Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data.

Designing public health responses to outbreaks requires close monitoring of population-level health indicators in real-time. Thus, an accurate estimation of the epidemic curve is critical. We propose an approach to reconstruct epidemic curves in near real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We address two data collection problems that affected the reliability of the available real-time epidemiological data, namely, the frequent missing information documenting when a patient first experienced symptoms, and the frequent retrospective revision of historical information (including right censoring). This is done by using a novel back-calculating procedure based on imputing patients' dates of symptom onset from reported cases, according to a dynamically-estimated "backward" reporting delay conditional distribution, and adjusting for right censoring using an existing package, NobBS , to estimate in real time (nowcast) cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number ( R t ) in real-time. At each step, we evaluate how different assumptions affect the recovered epidemiological events and compare the proposed approach to the alternative procedure of merely using curves of case counts, by report day, to characterize the time-evolution of the outbreak. Finally, we assess how these real-time estimates compare with subsequently documented epidemiological information that is considered more reliable and complete that became available later in time. Our approach may help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health surveillance systems in other locations.

Lockdown measures and relative changes in the age-specific incidence of SARS-CoV-2 in Spain.

During the first months of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) epidemic in 2020, Spain implemented an initial lockdown period on 15 March followed by a strengthened lockdown period on 30 March when only essential workers continued to commute to work. However, little is known about the epidemic dynamics in different age groups during these periods.We used the daily number of coronavirus 2019 cases (by date of symptom onset) reported to the National Epidemiological Surveillance Network among individuals aged 15-19 years through 65-69 years. For each age group g, we computed the proportion PrE(g) of individuals in age group g among all reported cases aged 15-69 years during the pre-lockdown period (1-10 March 2020) and the corresponding proportion PrL(g) during two lockdown periods (initial: 25 March-3 April; strengthened: 8-17 April 2020). For each lockdown period, we computed the proportion ratios PR(g) = PrL(g)/PrE(g). For each pair of age groups g1, g2, PR(g1)>PR(g2) implies a relative increase in the incidence of detected SARS-CoV-2 infection in the age group g1 compared with g2 for the lockdown period vs. the pre-lockdown period.For the initial lockdown period, the highest PR values were in age groups 50-54 years (PR = 1.21; 95% CI: 1.12,1.30) and 55-59 years (PR = 1.19; 1.11,1.27). For the second lockdown period, the highest PR values were in age groups 15-19 years (PR = 1.26; 0.95,1.68) and 50-54 years (PR = 1.20; 1.09,1.31).Our results suggest that different outbreak control measures led to different changes in the relative incidence by age group. During the initial lockdown period, when non-essential work was allowed, individuals aged 40-64 years, particularly those aged 50-59 years, had a higher relative incidence compared with the pre-lockdown period. Younger adults/older adolescents had an increased relative incidence during the later, strengthened lockdown. The role of different age groups during the epidemic should be considered when implementing future mitigation efforts.

Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study.

BACKGROUND: The optimal timing to start androgen deprivation therapy (ADT) in prostate cancer patients with rising prostate-specific antigen (PSA) as the only sign of relapse is unknown. METHODS: We identified men with prostate cancer in the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE) study who would have been eligible (⩽ cT3aN0M0, primary radical prostatectomy or radiotherapy, PSA relapse as the only evidence of recurrence) for a randomised trial comparing 'immediate' versus 'deferred' ADT initiation. We emulated such trial by assigning patients to the 'immediate' strategy if they initiated ADT within 3 months of PSA relapse and to the 'deferred' strategy if they initiated ADT when they presented with metastasis, symptoms or a short PSA doubling time. We censored patients when they deviated from the assigned strategy and adjusted for this censoring via inverse probability weighting. RESULTS: Of 2096 eligible patients (median age 69, interquartile range 63-75 years), 88% were white, 35% had a Gleason score ⩾ 7, 69% were treated with radical prostatectomy and 31% received radiotherapy only as primary treatment. The mean time from primary treatment to PSA relapse was 37.4 (standard deviation [SD] 34.2) months. Mean follow-up from primary treatment was 91.4 (SD 48.4) months. The adjusted mortality hazard ratio for immediate versus deferred ADT was 0.91 (95% confidence interval (CI), 0.52-1.60), which would be translated into a similar 5-year survival (difference between groups: -2.0% (95% CI: -10.0 to 5.9%). CONCLUSION: Our analysis suggests that prostate cancer patients undergoing immediate ADT initiation within three months after PSA-only relapse had similar survival to those who deferred ADT initiation within 3 months after clinical progression.

