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Heart failure—either with reduced or preserved ejection fraction (HFrEF/HFpEF)—is a clinical syndrome of multifactorial and gender-dependent aetiology, indicating the insufficiency of the heart to pump blood adequately to maintain blood flow to meet the body's needs. Typical symptoms commonly include shortness of breath, excessive fatigue with impaired exercise capacity, and peripheral oedema, thereby alluding to the fact that heart failure is a syndrome that affects multiple organ systems. Patients suffering from progressed heart failure have a very limited life expectancy, lower than that of numerous cancer types. In this position paper, we provide an overview regarding interactions between the heart and other organ systems, the clinical evidence, underlying mechanisms, potential available or yet-to-establish animal models to study such interactions and finally discuss potential new drug interventions to be developed in the future. Our working group suggests that more experimental research is required to understand the individual molecular mechanisms underlying heart failure and reinforces the urgency for tailored therapeutic interventions that target not only the heart but also other related affected organ systems to effectively treat heart failure as a clinical syndrome that affects and involves multiple organs. [ABSTRACT FROM AUTHOR]

Background: Genetic epidemiology deals with the aetiology, distribution and control of disease in groups of relatives, and with inherited causes of disease in populations. The main goal of this overview, part of the collaborative study SPHERE (Strengthening Public Health Research in Europe) was to have an up-to-date, detailed summary of the available information for epidemiologists and researchers on the present status of genetic epidemiology in Europe. Methods: The PubMed literature search engine was used to recruit papers published in Europe (EU15, EU + 10 and non-EU countries) in this field restricted to the time period of 1 January 1987 and 31 December 2004. Results: The number of publications increased significantly in Europe in the period analysed, however, the publication activity was restricted mainly to EU15 countries, with only sporadic papers from EU + 10 countries. Research areas studied are slightly different in Europe and in the USA with a larger emphasis on cancer, mental disease and behavioural disease genetic epidemiology in Europe. Conclusion: The aim must be to develop research to support policy in this important field as is already seen in the United States. [ABSTRACT FROM AUTHOR]

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.

Background Although many musicians suffer from musculoskeletal disorders, aetiological factors are unclear. Aims To systematically search for and synthesize the best available evidence on risk factors for musculoskeletal disorders in musicians. Methods A database search was performed in PubMed, EMBASE, CINAHL, Pedro, OTseeker and Psychinfo. A manual search was conducted in the journals Medical Problems of Performing Artists and Psychology of Music. Studies with an objective to investigate determinants associated with playing-related musculoskeletal disorders were included. Papers were selected based on adequacy of statistical methods for the purpose of the study. Search, first screening and selection were performed by one author. Two reviewers independently performed the final selection using full-text reports. Methodological quality assessment was performed by two reviewers independently. Results One case-control and 14 cross-sectional studies were included. Methodological quality was in general low. Large heterogeneity existed in study design, population, measurement of determinant and outcome and analysis techniques. Data were presented descriptively. Consistent results were found indicating that previous musculoskeletal injury, music performance anxiety, high levels of stress and being a female playing a stringed instrument seemed to be associated with more musculoskeletal disorders. Influence over or support at work, orchestra category/status, exercise behaviour and cigarette smoking seemed to be unrelated with musculoskeletal disorders. No conclusions could be made on causality, as the current data only represent cross-sectional associations. Conclusions Because of lack of prospective studies, no causal relations could be identified in the aetiology of (playing-related) musculoskeletal disorders in instrumental musicians. [ABSTRACT FROM AUTHOR]

