Bruce Levin

“Fundamental Causes” of Social Inequalities in Mortality: A Test of the Theory

Medicine and epidemiology currently dominate the study of the strong association between socioeconomic status and mortality. Socioeconomic status typically is viewed as a causally irrelevant “confounding variable” or as a less critical variable marking only the beginning of a causal chain in which intervening risk factors are given prominence. Yet the association between socioeconomic status and mortality has persisted despite radical changes in the diseases and risk factors that are presumed to explain it. This suggests that the effect of socioeconomic status on mortality essentially cannot be understood by reductive explanations that focus on current mechanisms. Accordingly, Link and Phelan (1995) proposed that socioeconomic status is a “fundamental cause” of mortality disparities—that socioeconomic disparities endure despite changing mechanisms because socioeconomic status embodies an array of resources, such as money, knowledge, prestige, power, and beneficial social connections, that protect health no matter what mechanisms are relevant at any given time. We identified a situation in which resources should be less helpful in prolonging life, and derived the following prediction from the theory: For less preventable causes of death (for which we know little about prevention or treatment), socioeconomic status will be less strongly associated with mortality than for more preventable causes. We tested this hypothesis with the National Longitudinal Mortality Study, which followed Current Population Survey respondents (N = 370,930) for mortality for nine years. Our hypothesis was supported, lending support to the theory of fundamental causes and more generally to the importance of a sociological approach to the study of socio-economic disparities in mortality.

Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm

BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.).

Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan

To investigate the carcinogenic effect of environmental aflatoxin exposure, 56 cases of hepatocellular carcinoma (HCC) diagnosed between 1991 and 1995 were identified and individually matched by age, sex, residence and date of recruitment to 220 healthy controls from the same large cohort in Taiwan. Blood samples were analyzed for hepatitis B and C viral markers and for aflatoxin‐albumin adducts; urine was tested for aflatoxin metabolites. We obtained information about socio‐demographic characteristics, habitual alcohol drinking, cigarette smoking and diet in a structured interview. Hepatitis B virus surface antigen (HBsAg) carriers had a significantly increased risk for HCC. After adjustment for HBsAg serostatus, the matched odds ratio (ORm) was significantly elevated for subjects with high levels of urinary aflatoxin metabolites. When stratified into tertiles, a dose‐response relationship with HCC was observed. The ORm for detectable aflatoxin‐albumin adducts was not significant after adjustment for HBsAg serostatus. HBsAg‐seropositive subjects with high aflatoxin exposure had a higher risk than subjects with high aflatoxin exposure only or HBsAg seropositivity only. In male HBsAg‐seropositive subjects, adjusted ORs were 2.8 (95% confidence interval [Cl] = 0.9–9.1) for detectable compared with non‐detectable aflatoxin‐albumin adducts and 5.5 (Cl = 1.3–23.4) for high compared with low urinary aflatoxin metabolite levels. Our results suggest that environmental aflatoxin exposure may enhance the hepatic carcinogenic potential of hepatitis B virus. A large‐scale study will be needed to evaluate the effect of aflatoxin exposure on HBsAg non‐carriers.

Pregnancy rates after hysteroscopic polypectomy and myomectomy in infertile women

OBJECTIVE To compare reproductive benefits of hysteroscopic myomectomy and polypectomy for infertility to outcomes in infertile couples with normal hysteroscopic findings. METHODS Women with diagnoses of infertility who had hysteroscopic evaluations by a single surgeon between 1975 and 1996 were sent a routine follow-up questionnaire regarding their reproductive histories. All 92 subjects who were located responded to the questionnaire, and 78 met inclusion criteria: age under 45 years, at least 12 months of infertility, and at least 18 months of follow-up with attempts to conceive, including in vitro fertilization in women with bilateral tubal occlusion. RESULTS Of the 78 subjects, 36 had myomectomies, 23 had polypectomies, and 19 had normal cavities. Among the three groups, there were no significant differences in age, type of infertility, length of infertility, or follow-up after the procedure. Polypectomy subjects had significantly higher pregnancy and live birth rates than women with normal cavities. Women who had myomectomies larger than 2 cm had significantly higher pregnancy and live birth rates, achieving statistical significance at a myoma size of 3 cm or greater for live births. Spontaneous abortion rates among first pregnancies after myomectomy, polypectomy, or normal study were similar: 31.5%, 27.7%, and 37.5%, respectively. CONCLUSION Both hysteroscopic polypectomy and hysteroscopic myomectomy appeared to enhance fertility compared with infertile women with normal cavities. Despite concern that hysteroscopic resection of a large myoma might ablate a large surface area of the endometrial cavity, the reproductive benefit appears greater than the risk.