Similar Outcomes for Two Anemia Treatment Strategies among Elderly Hemodialysis Patients with Diabetes.

BACKGROUND/AIMS: To compare mortality and cardiovascular risk in elderly dialysis patients with diabetes under two clinical strategies of anemia correction: maintaining hematocrit (Hct) between 34.5 and < 39.0% (high Hct strategy), and between 30.0 and <34.5% (low Hct strategy) using intravenous alpha epoetin. METHODS: Observational data were used to emulate a randomized trial in which diabetic patients who initiated hemodialysis in 2006-2008 were assigned to each anemia correction strategy. Inverse-probability weighting was used to adjust for measured time-dependent confounding. RESULTS: Comparing high with low hematocrit strategy, the hazard ratio (95% confidence interval) was 1.07 (0.83, 1.38) for all-cause mortality and 1.00 (0.81, 1.24) for a composite mortality and cardiovascular endpoint. CONCLUSIONS: Among a cohort of elderly hemodialysis patients with diabetes, no differences were found between the low and high hematocrit strategies. A lower target hematocrit - per current Food and Drug Administration (FDA) guidelines - appears to be as safe as higher targets among this population.

The NordICC Study: rationale and design of a randomized trial on colonoscopy screening for colorectal cancer.

BACKGROUND AND STUDY AIM: While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial. STUDY DESIGN: Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. POWER ANALYSIS: We hypothesize a 50 % CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50 % compliance, yielding a 25 % mortality reduction among those invited to screening. For 90 % power and a two-sided alpha level of 0.05, using a 2:1 randomization, 45 600 individuals will be randomized to control, and 22 800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up. CONCLUSIONS: The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.

Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study.

BACKGROUND AND PURPOSE: To estimate the incidence and lifetime risk of motor neuron disease (MND) in a population-based sample in the United Kingdom. METHODS: We identified new cases of MND during the period 1990-2005 in the General Practice Research Database, which includes clinical information from more than 3 million Britons enrolled with selected general practitioners. Individuals with a first medical diagnosis of MND recorded in the database were considered incident cases of the disease. The positive predictive value of the computer-based diagnosis was estimated through review of a sample of medical records from potential MND cases. RESULTS: In the period 1990-2005, 830 new cases of MND were identified. Age-standardized incidence of MND was 2.6 per 100 000 persons per year in women (95% CI: 2.3, 2.8) and 3.9 in men (95% CI: 3.6, 4.3). Incidence for both sexes peaked between 75 and 79 years. The rate of MND in men was 54% higher than in women (95% CI: 33%, 77%). The lifetime risk of MND, adjusting for competing causes of death, was 1 in 472 (2.1 per 1000) in women and 1 in 350 (2.9 per 1000) in men. No increase in MND incidence over time was apparent. CONCLUSION: In this population-based database, we found that MND incidence is higher in men than women, peaking in both sexes between 75 and 79 years.

Use of antidepressants and the risk of Parkinson's disease: a prospective study.

BACKGROUND: Individuals with depression have a higher risk of Parkinson's disease (PD) but the timing of the association is unknown. Therefore, the relationship between initiation of antidepressant therapy and PD risk was assessed in a large population based database from the UK and the timing of this association was explored. METHODS: A case control study nested in the General Practice Research Database cohort, a large computerised database with clinical information from more than 3 million individuals in the UK, was conducted. Cases of PD were identified from the computer records from 1995 to 2001 and matched with up to 10 controls by age, sex and practice. Use of antidepressants was obtained from the computer records. RESULTS: 999 PD cases and 6261 controls were included. The rate ratio (RR) and 95% CI of PD in initiators of antidepressant therapy compared with non-initiators was 1.85 (1.25 to 2.75). The association was stronger during the first 2 years after initiation of medication use (RR 2.19; 95% CI 1.38 to 3.46) than later (RR 1.23; 95% CI 0.57 to 2.67). Results were similar for selective serotonin reuptake inhibitors and tricyclic antidepressants separately. CONCLUSION: Initiation of any antidepressant therapy was associated with a higher risk of PD in the 2 years after the start of treatment, which suggests that depressive symptoms could be an early manifestation of PD, preceding motor dysfunction.

Does obesity shorten life? The importance of well-defined interventions to answer causal questions.

