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1.  Snippets From the Past: Is Flint, Michigan, the Birthplace of the Case-Control Study? 
American Journal of Epidemiology  2013;178(12):1687-1690.
In the summer of 1924, an outbreak of scarlet fever occurred in Flint, Michigan. Unable to trace it to the usual causes, particularly fresh milk, the Michigan Department of Health used a novel approach to disentangle the enigma: The 116 cases of scarlet fever were compared with 117 “controls” selected from neighbors of the quarantined cases and from patients at the City Health Center who had been treated for ailments unrelated to scarlet fever. The extraordinary culprit was ice cream, which had a frequent/occasional/none consumption prevalence of 60%, 34%, and 6% among the cases and 24%, 51%, and 25% among the controls, respectively. The 1925 report reads, “Detailed epidemiological investigation, by means of case histories and control histories on well persons, confirmed early suspicions and established the fact that the epidemic was spread by ice cream” (Am J Hyg. 1925;5(5):669–681). This forgotten epidemiologic study is the oldest study using the case-control design to have been resurrected thus far. The case-control study design may have been conceived simultaneously, but independently and for different purposes, in England (Janet Lane-Claypon's 1926 report on the determinants of breast cancer) and the United States.
PMCID: PMC3858108  PMID: 24064743
case-control studies; disease transmission; epidemiologic methods; history of medicine; ice cream; scarlet fever
2.  Hume, Mill, Hill, and the Sui Generis Epidemiologic Approach to Causal Inference 
American Journal of Epidemiology  2013;178(10):1526-1532.
The epidemiologic approach to causal inference (i.e., Hill's viewpoints) consists of evaluating potential causes from the following 2, noncumulative angles: 1) established results from comparative, observational, or experimental epidemiologic studies; and 2) reviews of nonepidemiologic evidence. It does not involve statements of statistical significance. The philosophical roots of Hill's viewpoints are unknown. Superficially, they seem to descend from the ideas of Hume and Mill. Hill's viewpoints, however, use a different kind of evidence and have different purposes than do Hume's rules or Mill's system of logic. In a nutshell, Hume ignores comparative evidence central to Hill's viewpoints. Mill's logic disqualifies as invalid nonexperimental evidence, which forms the bulk of epidemiologic findings reviewed from Hill's viewpoints. The approaches by Hume and Mill cannot corroborate successful implementations of Hill's viewpoints. Besides Hume and Mill, the epidemiologic literature is clueless about a plausible, pre-1965 philosophical origin of Hill's viewpoints. Thus, Hill's viewpoints may be philosophically novel, sui generis, still waiting to be validated and justified.
PMCID: PMC3888277  PMID: 24071010
causality; David Hume; evidence; inference; John Stuart Mill; lung cancer; philosophy; tobacco
3.  Snippets From the Past: The Evolution of Wade Hampton Frost's Epidemiology as Viewed From the American Journal of Hygiene/Epidemiology 
American Journal of Epidemiology  2013;178(7):1013-1019.
Wade Hampton Frost, who was a Professor of Epidemiology at Johns Hopkins University from 1919 to 1938, spurred the development of epidemiologic methods. His 6 publications in the American Journal of Hygiene, which later became the American Journal of Epidemiology, comprise a 1928 Cutter lecture on a theory of epidemics, a survey-based study of tonsillectomy and immunity to Corynebacterium diphtheriae (1931), 2 papers from a longitudinal study of the incidence of minor respiratory diseases (1933 and 1935), an attack rate ratio analysis of the decline of diphtheria in Baltimore (1936), and a 1936 lecture on the age, time, and cohort analysis of tuberculosis mortality. These 6 American Journal of Hygiene /American Journal of Epidemiology papers attest that Frost's personal evolution mirrored that of the emerging “early” epidemiology: The scope of epidemiology extended beyond the study of epidemics of acute infectious diseases, and rigorous comparative study designs and their associated quantitative methods came to light.
PMCID: PMC3783101  PMID: 24022889
5.  “If It Isn't Ultimately Aimed at Policy, It's Not Worth Doing” 
American Journal of Epidemiology  2013;177(7):595-600.