The Long Island Breast Cancer Study Project: Description of a multi-institutional collaboration to identify environmental risk factors for breast cancer

The Long Island Breast Cancer Study Project is a federally mandated, population-based case-control study to determine whether breast cancer risk among women in the counties of Nassau and Suffolk, NY, is associated with selected environmental exposures, assessed by blood samples, self-reports, and environmental home samples. This report describes the collaborative projects background, rationale, methods, participation rates, and distributions of known risk factors for breast cancer by case-control status, by blood donation, and by availability of environmental home samples. Interview response rates among eligible cases and controls were 82.1% (n, = 1,508) and 62.8% (n = 1,556), respectively. Among case and control respondents who completed the interviewer-administered questionnaire, 98.2 and 97.6% self-completed the food frequency questionnaire; 73.0 and 73.3% donated a blood sample; and 93.0 and 83.3% donated a urine sample. Among a random sample of case and control respondents who are long-term residents, samples of dust (83.6 and 83.0%); soil (93.5 and 89.7%); and water (94.3 and 93.9%) were collected. Established risk factors for breast cancer that were found to increase risk among Long Island women include lower parity, late age at first birth, little or no breast feeding, and family history of breast cancer. Factors that were found to be associated with a decreased likelihood that a respondent would donate blood include increasing age and past smoking; factors associated with an increased probability include white or other race, alcohol use, ever breastfed, ever use of hormone replacement therapy, ever use of oral contraceptives, and ever had a mammogram. Long-term residents (defined as 15+ years in the interview home) with environmental home samples did not differ from other long-term residents, although there were a number of differences in risk factor distributions between long-term residents and other participants, as anticipated.

Environmental Toxins and Breast Cancer on Long Island. I. Polycyclic Aromatic Hydrocarbon DNA Adducts

Polycyclic aromatic hydrocarbons (PAH) are potent mammary carcinogens in rodents, but their effect on breast cancer development in women is not clear. To examine whether currently measurable PAH damage to DNA increases breast cancer risk, a population-based case-control study was undertaken on Long Island, NY. Cases were women newly diagnosed with in situ and invasive breast cancer; controls were randomly selected women frequency matched to the age distribution of cases. Blood samples were donated by 1102 (73.0%) and 1141 (73.3%) of case and control respondents, respectively. Samples from 576 cases and 427 controls were assayed for PAH-DNA adducts using an ELISA. The geometric mean (and geometric SD) of the log-transformed levels of PAH-DNA adducts on a natural scale was slightly, but nonsignificantly, higher among cases [7.36 (7.29)] than among controls [6.21 (4.17); P = 0.51]. The age-adjusted odds ratio (OR) for breast cancer in relation to the highest quintile of adduct levels compared with the lowest was 1.51 [95% confidence interval (CI), 1.04-2.20], with little or no evidence of substantial confounding (corresponding multivariate-adjusted OR, 1.49; 95% CI, 1.00-2.21). There was no consistent elevation in risk with increasing adduct levels, nor was there a consistent association between adduct levels and two of the main sources of PAH, active or passive cigarette smoking or consumption of grilled and smoked foods. These data indicate that PAH-DNA adduct formation may influence breast cancer development, although the association does not appear to be dose dependent and may have a threshold effect.