Many observational studies have estimated a strong effect of obesity on mortality. In this paper, we explicitly define the causal question that is asked by these studies and discuss the problems associated with it. We argue that observational studies of obesity and mortality violate the condition of consistency of counterfactual (potential) outcomes, a necessary condition for meaningful causal inference, because (1) they do not explicitly specify the interventions on body mass index (BMI) that are being compared and (2) different methods to modify BMI may lead to different counterfactual mortality outcomes, even if they lead to the same BMI value in a given person. Besides precluding the estimation of unambiguous causal effects, this violation of consistency affects the ability to address two additional conditions that are also necessary for causal inference: exchangeability and positivity. We conclude that consistency violations not only preclude the estimation of well-defined causal effects but also compromise our ability to estimate ill-defined causal effects.

Allergy, family history of autoimmune diseases, and the risk of multiple sclerosis.

OBJECTIVE: Previous reports suggested an association between allergy, autoimmunity, and risk of multiple sclerosis (MS), but results have been inconsistent. The present study assessed the association between history of allergy and autoimmune diseases, and the risk of MS. METHODS: We conducted a case-control study nested in the Nurses' Health Study (NHS) and NHS II cohorts. A total of 298 women with MS were matched with 1248 healthy controls and 248 women with history of breast cancer. A mailed questionnaire gathered information about history of allergic conditions and autoimmune disorders. RESULTS: History of allergy was not associated with MS risk [odds ratio (OR) 1.0, 95% confidence interval (CI) 0.8-1.4]. As expected, cases were more likely to have a positive family history of MS than controls (OR 9.7, 95% CI 6.1-15.3). A modest association was found between family history of other autoimmune diseases and MS risk (OR 1.4, 95% CI 1.0-1.8). We obtained similar results when we used women with breast cancer as comparison group. CONCLUSION: Family history of other autoimmune diseases was associated with a higher MS risk, suggesting a common genetic background or shared environmental triggers. There was no clear association between personal history of allergy and risk of MS.

The effect of epoetin dose on hematocrit.

Nearly all dialysis patients receive epoetin therapy to treat anemia. Using the United States Renal Data System, we monitored the 14,001 patients aged 65 and older who started dialysis and epoetin treatment in 2003-2004. We estimated the dose-response relationship for the average epoetin dose and hematocrit during a 3-month initiation and subsequent 3-month maintenance phase using a marginal structural model to adjust for measured time-dependent confounding by indication. During the initiation phase, an S-shaped dose-response relationship for average weekly epoetin dose and hematocrit response was found. Average hematocrit levels rose as the epoetin dose was increased from 9,000 to approximately 22,500 units per week. At higher doses, the effect of increasing epoetin was minimal with average hematocrit levels plateauing at 38.5%, but this was less evident in the maintenance phase. Among patients who reached this phase, doses required to maintain the hematocrit level were lower than those required to achieve similar hematocrit levels in the initiation phase. The dose-response curve found in our study suggests that published recommendations for starting dose are appropriate, and a starting dose of 7,500-15,000 units per week can maintain the hematocrit level in the desired target range of 33-36%.

Incidence of multiple sclerosis in the United Kingdom : findings from a population-based cohort.

Existing data on the incidence of multiple sclerosis (MS) in the UK have some limitations. Few studies have reported age- and sex-specific incidence rates of MS, and none of those is based on a large sample of the general population. Further, no published reports have provided age- and sex-specific incidence rates of MS by clinical course from onset. To estimate the age- and sex-specific incidence rate and lifetime risk of multiple sclerosis, we identified all new cases of MS during the period 1993-2000 in the General Practice Research Database, which includes health information on over three million Britons. Based on 642 incident cases, incidence rates of MS adjusted to the world population were 7.2 (95 % CI 6.5, 7.8) in women and 3.1 (95 % CI 2.6, 3.5) in men. The incidence of MS with relapsing-remitting onset was higher in women than in men (incidence rate ratio 2.5, 95% CI 2.1, 3.1), but there were no sex differences for primary-progressive MS (incidence rate ratio 1.1, 95% CI 0.7, 1.8). The estimated lifetime risk from birth of receiving an MS diagnosis was 5.3 per 1,000 in women and 2.3 per 1,000 in men. These results confirm the relatively high incidence of MS in the UK and show marked differences in the sex-specific pattern of MS incidence by clinical course from onset.

Physical activity and the risk of Parkinson disease.