Motivation: Exploring the potential long noncoding RNA (lncRNA)-disease associations (LDAs) plays a critical role for understanding disease etiology and pathogenesis. Given the high cost of biological experiments, developing a computational method is a practical necessity to effectively accelerate experimental screening process of candidate LDAs. However, under the high sparsity of LDA dataset, many computational models hardly exploit enough knowledge to learn comprehensive patterns of node representations. Moreover, although the metapath-based GNN has been recently introduced into LDA prediction, it discards intermediate nodes along the meta-path and results in information loss. Results: This paper presents a new multi-view contrastive heterogeneous graph attention network (GAT) for lncRNA-disease association prediction, MCHNLDA for brevity. Specifically, MCHNLDA firstly leverages rich biological data sources of lncRNA, gene and disease to construct two-view graphs, feature structural graph of feature schema view and lncRNA-gene-disease heterogeneous graph of network topology view. Then, we design a cross-contrastive learning task to collaboratively guide graph embeddings of the two views without relying on any labels. In this way, we can pull closer the nodes of similar features and network topology, and push other nodes away. Furthermore, we propose a heterogeneous contextual GAT, where long short-term memory network is incorporated into attention mechanism to effectively capture sequential structure information along the meta-path. Extensive experimental comparisons against several state-of-the-art methods show the effectiveness of proposed framework.The code and data of proposed framework is freely available at  https://github.com/zhaoxs686/MCHNLDA. [ABSTRACT FROM AUTHOR]

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug–disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug–disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug–disease associations. [ABSTRACT FROM AUTHOR]

Molecular pathological epidemiology research provides information about pathogenic mechanisms. A common study goal is to evaluate whether the effects of risk factors on disease incidence vary between different disease subtypes. A popular approach to carrying out this type of research is to implement a multinomial regression in which each of the non-zero values corresponds to a bona fide disease subtype. Then, heterogeneity in the exposure effects across subtypes is examined by comparing the coefficients of the exposure between the different subtypes. In this paper, we explain why this common method potentially cannot recover causal effects, even when all confounders are measured, due to a particular type of selection bias. This bias can be explained by recognizing that the multinomial regression is equivalent to a series of logistic regressions; each compares cases of a certain subtype to the controls. We further explain how this bias arises using directed acyclic graphs and we demonstrate the potential magnitude of the bias by analysis of a hypothetical data set and by a simulation study. [ABSTRACT FROM AUTHOR]

Since the mid-1970s, there have been many reports that purport to implicate aluminium in the aetiology of neurodegenerative disease. After several decades of research, the role of aluminium in such disease remains controversial and is not the subject of this review. However, if aluminium is implicated in such disease then it follows that there must be a toxicological mechanism or mode of action, and many researchers have investigated various potential mechanisms including the involvement of oxidative damage, cytotoxicity and genotoxicity. This paper reviews many of the publications of studies using various salts of aluminium and various genotoxicity end points, both in vitro and in vivo , with a focus on oxidative damage. The conclusion of this review is that the majority, if not all, of the publications that report positive results have serious technical flaws and/or implausible findings and consequently should contribute little or no weight to a weight of evidence (WoE) argument. There are many high-quality, Good Laboratory Practice (GLP)-compliant genotoxicity studies, that follow relevant OECD test guidelines and the European Chemicals Agency (ECHA) integrated mutagenicity testing strategy, on several salts of aluminium; all demonstrate clear negative results for both in vitro and in vivo genotoxicity. In addition, the claim for an oxidative mode of action for aluminium can be shown to be spurious. This review concludes that there are no reliable studies that demonstrate a potential for genotoxicity, or oxidative mode of action, for aluminium. [ABSTRACT FROM AUTHOR]

Motivation: Copy number variants (CNVs) have been implicated in a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability and schizophrenia. Recent advances in high-throughput genomic technologies have enabled rapid discovery of many genetic variants including CNVs. As a result, there is increasing interest in studying the role of CNVs in the etiology of many complex diseases. Despite the availability of an unprecedented wealth of CNV data, methods for testing association between CNVs and disease-related traits are still underdeveloped due to the low prevalence and complicated multi-scale features of CNVs. Results: We propose a novel CNV kernel association test (CKAT) in this paper. To address the low prevalence, CNVs are first grouped into CNV regions (CNVR). Then, taking into account the multiscale features of CNVs, we first design a single-CNV kernel which summarizes the similarity between two CNVs, and next aggregate the single-CNV kernel to a CNVR kernel which summarizes the similarity between two CNVRs. Finally, association between CNVR and disease-related traits is assessed by comparing the kernel-based similarity with the similarity in the trait using a score test for variance components in a random effect model. We illustrate the proposed CKAT using simulations and show that CKAT is more powerful than existing methods, while always being able to control the type I error. We also apply CKAT to a real dataset examining the association between CNV and autism spectrum disorders, which demonstrates the potential usefulness of the proposed method. [ABSTRACT FROM AUTHOR]

