuated the association (OR = 0.88, 95% CI: 0.78, 0.99), and it was no longer statistically significant after including body mass index and the waist:hip ratio (OR = 0.91, 95% CI: 0.81, 1.03). This prospective study showed that an increased dietary polyunsaturated:saturated fat ratio was associated with a reduced risk of diabetes, independent of age, sex, family history of diabetes, and other lifestyle factors. [ABSTRACT FROM AUTHOR]

A critical role for infection in the etiology of childhood leukemia has repeatedly been suggested. The authors undertook a case-control study nested within national maternity cohorts with altogether 7 million years of follow-up to assess the relative role of three maternal herpesvirus infections in childhood acute lymphoblastic leukemia (ALL). Offspring of 550,000 mothers in Finland and Iceland formed the joint study cohort that was followed up for cancer in the offspring before age 15 years during 1975-1997 through national cancer registries. For each index mother-case pair, three or four matched control mother-control pairs were identified from national population registers. First-trimester sera were retrieved from mothers of 342 ALL and 61 other leukemia cases and from 1,216 control mothers and were tested for antibodies to cytomegalovirus, Epstein-Barr virus (EBV), and human herpesvirus 6. Serum EBV DNA was also analyzed. Conditional logistic regression-based estimates of relative risk (odds ratio) adjusted for birth order and sibship size, and population attributable fractions, were calculated. Only EBV immunoglobulin M positivity in EBV-immunoglobulin-G-positive mothers was associated with a highly significant increased risk of ALL in the offspring (adjusted odds ratio = 2.9, 95% confidence interval: 1.5, 5.8). Results indicate that reactivation of maternal EBV infection is probably associated with childhood ALL. [ABSTRACT FROM AUTHOR]

A long interpregnancy interval is associated with preeclampsia. If some women experiencing a long interval between births had difficulty conceiving, subfecundity and preeclampsia may share a common etiology. Therefore, the authors examined the association between subfecundity and preeclampsia. By using interview data collected during the second trimester of pregnancy (1998–2001) from women participating in the Danish National Birth Cohort, they identified 20,034 and 24,698 singleton livebirths to primiparous and multiparous women, respectively, for whom preeclampsia information was available from hospital birth records. Among women with no known hypertension, the authors estimated a higher risk of preeclampsia in those with longer times to pregnancy (TTPs), after adjustment for maternal age, prepregnancy body mass index, and smoking. Compared with primiparas who became pregnant right away (referent category), the risk of preeclampsia increased with TTP and then stabilized for women taking 6 months or longer to conceive, whose risk of preeclampsia increased by 50%. Multiparas also had an increased risk, but only those reporting a TTP longer than 12 months (odds ratio = 2.47, 95% confidence interval: 1.30, 4.69). The authors found that a long TTP was associated with preeclampsia, supporting the hypothesis that some factors delaying clinically recognized conception may also be in a causal pathway for preeclampsia. [ABSTRACT FROM PUBLISHER]

Bell’s palsy is a relatively common disease characterized by the sudden onset of unilateral facial paralysis. Using a centralized surveillance system that contains demographic, military assignment, and medical encounter data of US military service members, the authors estimated rates, trends, and demographic correlates of risk of Bell’s palsy during a 2-year period. Poisson regression was used to estimate the independent effects of climate, season, and latitude. From October 1997 to September 1999, there were 1,181 incident cases of Bell’s palsy among US service members. The crude incidence rate was 42.77 per 100,000 person-years. Incidence rates increased with age and were higher among females, Blacks, Hispanics, married persons, and enlisted service members. Both climate (adjusted rate ratio for arid vs. nonarid climate = 1.34) and season (adjusted rate ratio for cold vs. warm months = 1.31) were independent predictors of risk of Bell’s palsy. Latitude was not a statistically significant predictor when demographic, climate, and season effects were taken into account. The results are consistent with hypotheses regarding viral etiologies (e.g., reactivation of herpes simplex) of Bell’s palsy. [ABSTRACT FROM PUBLISHER]