OBJECTIVE: To investigate whether greater physical activity is associated with a lower risk of Parkinson disease (PD). METHODS: The authors prospectively followed 48,574 men and 77,254 women who provided information on physical activity in 1986 or in early adulthood. During the follow-up, a total of 252 (male) and 135 (female) incident PD cases were identified. RESULTS: In men, greater baseline physical activity was associated with a lower PD risk; compared with the lowest quintile, the multivariate relative risk (RR) of PD for the highest quintile was 0.7 (95% CI 0.5 to 1.1; p value, test for trend = 0.007), and the inverse association was still present after excluding the first 10 years of follow-up (RR = 0.5; p value, test for trend = 0.02). Further, strenuous exercise in early adult life was also inversely related to PD risk in men: compared with men who regularly exercised < or =2 months/year, those with > or =10 months of strenuous exercise had a 60% lower PD risk (RR = 0.4; p value, test for trend = 0.005). In women, physical activity assessed at baseline was not related to PD risk, whereas strenuous exercise in early adulthood tended to be inversely related to PD risk later in life (highest vs lowest categories, RR = 0.5, 95% CI 0.2 to 1.4; p value, test for trend = 0.06). CONCLUSION: This study suggests either that higher levels of physical activity may lower the risk of Parkinson disease (PD) in men or that men predisposed to PD tend to avoid strenuous physical activity in their early adult years.

A definition of causal effect for epidemiological research.

Estimating the causal effect of some exposure on some outcome is the goal of many epidemiological studies. This article reviews a formal definition of causal effect for such studies. For simplicity, the main description is restricted to dichotomous variables and assumes that no random error attributable to sampling variability exists. The appendix provides a discussion of sampling variability and a generalisation of this causal theory. The difference between association and causation is described-the redundant expression "causal effect" is used throughout the article to avoid confusion with a common use of "effect" meaning simply statistical association-and shows why, in theory, randomisation allows the estimation of causal effects without further assumptions. The article concludes with a discussion on the limitations of randomised studies. These limitations are the reason why methods for causal inference from observational data are needed.

Vitamin D intake and incidence of multiple sclerosis.

BACKGROUND: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed, but no prospective studies have addressed this hypothesis. METHODS: Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). Diet was assessed at baseline and updated every 4 years thereafter. During the follow-up, 173 cases of MS with onset of symptoms after baseline were confirmed. RESULTS: The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (95% CI = 0.40 to 1.12; p for trend = 0.03). Intake of vitamin D from supplements was also inversely associated with risk of MS; the RR comparing women with intake of >or=400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI = 0.38 to 0.91; p for trend = 0.006). No association was found between vitamin D from food and MS incidence. CONCLUSION: These results support a protective effect of vitamin D intake on risk of developing MS.

Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk.

BACKGROUND: Oxidative damage has been implicated in the pathogenesis of PD. Limited and mostly retrospective epidemiologic data suggest a reduction or no change in risk of PD associated with high vitamin E intake. OBJECTIVE: To examine prospectively the associations between intakes of vitamins E and C, carotenoids, vitamin supplements, and risk of PD. METHODS: The authors documented the occurrence of PD within two large cohorts of men and women who completed detailed and validated semiquantitative food frequency questionnaires. A total of 371 incident PD cases were ascertained in the Nurses' Health Study, which comprised 76,890 women who were followed for 14 years, and the Health Professionals Follow-Up Study, which comprised 47,331 men who were followed for 12 years. RESULTS: Neither intake of total vitamins E or C or use of vitamin E or vitamin C supplements or multivitamins was significantly associated with risk of PD. The risk of PD, however, was significantly reduced among men and women with high intake of dietary vitamin E (from foods only). The pooled multivariate relative risk (RR) comparing individuals in the highest quintile with those in the lowest quintile was 0.68 (95% CI, 0.49 to 0.93). Consumption of nuts was also significantly associated with a reduced risk of PD (for >or=5/week vs <1/month, pooled RR, 0.57; 95% CI, 0.34 to 0.95). Intakes of dietary vitamin C and carotenoids were not significantly associated with risk of PD. CONCLUSIONS: Use of vitamin supplements and high intake of carotenoids do not appear to reduce the risk of PD. The reduction in risk of PD associated with high dietary vitamin E intake suggests that other constituents of foods rich in vitamin E may be protective. Alternatively, moderate amounts of vitamin E may reduce risk of PD, but this benefit may be lost with higher intakes.

MAOB intron 13 and COMT codon 158 polymorphisms, cigarette smoking, and the risk of PD.