Background Geographical variation in dementia prevalence and incidence may indicate important socio-environmental contributions to dementia aetiology. However, previous comparisons have been hampered by combining studies with different methodologies. This review systematically collates and synthesizes studies examining geographical variation in the prevalence and incidence of dementia based on comparisons of studies using identical methodologies.Methods Papers were identified by a comprehensive electronic search of relevant databases, scrutinising the reference sections of identified publications, contacting experts in the field and re-examining papers already known to us. Identified articles were independently reviewed against inclusion/exclusion criteria and considered according to geographical scale. Rural/urban comparisons were meta-analysed.Results Twelve thousand five hundred and eighty records were reviewed and 51 articles were included. Dementia prevalence and incidence varies at a number of scales from the national down to small areas, including some evidence of an effect of rural living [prevalence odds ratio (OR) = 1.11, 90% confidence interval (CI) 0.79–1.57; incidence OR = 1.20, 90% CI 0.84–1.71]. However, this association of rurality was stronger for Alzheimer disease, particularly when early life rural living was captured (prevalence OR = 2.22, 90% CI 1.19–4.16; incidence OR = 1.64, 90% CI 1.08–2.50).Conclusions There is evidence of geographical variation in rates of dementia in affluent countries at a variety of geographical scales. Rural living is associated with an increased risk of Alzheimer disease, and there is a suggestion that early life rural living further increases this risk. However, the fact that few studies have been conducted in resource-poor countries limits conclusions. [ABSTRACT FROM PUBLISHER]

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]

Set-based association analysis is a valuable tool in studying the etiology of complex diseases in genome-wide association studies, as it allows for the joint testing of variants in a region or group. Two common types of single nucleotide polymorphism (SNP)–disease functional models are recognized when evaluating the joint function of a set of SNP: the cumulative weak signal model, in which multiple functional variants with small effects contribute to disease risk, and the dominating strong signal model, in which a few functional variants with large effects contribute to disease risk. However, existing methods have two main limitations that reduce their power. Firstly, they typically only consider one disease–SNP association model, which can result in significant power loss if the model is misspecified. Secondly, they do not account for the high-dimensional nature of SNPs, leading to low power or high false positives. In this study, we propose a solution to these challenges by using a high-dimensional inference procedure that involves simultaneously fitting many SNPs in a regression model. We also propose an omnibus testing procedure that employs a robust and powerful P-value combination method to enhance the power of SNP-set association. Our results from extensive simulation studies and a real data analysis demonstrate that our set-based high-dimensional inference strategy is both flexible and computationally efficient and can substantially improve the power of SNP-set association analysis. Application to a real dataset further demonstrates the utility of the testing strategy. [ABSTRACT FROM AUTHOR]

Motivation Somatic mutations result from processes related to DNA replication or environmental/lifestyle exposures. Knowing the activity of mutational processes in a tumor can inform personalized therapies, early detection, and understanding of tumorigenesis. Computational methods have revealed 30 validated signatures of mutational processes active in human cancers, where each signature is a pattern of single base substitutions. However, half of these signatures have no known etiology, and some similar signatures have distinct etiologies, making patterns of mutation signature activity hard to interpret. Existing mutation signature detection methods do not consider tumor-level clinical/demographic (e.g. smoking history) or molecular features (e.g. inactivations to DNA damage repair genes). Results To begin to address these challenges, we present the Tumor Covariate Signature Model (TCSM), the first method to directly model the effect of observed tumor-level covariates on mutation signatures. To this end, our model uses methods from Bayesian topic modeling to change the prior distribution on signature exposure conditioned on a tumor's observed covariates. We also introduce methods for imputing covariates in held-out data and for evaluating the statistical significance of signature-covariate associations. On simulated and real data, we find that TCSM outperforms both non-negative matrix factorization and topic modeling-based approaches, particularly in recovering the ground truth exposure to similar signatures. We then use TCSM to discover five mutation signatures in breast cancer and predict homologous recombination repair deficiency in held-out tumors. We also discover four signatures in a combined melanoma and lung cancer cohort—using cancer type as a covariate—and provide statistical evidence to support earlier claims that three lung cancers from The Cancer Genome Atlas are misdiagnosed metastatic melanomas. Availability and implementation TCSM is implemented in Python 3 and available at https://github.com/lrgr/tcsm , along with a data workflow for reproducing the experiments in the paper. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Qualitative theories of illness experience are about the individual interpretations of the psychosocial and cultural aspects of living with illness. Thus, they contribute to a better understanding of health and health care provision. In this paper, we examine how a grounded theory (GT) of heart disease experience can inform secondary prevention. In-depth interviews of individual experience of heart disease were conducted with 26 patients, using GT iterative data collection and analysis framework. A GT was compiled from data and examined within a sociocultural framework to ascertain how experience influenced health behaviour. Despite individual contextual variations, the theory of 'keeping it going' describes the study sample's common attitude to living with heart disease. The theory was adequate in explaining secondary cardiac behaviour, because it identified the aspects of patients' beliefs and attitudes which are key to effective secondary prevention. The assessment of the impact of illness experience on health behaviour within a sociocultural framework helped to articulate the strong influence of social and contextual factors. The study offers an appropriate explanatory framework for encouraging health behaviour change. It emphasizes the importance of interventions being relevant to individual perceptions and interpretations. It provides a framework for designing and evaluating cardiac interventions and the theoretical principles which underpin them. [ABSTRACT FROM AUTHOR]

