Critérios para avaliar a validade dos resultados apresentados em análises de subgrupo em ensaios clínicos

In observational studies, identification of associations within particular subgroups is the usual method of investigation. As an exploratory method, it is the bread and butter of epidemiological research. Nearly everything that has been learned in epidemiology has been derived from the analysis of subgroups. In a randomized clinical trial, the entire purpose is the comparison of the test subjects and the controls, and when there is particular interest in the results of treatment in a certain section of trial participants, a subgroup analysis is performed. These subgroups are examined to see if they are liable to a greater benefit or risk from treatment. Thus, analyzing patient subsets is a natural part of the process of improving therapeutic knowledge through clinical trials. Nevertheless, the reliability of subgroup analysis can often be poor because of problems of multiplicity and limitations in the numbers of patients studied. The naive interpretation of the results of such examinations is a cause of great confusion in the therapeutic literature. We emphasize the need for readers to be aware that inferences based on comparisons between subgroups in randomized clinical trials should be approached more cautiously than those based on the main comparison. That is, subgroup analysis results derived from a sound clinical trial are not necessarily valid; one must not jump to conclusions and accept the validity of subgroup analysis results without an appropriate judgment.Em estudos de observação, a identificação de associações dentro de subgrupos particulares é o método habitual de investigação. Como um método exploratório, faz parte do dia-a-dia da pesquisa epidemiológica. Quase tudo o que se sabe hoje em Epidemiologia foi derivado da análise de subgrupo. Em ensaios clínicos randomizados, o propósito principal é a comparação dos indivíduos sob experimentação e os controles, e quando nós estamos particularmente interessados nos resultados do tratamento em uma certa seção de participantes do ensaio, uma análise de subgrupo é executada. Estes subgrupos são examinados para verificar se eles foram objeto de um maior benefício ou malefício secundário ao tratamento. Assim, analisar subconjuntos de pacientes é uma parte natural do processo de melhorar o conhecimento terapêutico através de ensaios clínicos randomizados. Não obstante, a confiança na análise de subgrupo pode ser pobre devido a problemas de multiplicidade de comparações e limitações em números de pacientes estudados. A interpretação simplista dos resultados de tal técnica é uma causa de grande confusão na literatura terapêutica. Nós enfatizamos a necessidade de chamar a atenção dos leitores que as conclusões baseadas em comparações entre subgrupos em ensaios clínicos randomizados sejam examinadas com mais cautela do que aquelas baseadas na comparação principal. Ou seja, resultados de análise de subgrupo provenientes de ensaios clínicos corretamente desenhados não são necessariamente válidos, portanto, não devemos tirar conclusões precipitadas e aceitar a validade dos resultados sem um julgamento judicioso

Leukocyte Telomere Length and the Father's Age Enigma: Implications for Population Health and for Life Course

What are the implications for population health of the demographic trend toward increasing paternal age at conception (PAC) in modern societies? We propose that the effects of older PAC are likely to be broad and harmful in some domains of health but beneficial in others. Harmful effects of older PAC have received the most attention. Thus, for example, older PAC is associated with an increased risk of offspring having rare conditions such as achondroplasia and Marfan syndrome, as well as with neurodevelopmental disorders such as autism. However, newly emerging evidence in the telomere field suggests potentially beneficial effects, since older PAC is associated with a longer leukocyte telomere length (LTL) in offspring, and a longer LTL is associated with a reduced risk of atherosclerosis and with increased survival in the elderly. Thus, older PAC may cumulatively increase resistance to atherosclerosis and lengthen lifespan in successive generations of modern humans. In this paper we: (i) introduce these novel findings; (ii) discuss potential explanations for the effect of older PAC on offspring LTL; (iii) draw implications for population health and for life course; (iv) put forth an evolutionary perspective as a context for the multigenerational effects of PAC; and (v) call for broad and intensive research to understand the mechanisms underlying the effects of PAC. We draw together work across a range of disciplines to offer an integrated perspective of this issue

