A conceptual and methodological framework for investigating etiologic heterogeneity

Cancer has traditionally been studied using the disease site of origin as the organizing framework. However, recent advances in molecular genetics have begun to challenge this taxonomy, as detailed molecular profiling of tumors has led to discoveries of subsets of tumors that have profiles that possess distinct clinical and biological characteristics. This is increasingly leading to research that seeks to investigate whether these subtypes of tumors have distinct etiologies. However, research in this field has been opportunistic and anecdotal, typically involving the comparison of distributions of individual risk factors between tumors classified on the basis of candidate tumor characteristics. The purpose of this article is to place this area of investigation within a more general conceptual and analytic framework, with a view to providing more efficient and practical strategies for designing and analyzing epidemiologic studies to investigate etiologic heterogeneity. We propose a formal definition of etiologic heterogeneity and show how classifications of tumor subtypes with larger etiologic heterogeneities inevitably possess greater disease risk predictability overall. We outline analytic strategies for estimating the degree of etiologic heterogeneity among a set of subtypes and for choosing subtypes that optimize the heterogeneity, and we discuss technical challenges that require further methodologic research. We illustrate the ideas by using a pooled case‐control study of breast cancer classified by expression patterns of genes known to define distinct tumor subtypes. Copyright © 2013 John Wiley & Sons, Ltd.     

Advances in statistical methodology for diagnostic medicine in the 1980's.

Research on diagnostic medicine has been directed at a number of topics in the past decade. Issues which have received a lot of attention are ROC analysis and the identification and correction of various analytic biases. Other topics of widespread interest include the use of expert systems, the relationship of such systems to statistical data-based systems, and the evaluation of tests using cost-effectiveness analysis. Increasingly there is a sentiment that well-designed, prospective trials are required to provide credible information on the accuracy of diagnostic technologies, and so a consensus on methodological standards is needed, paralleling the earlier development of such standards in clinical trials and epidemiology.     

Race and risk of schizophrenia in a US birth cohort: another example of health disparity?

BACKGROUND: Immigrant groups in Western Europe have markedly increased rates of schizophrenia. The highest rates are found in ethnic groups that are predominantly black. Separating minority race/ethnicity from immigration in Western Europe is difficult; in the US, these issues can be examined separately. Here we compared rates of schizophrenia between whites and African Americans and evaluated whether the association was mediated by socioeconomic status (SES) of family of origin in a US birth cohort. METHODS: Study subjects were offspring of women enrolled during pregnancy at Alameda County Kaiser Permanente Medical Care Plan clinics (1959-66) in the Child Health and Development Study. For schizophrenia spectrum disorders, 12 094 of the 19 044 live births were followed over 1981-97. The analysis is restricted to cohort members whose mothers identified as African American or white at intake. Stratified proportional hazards regression was the method of analysis; the robustness of findings to missing data bias was assessed using multiple imputation. RESULTS: African Americans were about 3-fold more likely than whites to be diagnosed with schizophrenia [Rate Ratio (RR) = 3.27; 95% confidence interval (CI): 1.71-6.27]. After adjusting for indicators of family SES at birth, the RR was about 2-fold (RR = 1.92; 95% CI: 0.86-4.28). Using multiple imputation in the model including family SES indicators, the RR for race and schizophrenia was strengthened in comparison with the estimate obtained without imputation. CONCLUSION: The data indicate substantially elevated rates of schizophrenia among African Americans in comparison with whites in this birth cohort. The association may have been partly but not wholly mediated by an effect of race on family SES.     