The precautionary principle brings a special challenge to the practice of evidence-based public health decision-making, suggesting changes in the interpretative methods of public health used to identify causes of disease. In this paper, precautionary changes to these methods are examined: including discounting contrary evidence, reducing the number of causal criteria, weakening the rules of evidence assigned to the criteria, and altering thresholds for statistical significance. All such changes reflect the precautionary goal of earlier primary preventive intervention, i.e. acting on insufficient evidence, the least amount, or minimum level, of evidence for causation. Evaluating the impact of these changes will be difficult without a careful study of how well the current methods of causal inference work, their theoretical foundations, and the ethical implications of their applications. That research program will be most productive if it is jointly developed by public health professionals trained in the ethics and philosophy and by bioethicists and philosophers trained in the theories, methods, and practice of public health. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a chronic degenerative disorder characterised by cartilage loss. It is extremely prevalent in society and is a major cause of disability. It is important to treat osteoarthritis effectively using a multidisciplinary approach tailored to the patient's needs. This paper reviews current thinking on the aetiology, pathogenesis, investigations, and management of osteoarthritis. The paper also discusses the challenges for developing good quality outcome measures for use in large scale multicentre clinical trials for new osteoarthritis treatments, especially disease modifying osteoarthritis drugs. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) develops when there are insufficient insulinproducing beta cells to maintain glucose homeostasis. The prevailing view has been that T1D is caused by immune-mediated destruction of the pancreatic beta cells. However, several recent papers have challenged the long-standing paradigm describing T1D as a tissue-specific autoimmune disease. These authors have highlighted the gaps in our knowledge and understanding of the aetiology of T1D in humans. Here we review the evidence and argue the case for the autoimmune basis of human T1D. In particular, recent analysis of human islet-infiltrating T cells brings important new evidence to this question. Further data in support of the autoimmune basis of T1D from many fields, including genetics, experimental therapies and immunology, is discussed. Finally, we highlight some of the persistent questions relating to the pathogenesis of human type 1 diabetes that remain to be answered. [ABSTRACT FROM AUTHOR]