The disappearing seasonality of Autism conceptions in California

BACKGROUND Autism incidence and prevalence have increased dramatically in the last two decades. The autism caseload in California increased 600% between 1992 and 2006, yet there is little consensus as to the cause. Studying the seasonality of conceptions of children later diagnosed with autism may yield clues to potential etiological drivers. OBJECTIVE To assess if the conceptions of children later diagnosed with autism cluster temporally in a systematic manner and whether any pattern of temporal clustering persists over time. METHOD We searched for seasonality in conceptions of children later diagnosed with autism by applying a one-dimensional scan statistic with adaptive temporal windows on case and control population data from California for 1992 through 2000. We tested for potential confounding effects from known risk factors using logistic regression models. RESULTS There is a consistent but decreasing seasonal pattern in the risk of conceiving a child later diagnosed with autism in November for the first half of the study period. Temporal clustering of autism conceptions is not an artifact of composition with respect to known risk factors for autism such as socio-economic status. CONCLUSION There is some evidence of seasonality in the risk of conceiving a child later diagnosed with autism. Searches for environmental factors related to autism should allow for the possibility of risk factors or etiological drivers that are seasonally patterned and that appear and remain salient for a discrete number of years.Support for this article comes from the NIH Director’s Pioneer Award Program, part of the NIH Roadmap for Medical Research through grant number 1. DP1 OD003635-01

Are social causes so different from all other causes? A comment on Sander Greenland

Sander Greenland's elegant paper raises deep questions about the way in which we choose and evaluate public health actions. We agree with the main thrust of his argument with respect to public health policy. We have some concerns, however, about his treatment of social causes, and on this point we focus our critique

Can Sibling Sex Ratios Be Used as a Valid Test for the Prenatal Androgen Hypothesis of Autism Spectrum Disorders?

Sibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children

Ancestral calling, traditional health practitioner training and mental illness:An ethnographic study from rural KwaZulu-Natal, South Africa

This qualitative ethnographic study complements an epidemiological study on first episode psychosis in Vulindlela, a rural area in KwaZulu-Natal, South Africa. It focuses on two themes that emerged from our data: (1) the calling of the ancestors to become a traditional health practitioner and (2) ukuthwasa, the training to become a traditional health practitioner. The purpose of this study is to describe the ancestral calling, and to explore whether ukuthwasa may help with the management of mental disturbances, including unusual perceptual experiences. We also provide a discussion of the changing sociopolitical context of healing in KwaZulu-Natal, as a background to our study. In-depth interviews were conducted with 20 (apprentice) traditional health practitioners, formal health practitioners, patients and relatives recruited through local traditional health practitioners and a health care clinic. Our results show that the ancestral calling might announce itself with symptoms of mental illness including unusual perceptual experiences, for which some participants consider ukuthwasa as the only effective cure. We found indications that in some individuals successful completion of ukuthwasa might promote recovery from their illness and lead to a profession in which the unusual perceptual experiences become a legitimate and positively valued aspect. We suggest that - in this particular community today, which has been subject to several sociopolitical changes - ukuthwasa may be a culturally sanctioned healing process which moderates experiences that a Western psychiatric system might characterize as psychotic symptoms, providing some individuals with a lucrative and respected role in society

Fetal Environment and Schizophrenia

Schizophrenia and related disorders are adult-onset illnesses with no definitively established risk factors. Several studies report that exposures to infection and nutritional deprivation during early development may elevate the risk of later developing schizophrenia, specifically during the prenatal period. Preliminary evidence implicates lead exposure as well, suggesting that chemical exposures during early development may constitute a new class of risk factors for schizophrenia that has not been adequately investigated. Exposure to lead is given as an example of a chemical agent for which some effects have been described throughout the life course on both general neurodevelopmental outcomes and now on a specific psychiatric diagnosis. Findings from prospectively collected birth cohorts are offered as examples of both innovations in methodology and opportunities for future generations of investigators

Workshop to identify critical windows of exposure for children\u27s health: Neurobehavioral work group summary

Summarizes the deliberations of a work group charged with addressing specific questions relevant to risk estimation in developmental neurotoxicology. Importance of multiple factors addressing critical windows of exposure on neurological function; Role that compensatory mechanisms play in the manifestation of the effects of developmental exposures

Telomere Length and the Cancer–Atherosclerosis Trade-Off

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan

Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California

The incidence and prevalence of autism have dramatically increased over the last 20 years. Decomposition of autism incidence rates into age, period and cohort effects disentangle underlying domains of causal factors linked to time trends. We estimate an age-period-cohort effect model for autism diagnostic incidence overall and by level of functioning