Ezra Susser

Choosing a future for epidemiology: I. Eras and paradigms.

To inform choices about the future of epidemiology, the present condition of epidemiology is examined, in terms of its evolution through three eras, each demarcated by its own paradigm: (1) the era of sanitary statistics with its paradigm, miasma; (2) the era of infectious disease epidemiology with its paradigm, the germ theory; and (3) the era of chronic disease epidemiology with its paradigm, the black box. The historical context in which these eras arose is briefly described. In each era, the public health was at the center of the concerns of the founders and early protagonists of the prevailing paradigm. Around this intellectual development we weave a further theme. We argue that in the present era, the public health has become less central a concern. At the same time, in epidemiology today the dominant black box paradigm is of declining utility and is likely soon to be superseded.

Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia

Converging evidence suggests that a neurodevelopmental disruption plays a role in the vulnerability to schizophrenia. The authors review evidence supporting in utero exposure to nutritional deficiency as a determinant of schizophrenia. We first describe studies demonstrating that early gestational exposure to the Dutch Hunger Winter of 1944--1945 and to a severe famine in China are each associated with an increased risk of schizophrenia in offspring. The plausibility of several candidate micronutrients as potential risk factors for schizophrenia and the biological mechanisms that may underlie these associations are then reviewed. These nutrients include folate, essential fatty acids, retinoids, vitamin D, and iron. Following this discussion, we describe the methodology and results of an epidemiologic study based on a large birth cohort that has tested the association between prenatal homocysteine, an indicator of serum folate, and schizophrenia risk. The study capitalized on the use of archived prenatal serum specimens that make it possible to obtain direct, prospective biomarkers of prenatal insults, including levels of various nutrients during pregnancy. Finally, we discuss several strategies for subjecting the prenatal nutritional hypothesis of schizophrenia to further testing. These approaches include direct assessment of additional prenatal nutritional biomarkers in relation to schizophrenia in large birth cohorts, studies of epigenetic effects of prenatal starvation, association studies of genes relevant to folate and other micronutrient deficiencies, and animal models. Given the relatively high prevalence of nutritional deficiencies during pregnancy, this work has the potential to offer substantial benefits for the prevention of schizophrenia in the population.

Folic Acid Supplements in Pregnancy and Severe Language Delay in Children

CONTEXTnPrenatal folic acid supplements reduce the risk of neural tube defects and may have beneficial effects on other aspects of neurodevelopment.nnnOBJECTIVEnTo examine associations between mothers use of prenatal folic acid supplements and risk of severe language delay in their children at age 3 years.nnnDESIGN, SETTING, AND PATIENTSnThe prospective observational Norwegian Mother and Child Cohort Study recruited pregnant women between 1999 and December 2008. Data on children born before 2008 whose mothers returned the 3-year follow-up questionnaire by June 16, 2010, were used. Maternal use of folic acid supplements within the interval from 4 weeks before to 8 weeks after conception was the exposure. Relative risks were approximated by estimating odds ratios (ORs) with 95% CIs in a logistic regression analysis.nnnMAIN OUTCOME MEASUREnChildrens language competency at age 3 years measured by maternal report on a 6-point ordinal language grammar scale. Children with minimal expressive language (only 1-word or unintelligible utterances) were rated as having severe language delay.nnnRESULTSnAmong 38,954 children, 204 (0.5%) had severe language delay. Children whose mothers took no dietary supplements in the specified exposure interval were the reference group (n = 9052 [24.0%], with severe language delay in 81 children [0.9%]). Adjusted ORs for 3 patterns of exposure to maternal dietary supplements were (1) other supplements, but no folic acid (n = 2480 [6.6%], with severe language delay in 22 children [0.9%]; OR, 1.04; 95% CI, 0.62-1.74); (2) folic acid only (n = 7127 [18.9%], with severe language delay in 28 children [0.4%]; OR, 0.55; 95% CI, 0.35-0.86); and (3) folic acid in combination with other supplements (n = 19,005 [50.5%], with severe language delay in 73 children [0.4%]; OR, 0.55; 95% CI, 0.39-0.78).nnnCONCLUSIONnAmong this Norwegian cohort of mothers and children, maternal use of folic acid supplements in early pregnancy was associated with a reduced risk of severe language delay in children at age 3 years.

Schizophrenia and impaired homocysteine metabolism: a possible association

BACKGROUNDnAn increased risk of both schizophrenia and neural tube defects was observed in a birth cohort exposed to famine during early gestation. Neural tube defects have been related to a folate-sensitive genetic defect in homocysteine metabolism. If this were also true for schizophrenia, then cases with low folate (LF)--and only these cases--should have increased homocysteine levels compared with controls.nnnMETHODSnWe compared homocysteine levels of schizophrenia cases and normal controls with low folate (LF) and without low folate (non-LF). Low folate was defined by the bottom tertile for controls.nnnRESULTSnIn the LF group (6 cases, 8 controls), mean homocysteine was 10.7 microM in cases compared with 7.7 microM in controls (p = .03). In the non-LF group (11 cases, 16 controls) mean homocysteine did not differ for cases and controls.nnnCONCLUSIONSnThese pilot data are compatible with the hypothesis that a folate-sensitive defect in homocysteine metabolism contributes to cases of schizophrenia.

Reliability of post-mortem chart diagnoses of schizophrenia and dementia

The reliability of psychiatric diagnosis has a direct effect on the validity of post-mortem analyses of neuropathological data, yet little is known about the reliability of retrospective diagnostic procedures which rely on review of medical records. In this paper, we report on the reliability of DSM-III-R psychiatric diagnoses assigned by a pool of 8 raters to a set of 106 state hospital charts of elderly, chronic patients who had died while institutionalized and were autopsied. Diagnoses were grouped by general diagnostic class, and Kappa coefficients computed for agreement among raters, as well as for agreement between ultimate consensus diagnoses and those made while subjects were living. Interrater agreement for those diagnoses that occurred most frequently in this sample (e.g. Schizophrenia and Dementia) was excellent, and comparable to the the agreement observed for ratings of live patients. Interrater agreement for less frequently occurring diagnoses (e.g. Mental Retardation, Mood Disorders, other non-Schizophrenic Psychoses) ranged from excellent to poor. We found high agreement between our rates diagnoses and those assigned by state hospital personnel while patients were living, although post-mortem review produced lower rates of diagnosis of both schizophrenia and Alzheimer-type dementias. Overall, results suggest that the reliability of chart review diagnosis is comparable to that obtained from interviews of live patients when experienced raters are used and diagnostic base rates are high enough to produce stable estimates of reliability.

Schizophrenia after prenatal exposure to the Dutch hunger winter of 1944–1945

We tested the hypothesis that first-trimester exposure to acute food deprivation is a risk factor for schizophrenia. A sharp and time-limited decline in the food intake of the Dutch population following a Nazi blockade in 1944 to 1945 created a unique if tragic natural experiment to test this hypothesis in three regions of Holland (west, north, and south). In the west, or famine region, birth cohorts exposed to severe food deprivation (an average daily ration under 4200 kJ) during the first trimester showed a substantial increase in hospitalized schizophrenia for women but not for men. Relative risks for women were 2.17 for broad and 2.56 for restricted schizophrenia. Moderate food deprivation during the first trimester (average daily ration under 6300 kJ) was not associated with increased risk of schizophrenia in the famine region. In the north and south regions, numbers were smaller and there was no exposure to severe famine. Birth cohorts exposed to moderate food deprivation during the first trimester showed a trend toward increased risk of schizophrenia for women. These findings give plausibility to the proposition that early prenatal nutrition can have a gender-specific effect on the risk of schizophrenia.