Regression models are being used to quantify the effect of an exposure on an outcome, while adjusting for potential confounders. While the type of regression model to be used is determined by the nature of the outcome variable, e.g. linear regression has to be applied for continuous outcome variables, all regression models can handle any kind of exposure variables. However, some fundamentals of representation of the exposure in a regression model and also some potential pitfalls have to be kept in mind in order to obtain meaningful interpretation of results. The objective of this educational paper was to illustrate these fundamentals and pitfalls, using various multiple regression models applied to data from a hypothetical cohort of 3000 patients with chronic kidney disease. In particular, we illustrate how to represent different types of exposure variables (binary, categorical with two or more categories and continuous), and how to interpret the regression coefficients in linear, logistic and Cox models. We also discuss the linearity assumption in these models, and show how wrongly assuming linearity may produce biased results and how flexible modelling using spline functions may provide better estimates. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to develop and test a simulation method of conducting investigation of the causality of adverse surgical outcomes. Design Six hundred and thirty-one closed claims of a major medical malpractice insurance company were reviewed. Each case had undergone conventional root cause analysis (RCA). Claims were categorized by comparing the predominant underlying cause documented in the case files. Three cases were selected for simulation. Setting All records (medical and legal) were analyzed. Simulation scenarios were developed by abstracting data from the records and then developing paper and electronic medical records, choosing appropriate study participants including test subjects and confederates, scripting the simulation and choosing the appropriate simulated environment. Intervention In a simulation center, each case simulation was run 6–7 times and recorded, with participants debriefed at the conclusion. Main Outcome Measures Sources of error identified during simulation were compared with those noted in the closed claims. Test subject decision-making was assessed qualitatively. Results Simulation of adverse outcomes (SAOs) identified more system errors and revealed the way complex decisions were made by test subjects. Compared with conventional RCA, SAO identified root causes less focused on errors by individuals and more on systems-based error. Conclusions The use of simulation for investigation of adverse surgical outcomes is feasible and identifies causes that may be more amenable to effective systems changes than conventional RCA. The information that SAO provides may facilitate the implementation of corrective measures, decreasing the risk of recurrence and improving patient safety. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do advanced glycation end products (AGEs) and their receptors play a role in female reproduction? SUMMARY ANSWER AGEs might contribute to the etiology of polycystic ovary syndrome (PCOS) and infertility. WHAT IS KNOWN ALREADY The endogenous AGEs are produced in the body by chemical reactions. Exogenous sources of AGEs are diet and smoking. AGEs have been proposed to be among the main intermediaries involved in several diseases, such as metabolic syndrome, type 2 diabetes mellitus, cardiovascular disease, ovarian aging, inflammation, neurodegenerative disorders and PCOS. STUDY DESIGN, SIZE, DURATION A systematic review was performed for all available basic science and clinical peer-reviewed articles published in PubMed from 1987 to date. Abstracts of annual meetings of the Endocrine Society and American Society for Reproductive Medicine were also reviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 275 publications and scientific abstracts were identified from the initial search. Sixty-two papers and four published scientific abstracts were selected for full review. The main outcomes were the regulatory effects of AGEs on: (i) granulosa cells, adipocyte physiology, obesity and insulin resistance in women with PCOS and in polycystic ovary animal models and (ii) infertility and measures of ovarian reserve. MAIN RESULTS AND THE ROLE OF CHANCE There is an intricate relationship between the AGE-RAGE (receptor for AGEs) system and some aspects of PCOS, such as granulosa cell dysfunction, adipocyte pathophysiology, obesity and insulin resistance. Additionally, irregular ovarian AGE signaling might in part explain the abnormal ovarian histology observed in women with PCOS. The ovarian dysfunction due to AGEs in women without PCOS suggests a role for the AGE-RAGE system in the ovarian follicular environment, and might relate to assisted reproduction technology outcome and measures of ovarian reserve. LIMITATIONS, REASONS FOR CAUTION The body of literature currently available limits these findings. The results obtained from granulosa cell lines and animal models may not fully extrapolate to humans. WIDER IMPLICATIONS OF THE FINDINGS This review underscores a critical need to unveil the exact mechanistic actions of AGEs in reproductive physiology and more specifically the hypothalamic–pituitary–ovarian axis. AGE inhibitors might present an emerging therapeutic approach with significant applications in the context of PCOS and infertility. STUDY FUNDING/COMPETING INTEREST(S) American Society for Reproductive Medicine New Investigator Award and University of Vermont College of Medicine Internal Funds. No competing interests. [ABSTRACT FROM PUBLISHER]

The transcriptome during acute otitis media due to NTHi shows relatively weak immune activationNon-typeable Haemophilus influenzae (NTHi) causes acute otitis media (AOM) in young children. In our recent paper in Microbes and Infection we described the transcriptome signature elicited from PBMCs at onset of AOM caused by Streptococcus pneumoniae. In the current study we found very different results with NTHi AOM infections; 5.1% of 29 187 genes were differentially regulated by more than 2-fold at the onset of AOM compared with the pre-infection healthy state in the same children. Among the 1487 transcripts, 100 genes associated with the immune defense response were specifically analyzed. About half of the differentially regulated genes associated with antibacterial activity and the cell-mediated immune response were activated and half were suppressed. The important signatures for NTHi in children suggested that the balance of the immune response was toward suppression. Moreover, 90% of the genes associated with a pro-inflammatory cytokine response were down-regulated. The genes associated with the classic complement pathway were down-regulated, although the alternative complement pathway genes were up-regulated. These results provide the first human transcriptome data identifying gene expression in the immune response to be predominantly down-regulated at the onset of AOM due to NTHi. [ABSTRACT FROM AUTHOR]