In the past decade, there have been enormous advances in the use of Bayesian methodology for analysis of epidemiologic data, and there are now many practical advantages to the Bayesian approach. Bayesian models can easily accommodate unobserved variables such as an individual's true disease status in the presence of diagnostic error. The use of prior probability distributions represents a powerful mechanism for incorporating information from previous studies and for controlling confounding. Posterior probabilities can be used as easily interpretable alternatives to p values. Recent developments in Markov chain Monte Carlo methodology facilitate the implementation of Bayesian analyses of complex data sets containing missing observations and multidimensional outcomes. Tools are now available that allow epidemiologists to take advantage of this powerful approach to assessment of exposure-disease relations. Am J Epidemiol 2001;153:1222-6. [ABSTRACT FROM AUTHOR]

An infectious etiology for childhood acute lymphoblastic leukemia (ALL) has been suggested, yet few studies have focused on the role of early child care. Day-care histories were examined in a case-control study of ALL in New York State. Cases (n = 255) were diagnosed at one of four referral centers between 1980 and 1991; controls (n = 760) were randomly selected from livebirths in the 31 counties served by the referral centers. Self-administered questionnaires were mailed to the parents of cases and controls in 1995. Day-care histories were censored at the age of diagnosis for cases and at an equivalent date for controls. The odds ratio for children who stayed at home compared with those who attended day care for >36 months was 1.32 (95% confidence interval (CI): 0.70, 2.52); the odds ratios for 1–18 and 19–36 months of day care were 1.74 (95% CI: 0.89, 3.42) and 1.32 (95% CI: 0.64, 2.71), respectively. Elimination of cases with T-cell ALL enhanced the risk. Starting care at an earlier age was not associated with a decreased risk of ALL. These findings do not support the hypothesis that infrequent contact with peers during early childhood could delay exposure to infectious diseases and increase the risk of ALL. [ABSTRACT FROM PUBLISHER]

Alcohol consumption has been linked to kidney disorders in selected patient groups, but whether it contributes to the burden of end-stage renal disease (ESRD) in the general population is unknown. The authors conducted population-based case-control study to asess the realation between alcohol consumption and risk of ESRD. The study took place in Maryland, Virginia, West Virginia, and Washington, DC, in 1991. Participants were 716 patients who had started treatment for ESRD and 361 control subjects of similar age (20–64 years) selected by random digit dialing. The main risk factor of interest was self-reported consumption of alcoholic beverages (frequency of drinking days and number of drinks consumed per drinking day). In univariate analysis, consumption of alcohol exhibited a J-shaped association with risk of ESRD. The J shape disappeared after exclusion of persons who had ever consumed home-distilled whiskey (“moonshine”) and adjustment for age, race, sex, income, history of hypertension, history of diabetes mellitus, use of acetaminophen, use of opiates, and cigarette smoking; however, the odds ratio for ESRD remained significantly increased (odds ratio = 4.0; 95% confidence interval: 1.2, 13.0) among persons who consumed an average of >2 alcoholic drinks per day. The corresponding population attributable risk was 9 percent. Thus, consumption of more than two alcoholic drinks per day, on average, was associated with an increased risk of kidney failure In the general population. A lower intake of alcohol did not appear to be harmful. Because these results are based on self-reports in a case-control study, they should be seen as preliminary. Am J Epidemiol 1999; 150:1275-81. [ABSTRACT FROM PUBLISHER]

Studies of the etiology of colon cancer indicate that it is strongly associated with diet and lifestyle factors. The authors use data from a population-based study conducted in northern California, Utah, and Minnesota in 1991–1995 to determine lifestyle patterns and their association with colon cancer. Data obtained from 1,993 cases and 2,410 controls were grouped by using factor analyses to describe various aspects of lifestyle patterns. The first five lifestyle patterns for both men and women loaded heavily on dietary variables and were labeled: “Western,” “moderation,” “calcium/low-fat dairy, ” “meat and mutagens, ” and “nibblers, smoking, and coffee.” Other important lifestyle patterns that emerged were labeled “body size,” “medication and supplementation” “alcohol,” and “physical activity.” Among both men and women, the lifestyle characterized by high levels of physical activity was the most marked lifestyle associated with colon cancer (odds ratios = 0.42, 95% confidence interval: 0.32, 0.55 and odds ratio = 0.52, 95% confidence interval: 0.39, 0.69, for men and women, respectively) followed by medication and supplementation (odds ratio = 1.68, 95%confidence interval: 1.29, 2.18 and odds ratio = 1.63, 95% CI 1.23, 2.16, respectively). Other lifestyles that were associated with colon cancer were the Western lifestyle, the lifestyle characterized by large body size, and the one characterized by calcium and low-fat dairy. Different lifestyle patterns appear to have age- and tumor site-specific associations. Am J Epidemiol 1999;150:869-77. [ABSTRACT FROM AUTHOR]