George W. Comstock (1915–2007), MD, MPH, DrPH, was lecturer and then professor of epidemiology at the Johns Hopkins University School of Hygiene and Public Health from 1956 to 2007 and served as editor-in-chief of the American Journal of Epidemiology from 1979 to 1988. This interview of George W. Comstock took place in Hagerstown, Maryland, in the spring of 1990. The selection of questions and answers published here represent approximately 10% of the whole interview, which had been reviewed and hand-corrected by Dr. Comstock. He first describes how epidemiology was taught at Hopkins in the 1950s and 1960s. He then distinguishes “epidemiology per se” from a “practical epidemiology” that works closely with local health departments, and he finally expresses his wish that in the future, epidemiology would become more widely involved in policy and accepted by policy makers. Photo of George, Margaret, and Gordon Comstock taken during World War II, most likely in 1944, while Dr Comstock was serving as Medical Officer in an Escort Destroyer Division.
PMCID: PMC3657536  PMID: 23545720
history; interview; policy; teaching
6.  Cardiovascular Disease Hospitalizations in Relation to Exposure to the September 11, 2001 World Trade Center Disaster and Posttraumatic Stress Disorder 
A cohort study found that 9/11‐related environmental exposures and posttraumatic stress disorder increased self‐reported cardiovascular disease risk. We attempted to replicate these findings using objectively defined cardiovascular disease hospitalizations in the same cohort.
Methods and Results
Data for adult World Trade Center Health Registry enrollees residing in New York State on enrollment and no cardiovascular disease history (n=46 346) were linked to a New York State hospital discharge–reporting system. Follow‐up began at Registry enrollment (2003–2004) and ended at the first cerebrovascular or heart disease (HD) hospitalization, death, or December 31, 2010, whichever was earliest. We used proportional hazards models to estimate adjusted hazard ratios (AHRs) for HD (n=1151) and cerebrovascular disease (n=284) hospitalization during 302 742 person‐years of observation (mean follow‐up, 6.5 years per person), accounting for other factors including age, race/ethnicity, smoking, and diabetes. An elevated risk of HD hospitalization was observed among women (AHR 1.32, 95% CI 1.01 to 1.71) but not men (AHR 1.16, 95% CI 0.97 to 1.40) with posttraumatic stress disorder at enrollment. A high overall level of World Trade Center rescue and recovery–related exposure was associated with an elevated HD hospitalization risk in men (AHR 1.82, 95% CI 1.06 to 3.13; P for trend=0.05), but findings in women were inconclusive (AHR 3.29, 95% CI 0.85 to 12.69; P for trend=0.09). Similar associations were observed specifically with coronary artery disease hospitalization. Posttraumatic stress disorder increased the cerebrovascular disease hospitalization risk in men but not in women.
9/11‐related exposures and posttraumatic stress disorder appeared to increase the risk of subsequent hospitalization for HD and cerebrovascular disease. This is consistent with findings based on self‐reported outcomes.
PMCID: PMC3835258  PMID: 24157650
9/11 World Trade Center disaster; cardiovascular diseases; epidemiology; risk factors; stress
8.  Epidemiology and Public Health in 1906 England 
American journal of public health  2013;103(7):e17-e22.
In 1906 Arthur Newsholme linked artificial feeding and fatal diarrhea in infants aged one year and younger on the basis of two independent sources of information: mortality registration and a three-year (1903–1905) census of infants from Brighton, United Kingdom. Artificial feeding was more common in the infants who had died (89.3%) than in those in the survey (22.3%). However, boldly assuming the two data sources were nested, Newsholme computed the risks of fatal diarrhea: these were 48 times greater for infants fed fresh cow’s milk and 94 times greater for those fed condensed milk than for infants who were exclusively breast-fed. This mode of computing risks and risk ratios before the invention of the cohort study design was more innovative than was the usual investigation techniques of his contemporary epidemiologists. Newsholme’s conclusions were consistent with the current knowledge that breastfeeding protects against fatal diarrhea.
PMCID: PMC3682615  PMID: 23678939
Preventive medicine  2012;54(0):229-233.
Background and Aims
Commuting by public transportation (PT) entails more physical activity and energy expenditure than by cars, but its biologic consequences are unknown.
In 2009-2010, we randomly sampled New York adults, usually commuting either by car (n=79) or PT (n=101). Measures comprised diet and physical activity questionnaires, weight and height, white blood cell (WBC) count, C reactive protein, (CRP) gene-specific methylation (IL-6), and global genomic DNA methylation (LINE-1 methylation).