Background In this paper, we report two new original deletions and present an extended review of the previously characterized AVPR2 gene deletions to better understand the underlying deletion mechanisms. Methods The two novel deletions were defined using polymerase chain reaction mapping and junction fragment sequencing. Bioinformatic analysis was performed on both the previously mapped deletions and the novel ones through several web tools. Results In our two patients with nephrogenic diabetes insipidus, we found a 23 755 bp deletion and a 9264 bp deletion both comprising the entire AVPR2 gene and part of the ARHGAP4 gene. Through bioinformatic studies, the smallest overlapping region as well as several motifs and repeats that are known to promote rearrangements were confirmed. Conclusions Through this study, it was determined that the deletion mechanisms in the AVPR2 region do not follow the rules of non-allelic homologous recombination. Two of the 13 deletions can be attributed to the fork stalling and template switching (FoSTeS) mechanism, whereas the remaining 11 deletions could be caused either by non-homologous end joining or by the FoSTeS mechanism. Although no recurrence was found, several groupings of deletion breakpoints were identified. [ABSTRACT FROM PUBLISHER]

When the true end points (T) are difficult or costly to measure, surrogate markers (S) are often collected in clinical trials to help predict the effect of the treatment (Z). There is great interest in understanding the relationship among S, T, and Z. A principal stratification (PS) framework has been proposed by Frangakis and Rubin (2002) to study their causal associations. In this paper, we extend the framework to a multiple trial setting and propose a Bayesian hierarchical PS model to assess surrogacy. We apply the method to data from a large collection of colon cancer trials in which S and T are binary. We obtain the trial-specific causal measures among S, T, and Z, as well as their overall population-level counterparts that are invariant across trials. The method allows for information sharing across trials and reduces the nonidentifiability problem. We examine the frequentist properties of our model estimates and the impact of the monotonicity assumption using simulations. We also illustrate the challenges in evaluating surrogacy in the counterfactual framework that result from nonidentifiability. [ABSTRACT FROM PUBLISHER]

BACKGROUND Understanding the aetiology of subfertility and female reproductive tract disorders at a molecular level may improve success rates in fertility treatment. Such understanding may be gained by the application of metabonomics technologies to tissues or biofluids. Metabonomics is concerned with the quantification of molecules in the metabolome and uses nuclear magnetic resonance (NMR) spectroscopy as one of the main technological platforms. This review concentrates on NMR studies of the female reproductive tract and discusses further possible applications. While full metabolic profiling is relatively recent, targeted NMR studies of biofluid and tissue has a longer history. METHODS Searches were carried out on MEDLINE®, PubMed, SciFinder® Scholar 2007 and ISI Web of KnowledgeSM for papers about NMR spectroscopy or metabonomics of the female reproductive tract and subfertility. RESULTS NMR spectroscopy has been employed for the compositional analysis of various elements of the female reproductive tract, including cervical mucus, follicular fluid (FF), ovarian tissue, fallopian tubes and uterine matter. NMR was used to document for the first time a change in FF lipoprotein concentration during follicular development. NMR analysis of granulosa cells from rats has revealed that follicle-stimulating hormone increases the activity of the pentose pathway, having crucial implications for ovarian stimulation regimens. In the uterine matter work, it has been shown by NMR that glycolysis is rapidly stimulated by estrogen, and in another study, citrate in uterine fluid was found as a potential biomarker for adenomyosis. NMR has also been used to show that chlamydiae are able to achieve higher energy reserves by stimulating glucose transport in host cells. CONCLUSIONS A range of NMR spectroscopic techniques have been applied to the analysis of the female reproductive tract, however great potential remains for further studies. Incorporation of metabonomics techniques into female fertility research may be valuable for understanding subfertility and predicting outcomes of assisted conception treatments. [ABSTRACT FROM AUTHOR]