The association between sidewalk length and walking for different purposes in established neighborhoods

ABSTRACT: BACKGROUND: Walking in neighborhood environments is undertaken for different purposes including for transportation and leisure. We examined whether sidewalk availability was associated with participation in, and minutes of neighborhood-based walking for transportation (NWT) and recreation (NWR) after controlling for neighborhood self-selection. METHOD: Baseline survey data from respondents (n=1813) who participated in the RESIDential Environment (RESIDE) project (Perth, Western Australia) were used. Respondents were recruited based on their plans to move to another neighborhood in the following year. Usual weekly neighborhood-based walking, residential preferences, walking attitudes, and demographics were measured. Characteristics of the respondent's baseline neighborhood were measured including transportation-related walkability and sidewalk length. A Heckman two-stage modeling approach (multivariate Probit regression for walking participation, followed by a sample selection-bias corrected OLS regression for walking minutes) estimated the relative contribution of sidewalk length to NWT and NWR. RESULTS: After adjustment, neighborhood sidewalk length and walkability were positively associated with a 2.97 and 2.16 percentage point increase in the probability of NWT participation, respectively. For each 10km increase in sidewalk length, NWT increased by 5.38 min/wk and overall neighborhood-based walking increased by 5.26 min/wk. Neighborhood walkability was not associated with NWT or NWR minutes. Moreover, sidewalk length was not associated with NWR minutes. CONCLUSION: Sidewalk availability in established neighborhoods may be differentially associated with walking for different purposes. Our findings suggest that large investments in sidewalk construction alone would yield small increases in walking.     

Regional myocardial dysfunction: evaluation of patients with prior myocardial infarction with fast CT

A prototype ultrafast cine computed tomographic (CT) scanner, designed specifically for cardiac imaging, was used to evaluate a preliminary series of patients with prior myocardial infarction (n = 21) and a control group without coronary artery disease (n = 5). Multilevel 50-msec CT scan exposures were obtained during peripheral intravenous bolus injections of contrast medium. A comparison was made between cine-CT scans and standard left ventriculographic images in assessing segmental left ventricular motion. Results indicate that cine CT, performed at sufficiently rapid speeds (20 scans per second) to allow useful analysis of regional ventricular wall motion, can provide adequate image quality. Analysis of 110 segments revealed a good correlation (90.9%) between the two techniques in characterizing normal from abnormal regional wall motion. Cine CT, based on this initial study, demonstrates considerable potential for evaluating not only cardiac chamber dimensions but also segmental wall dynamics.     

Variability in the elimination of mianserin in elderly patients.

1. Two studies of the elimination of mianserin are reported. 2. In the first study, the oral clearance of mianserin was measured in 15 elderly patients at steady state. In a sub-group of eight patients who completed studies at two different doses there was evidence of enhanced oral clearance at the higher dose. 3. In the second study, the elimination half-life was estimated in 12 patients who were observed to have disproportionately high mianserin concentrations with respect to dose. All had half-lives greater than or equal to 2.5 days with a mean of 6 +/- 2.8 (s.d.) days. In six of the patients the profile of elimination was suggestive of saturable elimination. 4. The sparteine oxidation status was measured in seven of the patients showing slow mianserin elimination. Only one was a 'poor oxidiser' of sparteine, suggesting no concordance with this phenotype. 5. It is concluded that there is marked variability in the elimination of mianserin in elderly patients.     

Antibody state to poliovirus in first year university students, 1984.

Circulating antibodies to poliovirus were estimated in a group of 300 British and 84 foreign first year students who registered at the health centre of Nottingham University in 1984. Detectable antibodies to all three poliovirus serotypes were found in 212 (71%) of the British students but in only 47 (56%) of those from abroad. Most of the British students (280; 93%) had been born in 1965 or 1966, when uptake of poliomyelitis vaccine was declining. Immunisation histories showed that 10 British and 29 foreign students (3% and 35%) had no record of any immunisation; only five British and two foreign students, however, were negative for all three poliovirus serotypes. These findings provide evidence that a high proportion of British born people aged 18-29 have adequate circulating poliovirus antibodies despite incomplete immunisation schedules. Though this is reassuring, the absence of antibodies in some students and the lack of previous immunisation against poliomyelitis in 39 suggest that reinforcing doses of vaccine at the time of leaving school or beginning further education are still warranted, particularly for students from other countries. The findings also emphasise the need for accurate immunisation records.