Compared to the 101 PT commuters, the 79 car drivers were about 9 years older, 2 kg/m2 heavier, more often non-Hispanic whites, and ate more fruits and more meats. The 2005 guidelines for physical activity were met by more car drivers than PT users (78.5% vs. 65.0%). There were no differences in median levels of CRP (car vs. PT: 0.6 vs. 0.5 mg/dl), mean levels of WBC (car vs. PT: 6.7 vs. 6.5 cells/mm3), LINE-1 methylation (car vs. PT: 78.0% vs. 78.3%), and promoter methylation of IL-6 (car vs. PT: 56.1% vs. 58.0%).
PT users were younger and lighter than car drivers, but their commute mode did not translate into a lower inflammatory response or a higher DNA methylation, maybe because, overall, car drivers were more physically active.
PMCID: PMC3670595  PMID: 22313796
10.  White blood cell global methylation and IL-6 promoter methylation in association with diet and lifestyle risk factors in a cancer-free population 
Epigenetics  2012;7(6):606-614.
Altered levels of global DNA methylation and gene silencing through methylation of promoter regions can impact cancer risk, but little is known about their environmental determinants. We examined the association between lifestyle factors and levels of global genomic methylation and IL-6 promoter methylation in white blood cell DNA of 165 cancer-free subjects, 18–78 years old, enrolled in the COMIR (Commuting Mode and Inflammatory Response) study, New York, 2009–2010. Besides self-administrated questionnaires on diet and physical activity, we measured weight and height, white blood cell (WBC) counts, plasma levels of high sensitivity C-reactive protein (hs-CRP), and genomic (LINE-1) and gene-specific methylation (IL-6) by pyrosequencing in peripheral blood WBC. Mean levels of LINE-1 and IL-6 promoter methylation were 78.2% and 57.1%, respectively. In multivariate linear regression models adjusting for age, gender, race/ethnicity, body mass index, diet, physical activity, WBC counts and CRP, only dietary folate intake from fortified foods was positively associated with LINE-1 methylation. Levels of IL-6 promoter methylation were not significantly correlated with age, gender, race/ethnicity, body mass index, physical activity or diet, including overall dietary patterns and individual food groups and nutrients. There were no apparent associations between levels of methylation and inflammation markers such as WBC counts and hs-CRP. Overall, among several lifestyle factors examined in association with DNA methylation, only dietary folate intake from fortification was associated with LINE-1 methylation. The long-term consequence of folate fortification on DNA methylation needs to be further evaluated in longitudinal settings.
PMCID: PMC3398989  PMID: 22531363
DNA Methylation; cancer; diet; lifestyle factors
11.  Trends in Citations to Books on Epidemiological and Statistical Methods in the Biomedical Literature 
PLoS ONE  2013;8(5):e61837.
There are no analyses of citations to books on epidemiological and statistical methods in the biomedical literature. Such analyses may shed light on how concepts and methods changed while biomedical research evolved. Our aim was to analyze the number and time trends of citations received from biomedical articles by books on epidemiological and statistical methods, and related disciplines.
Methods and Findings
The data source was the Web of Science. The study books were published between 1957 and 2010. The first year of publication of the citing articles was 1945. We identified 125 books that received at least 25 citations. Books first published in 1980–1989 had the highest total and median number of citations per year. Nine of the 10 most cited texts focused on statistical methods. Hosmer & Lemeshow's Applied logistic regression received the highest number of citations and highest average annual rate. It was followed by books by Fleiss, Armitage, et al., Rothman, et al., and Kalbfleisch and Prentice. Fifth in citations per year was Sackett, et al., Evidence-based medicine. The rise of multivariate methods, clinical epidemiology, or nutritional epidemiology was reflected in the citation trends. Educational textbooks, practice-oriented books, books on epidemiological substantive knowledge, and on theory and health policies were much less cited. None of the 25 top-cited books had the theoretical or sociopolitical scope of works by Cochrane, McKeown, Rose, or Morris.
Books were mainly cited to reference methods. Books first published in the 1980s continue to be most influential. Older books on theory and policies were rooted in societal and general medical concerns, while the most modern books are almost purely on methods.
PMCID: PMC3646840  PMID: 23667447
13.  Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood 
Epigenetics  2011;6(5):623-629.