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]

This paper presents arguments for recognising and tackling Hepatitis C (HCV) as a major challenge for social work. Despite repeated warnings from a variety of sources and thousands of new infections each year, successive governments have failed to address a public health emergency of immense proportions—the HCV epidemic. The implications for social work are significant. Social care workers, particularly those working with physically disabled adults or older adults, will find themselves with vastly increased caseloads as HCV diagnoses increase. This will necessitate them being able to adequately support families in a non-judgemental and non-stigmatising manner, which will mean a significant expansion of training and awareness-raising among professionals, in addition to strong inter-agency links and a transparent integrated care pathway. [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]

Anemia is frequent in cancer patients and its incidence increases with chemotherapy. The probability of requiring transfusions also increases with chemotherapy. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin (EPO) production. Erythropoiesis-stimulating agents (ESAs) improve erythropoiesis and reduce transfusion needs in anemic cancer patients receiving chemotherapy. However, meta-analyses have shown an increased risk of thromboembolic (TE) events with ESA use during chemotherapy, but not increased on-study mortality or reduced overall survival. Three reasons have been proposed to explain why ESAs might have adverse effects in anemic cancer patients: tumor progression due to stimulation of tumor cell EPO receptors; increased risk of TE; and reduced survival. However, erythropoietin is not an oncogene, nor is the EPO receptor. It has also been demonstrated that erythropoietin does not stimulate tumor proliferation. Increased TE risk associated with ESAs is probably a consequence of increased blood viscosity due to excessive RBC mass elevation with concomitant plasma volume contraction, nitric oxide scavenging, and endothelial cell activation. Increased ESA dosing may also impact survival negatively because EPO contracts the plasma volume and stimulates inflammatory cytokine production independently of increasing erythropoiesis. Furthermore, transfusions themselves are associated with an increase in TE and plasma volume contraction, and these events are potentiated when ESAs are given with transfusions. An update on the management of anemia in oncology, the potential adverse events of ESAs, the benefits and risks of transfusions, and QoL are discussed in this paper. [ABSTRACT FROM AUTHOR]

Elucidation of human disease similarities has provided new insights into etiology, disease classification and drug repositioning. Since dysfunctional regulation would be manifested as the decoupling of expression correlation, disease similarity (DS) in terms of dysfunctional regulation mechanism (DRM) could be estimated by using a differential coexpression based approach, which is described in a companion paper. Due to the lack of tools for estimating DS from the viewpoint of DRM in public domain, we implemented an R package 'DSviaDRM' to identify significant DS via DRM based on transcriptomic data. DSviaDRM contains five easy-to-use functions, DCEA, DCpathway, DS, comDCGL and comDCGLplot, for identifying disease relationships and showing common differential regulation information shared by similar diseases. [ABSTRACT FROM AUTHOR]

Genetic and acquired abnormalities in complement factor H (CFH) have been associated with two different human renal diseases: haemolytic uraemic syndrome and membrano proliferative glomerulonephritis. The new genetic and pathogenetic findings in these diseases and their clinical implications for the management and cure of patients are reviewed in this paper. [ABSTRACT FROM AUTHOR]

Total hip replacement represents the most significant advance in orthopaedic surgery in the 20th century. Periprosthetic osteolysis remains the most significant long-term complication with total hip replacement. It has been reported with all materials and prosthetic devices in use or that have been used to date. This paper reviews the current thinking on the aetiology, pathogenesis, management and future treatment options for osteolysis. [ABSTRACT FROM AUTHOR]