The ALSFRSr predicts survival time in an ALS clinic population

Objective: To determine whether the Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRSr), a predictor of survival time in ALS clinical trials, predicts survival time in an ALS clinic population. Methods: The authors prospectively evaluated 267 consecutive patients with ALS at first visit to an ALS clinic using the ALSFRSr and pulmonary function testing. The association of ALSFRSr score at baseline with death or tracheostomy in ALS was examined using Cox proportional hazards models, adjusting for age at baseline, sex, and symptom duration. Results: Of 267 patients with ALS, 103 (39%) reached the endpoint, defined as either death (79 patients) or tracheostomy (24 patients), during a mean follow-up of 1.0 ± 0.7 years. Among the 103 patients who reached the endpoint during follow-up, 77 (75%) had a baseline ALSFRSr score of less than 38 (the median baseline score of all patients), compared to 53 of 164 (32%) who remained alive without tracheostomy. Patients with a total ALSFRSr score below the median had a 4.4-fold increased risk of death or tracheostomy compared to those who scored above the median (HR: 4.38, 95% CI: 2.79 to 6.86, p < 0.001). Both the total ALSFRSr score at baseline (HR: 0.94, 95% CI: 0.91 to 0.98, p < 0.001) and forced vital capacity at baseline (HR: 0.99, 95% CI: 0.98 to 1.00, p = 0.02) were associated with death or tracheostomy when included in the same Cox model. Conclusions: In an ALS clinic population, the total Amyotrophic Lateral Sclerosis Functional Rating Scale–revised score at baseline is a strong predictor of death or tracheostomy independently of forced vital capacity and after adjustment for age at baseline, sex, and symptom duration.

Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III

Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.

Trisomy Recurrence: A Reconsideration Based on North American Data

Few reliable data exist concerning the recurrence risk for individual trisomies or the risk for recurrence of trisomy for a different chromosome. We collected records from two sources: (1) prenatal diagnoses performed at the Hopital Sainte-Justine in Montreal and (2) karyotype analyses performed at Genzyme. Using the standardized morbidity ratio (SMR), we compared the observed number of trisomies at prenatal diagnosis with the expected numbers, given maternal age-specific rates (by single year). SMRs were calculated both for recurrence of the same trisomy (homotrisomy) and of a different trisomy (heterotrisomy). After all cases with an index trisomy 21 were combined, the SMR for homotrisomy was 2.4 (90% CI 1.6-3.4; P=.0005). For women with both the index trisomy and subsequent prenatal diagnosis at age <30 years, the SMR was 8.0; it was 2.1 for women with both pregnancies at age >/=30 years. For the other index viable trisomies (13, 18, XXX, and XXY) combined, the SMR for homotrisomy was 2.5 (90% CI 0.7-8.0). For heterotrisomy, the SMR after an index trisomy 21 was 2.3 (90% CI 1.5-3.8, P=.0007); the SMR did not vary with maternal age at the first trisomy. When all cases with index viable trisomies were combined, the SMR for heterotrisomy was 1.6 (90% CI 1.1-2.4; P=.04). For prenatal diagnoses following a nonviable trisomy diagnosed in a spontaneous abortion (from Genzyme data only), the SMR for a viable trisomy was 1.8 (90% CI 1.1-3.0; P=.04). The significantly increased risk for heterotrisomy supports the hypothesis that some women have a risk for nondisjunction higher than do others of the same age.

Effects of a behavioral intervention to reduce risk of transmission among people living with HIV: The Healthy Living Project randomized controlled study

Context:The US Centers for Disease Control and Prevention (CDC) strongly recommend comprehensive risk counceling and services for people living with HIV (PLH); yet, there are no evidence-based counseling protocols. Objective:To examine the effect of a 15-session, individually delivered, cognitive behavioral intervention on a diverse sample of PLH at risk of transmitting to others. Design:This was a multisite, 2-group, randomized, controlled trial. Participants:Nine hundred thirty-six HIV-infected participants considered to be at risk of transmitting HIV of 3818 persons screened were randomized into the trial. Participants were recruited in Los Angeles, Milwaukee, New York, and San Francisco. Intervention:Fifteen 90-minute individually delivered intervention sessions were divided into 3 modules: stress, coping, and adjustment; safer behaviors; and health behaviors. The control group received no intervention until the trial was completed. Both groups completed follow-up assessments at 5, 10, 15, 20, and 25 months after randomization. Main Outcome Measure:Transmission risk, as measured by the number of unprotected sexual risk acts with persons of HIV-negative or unknown status, was the main outcome measure. Results:Overall, a significance difference in mean transmission risk acts was shown between the intervention and control arms over 5 to 25 months (χ2 = 16.0, degrees of freedom = 5; P = 0.007). The greatest reduction occurred at the 20-month follow-up, with a 36% reduction in the intervention group compared with the control group. Conclusion:Cognitive behavioral intervention programs can effectively reduce the potential of HIV transmission to others among PLH who report significant transmission risk behavior.