Reduced levels of global DNA methylation are associated with genomic instability and are independent predictors of cancer risk. Little is known about the environmental determinants of global DNA methylation in peripheral blood. We examined the association between demographic and lifestyle factors and levels of global leukocyte DNA methylation in 161 cancer-free subjects enrolled in the North Texas Healthy Heart Study aged 45–75 years in 2008. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for diet, and bioelectrical impedance analysis and CT-scan for body composition. We measured genomic DNA methylation using bisulfite conversion of DNA and pyrosequencing for LINE-1. Body composition measures including body mass index, waist circumference, areas of subcutaneous fat and visceral fat, percent of fat mass and fat-free mass were not associated with global genomic DNA methylation after controlling the effect of age, gender and race/ethnicity. Instead, female gender was significantly associated with a reduced level of global methylation (β = −2.77, 95% CI: −4.33, −1.22). Compared to non-Hispanic whites, non-Hispanic blacks (β = −2.02, 95% CI: −3.55, −0.50) had significantly lower levels of global methylation. No association was found with age, cigarette smoking, alcohol drinking and dietary intake of nutrients in one-carbon metabolism. Global leukocyte DNA methylation differs by gender and race/ethnicity, suggesting these variables need to be taken into consideration in studies of global DNA methylation as an epigenetic marker for cancer.
PMCID: PMC3230547  PMID: 21739720
gender; race/ethnicity; DNA methylation
14.  Physical activity and global genomic DNA methylation in a cancer-free population 
Epigenetics  2011;6(3):293-299.
Changes in DNA methylation may represent an intermediate step between the environment and human diseases. Little is known on whether behavioral risk factors may modify gene expression through DNA methylation. To assess whether DNA methylation is associated with different levels of physical activity, we measured global genomic DNA methylation using bisulfite-converted DNA and real-time PCR (MethyLight) for LINE-1 in peripheral blood of 161 participants aged 45–75 years enrolled in the North Texas Healthy Heart Study and levels of physical activity using an accelerometer (Actigraph GT1M Monitor). We found that individuals with physical activity 26–30 min/day had a significantly higher level of global genomic DNA methylation compared to those with physical activity ≤10 min/day (β = 2.52, 95% CI: 0.70, 4.35). However, the association was attenuated and became statistically insignificant after multivariate adjustment (β = 1.24, 95% CI: −0.93, 3.40). There were some suggestions of a positive association between physical activity and global genomic DNA methylation in non-Hispanics (β = 1.50, 95% CI: −0.08, 3.08) that warrants further investigation.
PMCID: PMC3092677  PMID: 21178401
DNA methylation; physical activity; peripheral blood
15.  Joseph Goldberger's research on the prevention of pellagra 
PMCID: PMC2586852  PMID: 19029358
17.  Gender differentials in the evolution of cigarette smoking habits in a general European adult population from 1993–2003 
BMC Public Health  2006;6:130.
Describe the recent evolution of cigarette smoking habits by gender in Geneva, where incidence rates of lung cancer have been declining in men but increasing in women.
Continuous cross-sectional surveillance of the general adult (35–74 yrs) population of Geneva, Switzerland for 11 years (1993–2003) using a locally-validated smoking questionnaire, yielding a representative random sample of 12,271 individuals (6,164 men, 6,107 women).
In both genders, prevalence of current cigarette smoking was stable over the 11-year period, at about one third of men and one quarter of women, even though smoking began at an earlier age in more recent years. Older men were more likely to be former smokers than older women. Younger men, but not women, tended to quit smoking at an earlier age.
This continuous (1993–2003) risk factor surveillance system, unique in Europe, shows stable prevalence of smoking in both genders. However, sharp contrasts in age-specific prevalence of never and former smoking and of ages at smoking initiation indicate that smoking continues a long-term decline in men but has still not reached its peak in women.
PMCID: PMC1479327  PMID: 16696858
18.  Remarkable change in age-specific breast cancer incidence in the Swiss canton of Geneva and its possible relation with the use of hormone replacement therapy 
BMC Cancer  2006;6:78.
This article aims to explain the reasons for the remarkable change in age of breast cancer occurrence in the Swiss canton of Geneva.
We used population-based data from the Geneva cancer registry, which collects information on method of detection, stage and tumour characteristics since 1975. For patients diagnosed between 1997–2003, we obtained additional information on use of hormone replacement therapy from a large prospective study on breast cancer. Using generalized log linear regression analysis, we compared age-specific incidence rates with respect to period, stage, oestrogen receptor status, method of detection and use of hormone replacement therapy.