Primary failure of eruption (PFE) is a poorly understood condition associated with tooth eruption failure. This investigation systematically reviews the literature, evaluates clinical features and associations with PFE, and describes five further cases. Publications were selected and identified as describing PFE when there was no identifiable aetiological factor contributing to eruption failure and no evidence of successful orthodontic extrusion of the affected tooth or teeth. A data abstraction form recorded the following additional information; subject age, gender, general health status, and teeth present. Eighteen publications were sourced that detailed at least one case of PFE in a manner conforming to the selection criteria; these papers included a total of 35 individual cases, to which five previously unreported subjects were added. Within the whole sample of 40 cases, a total of 24 (60 per cent) were females and 16 (40 per cent) males. First and second molar teeth were most commonly affected; incisors, canines, and premolars were also involved, but with a reduced individual frequency. There was no significant difference in incidence between the maxilla and mandible, or between left and right sides. A family history of eruption failure was found in almost 50 per cent of the sample, with eruption failure or ankylosis affecting at least one primary tooth, also a common finding. Within the 40 cases, hypodontia was present at levels higher than population norms. PFE appears to be a condition that predominantly affects the molar dentition. The increased frequency of hypodontia in affected individuals and common findings of a family history regarding tooth eruption problems suggests a significant genetic component to the aetiology of this rare condition. [ABSTRACT FROM AUTHOR]

Objective. Erythromelalgia is a rare condition, of uncertain etiology, characterized by episodic erythema, intense burning pain and warmth of the hands and/or feet, and when chronic, associated with significant disability. The diagnosis is based on a thorough history and physical exam during a painful episode along with diagnostic testing to exclude other causes. This paper describes the unique syndrome of erythromelalgia through a case report and literature review. Design. Case presentation and literature review. Patients. A 44-year-old male with erythromelalgia. Conclusions. Despite multiple treatment options, erythromelalgia is a challenging disease to effectively manage. Early recognition and treatment, may offer patients the best probability of achieving remission or significant improvement. [ABSTRACT FROM AUTHOR]

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]

We consider estimation of the received treatment effect on a dichotomous outcome in randomised trials with non-compliance. We explore inference about the parameters of the structural mean models of Robins (1994, 1997) and Robins et al. (1999). We show that, in contrast to the additive and multiplicative structural mean models for continuous and count outcomes, unbiased estimating functions for a nonzero (structural) treatment effect parameter do not exist in the presence of many continuous and discrete baseline covariates, even when the randomisation probabilities are known. The best that can be hoped for are estimators, such as those proposed in this paper, that are guaranteed both to estimate consistently the (null) treatment effect when the null hypothesis of no treatment effect is true and to have small bias when the true treatment effect is close to but not equal to zero. [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]

This paper considers evidence for basic auditory processing impairments associated with dyslexia and specific language impairment, against a back-drop of findings from studies of the normal development of auditory and phonological processing. A broad range of auditory impairments have been implicated in the aetiology of these language-learning disorders, including deficits in discriminating the temporal order of rapid sequences of auditory signals, elevated thresholds for frequency discrimination and for detection of amplitude and frequency modulation, impaired binaural processing and increased susceptibility to backward masking. Current evidence is inconsistent, but suggests that not all children with language difficulties have non-verbal auditory processing impairments, and for those that do, the impact on language development is poorly understood. Some implications for clinical practice are discussed. [ABSTRACT FROM PUBLISHER]

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]

— In recent years, progress has been made in the identification of causative factors in most single gene disorders and those with genes of major effect. In comparison, no genes contributing to a complex disorder have been unambiguously identified. A number of reasons for this have been previously presented in theoretical papers. Alcoholism is such a complex illness and genetic studies into its underlying genetic causes have suffered from lack of power due to small subject numbers, poor selection of control subjects, and over-emphasis on markers with low prior probability of involvement. [ABSTRACT FROM PUBLISHER]

A growing trend in social research concerning illicit drug use has entailed suspending regard for conventional questions such as the etiology of drug problems and the outcomes achieved by assorted interventions in favor of focusing analytic attention on how drug problems are socially constructed in and through human praxis. In this paper, I use a constructionist approach to demonstrate and explain endogenous are accounts of what I am calling the ecology of addiction in drug abuse treatment discourse. These accounts posit a space "out there" marked by its degradation dirtiness, solitude, and savagery which commonly tempts those who must live there to also behave amorally, licentiously, and/or savagely I explain these accounts by showing their fundamental utility in light of specific conceptual puzzles that participants in drug abuse treatment discourse must inevitably solve. Namely, speaking in terms of this ecology of addiction provides participants with a compelling narrative means for reconciling the following two claims 1) they are chronically prone to enslavement by their addictions, and 2) their addictions can he controlled through ongoing participation in a communal project of mutual help. [ABSTRACT FROM AUTHOR]

Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors. [ABSTRACT FROM AUTHOR]

While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF. [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]