An inverse relation between adult height and risk of coronary heart disease (CHD) has been reported in many studies, but the association between adult height and stroke remains uncertain. The authors examined the relation between adult height and risk of stroke and CHD in a prospective study of 7, 735 men drawn from general medical practices in 24 towns in England, Wales, and Scotland. The men were followed up for an average of 16.8 years (range, 15.5–18.0 years) between 1978 and 1995. During this period, there were 351 major stroke events (63 fatal, 288 nonfatal) and 1, 093 major CHD events (465 fatal, 628 nonfatal). The mean height of the men was 173.3 cm. Total stroke risk was increased only in the men who fell into the lowest quintile of the height distribution (<167.7 cm), with little difference being seen between the other groups. When data were examined separately for fatal and nonfatal events, no relation was seen with nonfatal stroke. An apparent inverse association was seen with fatal stroke, even after adjustment for a wide range of confounding variables, but the number of deaths was small and the trend was not statistically significant (p = 0.17). By contrast, a significant inverse relation was seen between height and risk of major CHD events: Risk decreased progressively with increasing height, even after full adjustment (highest quintile vs. lowest: relative risk (RR) = 0.74, 95% confidence interval (Cl) 0.59–0.91; test for trend: p < 0.001). A stronger inverse association was seen with nonfatal CHD events (RR = 0.64, 95% Cl 0.49–0.84) than with fatal CHD events (RR = 0.82, 95% Cl 0.60–1.11). This study confirms the finding of an inverse association between height and CHD. The inverse association seen for fatal stroke but not nonfatal stroke suggests that height may be related to specific subtypes of stroke. There are different patterns of association between height and stroke and height and CHD. If the apparent association between short stature and increased risk of fatal stroke is confirmed in other prospective studies, this would suggest that different mechanisms underlie the effects of height on stroke and CHD. Am J Epidemiol 1998; 148: 1069-76. [ABSTRACT FROM PUBLISHER]

The authors describe a new simple noniterative, yet efficient method to estimate the risk ratio in studies using case-parental control design. The new method is compared with two other noniterative methods, Khoury's method and Flanders and Khoury's method, and with a maximum likelihood-based method of Schaid and Sommer. The authors found that the variance of the new estimation method is usually smaller than that of Khoury's method or Flanders and Khoury's method and that it is slightly larger than that of the maximum likelihood-based method of Schaid and Sommer. Despite the slightly large variance of the new estimator compared with that of the maximum likelihood-based method, the simplicity of the new estimator and its variance makes the new method appealing. When genotypic information for only one parent is available, the authors also describe a method to estimate the risk ratio without assuming Hardy-Weinberg equilibrium or random mating. A simple formula for the variance of the estimator is given. Am J Epidemiol 1998; 148:902–9. [ABSTRACT FROM AUTHOR]

A gene variant that increases disease risk will be overrepresented among diseased persons, even compared with their own biologic parents. This insight has led to tests based solely on the asymmetric distribution of a variant allele among cases and their parents (e.g., the transmission/disequilibrium test). Existing methods focus on effects of alleles that operate through the offspring genotype. Alleles can also operate through the mother's genotype, particularly for conditions such as birth defects that have their origins in fetal life. An allele working through the mother would have higher frequency in case-mothers than in case-fathers. The authors develop a log-linear method for estimating relative risks for alleles in the context of case-parent triads. This method is able to detect the effects of genes working through the offspring, the mother, or both. The authors assume Mendelian inheritance, but Hardy-Weinberg equilibrium is unnecessary. Their approach uses standard software, and simulations demonstrate satisfactory power and confidence interval coverage. This method is valid with a self-selected or hospital-based series of cases and helps to protect against misleading inference that can result when cases and controls are randomly sampled from a population not in Hardy-Weinberg equilibrium. Am J Epidemiol 1998; 148:893–901. [ABSTRACT FROM AUTHOR]