In the periods 1975–1979 and 1985–1989, breast cancer risk increased with age, showing the highest incidence rates among women aged ≥ 85 years. From 1997, the age-specific incidence curve changed completely (p < 0.0001), showing an incidence peak at 60–64 years and a reduced incidence among elderly women. This incidence peak concerned mainly early stage and oestrogen positive cancers and was exclusively observed among women who ever used hormone replacement therapy, regardless whether the tumour was screen-detected or not.
The increasing prevalence of hormone replacement therapy use during the 1990s could explain the important change in age-specific breast cancer incidence, not only by increasing breast cancer risk, but also by revealing breast cancer at an earlier age.
PMCID: PMC1440868  PMID: 16551373
20.  Optimal Step Length EM Algorithm (OSLEM) for the estimation of haplotype frequency and its application in lipoprotein lipase genotyping 
BMC Bioinformatics  2003;4:3.
Haplotype based linkage disequilibrium (LD) mapping has become a powerful and cost-effective method for performing genetic association studies, particularly in the search for genetic markers in linkage disequilibrium with complex disease loci. Various methods (e.g. Monte-Carlo (Gibbs sampling); EM (expectation maximization); and Clark's method) have been used to estimate haplotype frequencies from routine genotyping data.
These algorithms can be very slow for large number of SNPs. In order to speed them up, we have developed a new algorithm using numerical analysis technology, a so-called optimal step length EM (OSLEM) that accelerates the calculation. By optimizing approximately the step length of the EM algorithm, OSLEM can run at about twice the speed of EM. This algorithm has been used for lipoprotein lipase (LPL) genotyping analysis.
This new optimal step length EM (OSLEM) algorithm can accelerate the calculation for haplotype frequency estimation for genotyping data without pedigree information. An OSLEM on-line server is available, as well as a free downloadable version.
PMCID: PMC149347  PMID: 12529185
Haplotype frequency estimation; Expectation Maximization Algorithm; Genotype; Lipoprotein Lipase
21.  Long term vascular complications of Coxiella burnetii infection in Switzerland: cohort study 
BMJ : British Medical Journal  1999;319(7205):284-286.
To evaluate the range of long term vascular manifestations of Coxiella burnetii infection.
Cohort study in Switzerland of people affected in 1983 by the largest reported outbreak of Q fever and who were followed up 12 years later. Follow up information about possible vascular disease and endocarditis was obtained through a mailed questionnaire and death certificates.
Val de Bagnes, a rural Alpine valley in Switzerland.
2044 (87%) of 2355 people who had serum testing for Coxiella burnetii infection in 1983: 1247 were classed as not having been infected, 411 were classed as having been acutely infected, and 386 were classed as having been infected before 1983.
Main outcome measures
Relative risk controlled for age and sex and 12 year risk of vascular diseases and endocarditis among infected participants as compared with those who had never been infected.
The 12 year risk of endocarditis or venous thromboembolic disease was not increased among those who had been acutely infected. The 12 year risk of arterial disease was significantly higher among those who had been acutely infected (7%) as compared with those who had never been infected (4%) (relative risk 2.2, 95% confidence interval 1.4 to 3.6). Specifically, there was an increased risk of developing a cerebrovascular accident (relative risk 3.7, 1.6 to 8.4) and cardiac ischaemia (relative risk 1.9, 1.04 to 3.4). 12 year mortality was significantly higher among the 411 people who had been acutely infected in 1983 (9.7%; age adjusted relative risk 1.8, 1.2 to 2.6) when compared with the 1247 participants who had remained serologically negative in 1983 (7.0%).
Coxiella burnetii infection may cause long term complications including vascular disease.
Key messagesThe risk of developing venous or arterial disease after infection with Coxiella burnetii was assessed in a Swiss cohort of 2044 people exposed to the largest reported outbreak of Q feverTwelve year mortality was significantly higher among people who had been acutely infected in 1983The 12 year risk of arterial disease was significantly higher among those who had been acutely infected (7%) than among those who had not been infected (4%)Compared with those participants who tested negative, those who were acutely infected with C burnetii had an increased relative risk of having a cerebrovascular accident or cardiac ischaemia Infection with C burnetii may be responsible for the development of vascular diseases in addition to infection with Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori
PMCID: PMC28177  PMID: 10426735

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