BACKGROUND: A polymorphism (G to A transition) in intron 13 of the mitochondrial enzyme monoamine oxidase B (MAOB) gene may modify, alone or by interacting with the catechol-O-methyltransferase (COMT(LL)) genotype (low enzymatic activity), the risk of idiopathic PD. Also, the association between never smoking and PD risk may be present only in people with the MAOB G allele. METHODS: The authors studied two ongoing prospective cohorts-the Nurses' Health Study (121,700 women aged 30 to 55 in 1976) and the Health Professionals' Follow-up Study (51,529 men aged 40 to 75 in 1986). They identified new PD cases through 1996, selected random control subjects matched on age and study cohort, and obtained DNA samples from blood or buccal smears from 85% of the eligible cases and 84% of the control subjects. They included genotypes from 214 cases and 449 control subjects, all Caucasian. RESULTS: The odds ratio of PD was 1.2 (95% CI 0.9, 1.7) for MAOB genotypes G/GG/GA compared with genotypes A/AA, and 1.1 (0.7, 1.8) for COMT genotypes LL compared with HH. The odds ratio (95% CI) was 1.7 (0.7, 3.9) for those with MAOB G/GG and COMT(LL) genotypes compared with those with MAOB A/AA and COMT(HH). There was a strong association between never smoking and PD risk in all groups defined by MAOB and COMT genotypes. CONCLUSION: The findings do not support a major role of the MAOB intron 13 polymorphism in the development of PD, either by itself or by interacting with smoking.

Intakes of carotenoids, vitamin C, and vitamin E and MS risk among two large cohorts of women.

BACKGROUND: Antioxidant nutrients may reduce the risk of MS. In a recent case-control study, vitamin C intake was significantly inversely associated with MS risk among women. However, no prospective data are available. OBJECTIVE: To examine prospectively the associations of intakes of carotenoids, vitamin C, and vitamin E with the risk of MS among women. METHODS: The authors documented the occurrence of definite and probable MS within two large cohorts of women who completed detailed and validated semiquantitative food frequency questionnaires. One cohort (Nurses' Health Study) comprised 81,683 women aged 38 to 63 years in 1984, who were followed for 12 years; the other (Nurses' Health Study II) comprised 95,056 women aged 27 to 44 years in 1991, who were followed for 6 years. RESULTS: The authors documented a total of 214 cases of MS. After adjustments for age, latitude of birthplace, pack-years of smoking, and total energy intake, the pooled multivariate relative risks (95% CIs) comparing women in the highest quintile with those in the lowest quintile were 1.1 (0.7 to 1.7) for alpha-carotene, 1.1 (0.7 to 1.6) for beta-carotene, 1.4 (0.8 to 2.2) for beta-cryptoxanthin, 1.0 (0.6 to 1.5) for lycopene, 1.0 (0.7 to 1.6) for lutein/zeaxanthin, 1.4 (0.9 to 2.1) for total vitamin C, 1.3 (0.9 to 2.0) for dietary vitamin C, 0.8 (0.6 to 1.3) for total vitamin E, and 0.9 (0.6 to 1.4) for dietary vitamin E. The authors found no associations between intakes of fruits and vegetables and risk of MS. Use of vitamin C, vitamin E, and multivitamin supplements was also unrelated to risk of MS. CONCLUSIONS: These findings do not support hypotheses relating higher intakes of dietary carotenoids, vitamin C, and vitamin E to reduced risk of MS in women.

Prospective study of caffeine consumption and risk of Parkinson's disease in men and women.

Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in two ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23-0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.

Cigarette smoking and incidence of multiple sclerosis.

Experimental data suggest that cigarette smoking may play a role in the development of multiple sclerosis (MS), but epidemiologic studies have been small and inconclusive. The authors assessed the association between MS incidence and smoking in two cohort studies of US women, the Nurses' Health Study (121,700 women aged 30-55 years at baseline in 1976) and the Nurses' Health Study II (116,671 women aged 25-42 years at baseline in 1989). Smoking history was assessed at baseline and updated on biennial questionnaires. A total of 315 definite or probable cases of MS were documented. Compared with that for women who never smoked, the relative incidence rate was 1.6 (95% confidence interval: 1.2, 2.1) among current smokers and 1.2 (95% confidence interval: 0.9, 1.6) among past smokers after adjustment for age, latitude, and ancestry. The relative rate increased significantly with cumulative exposure to smoking (p for trend < 0.05), from 1.1 (95% confidence interval: 0.8, 1.6) for 1-9 pack-years to 1.5 (95% confidence interval: 1.2, 2.1) for 10-24 pack-years and 1.7 (95% confidence interval: 1.2, 2.4) for 25 or more pack-years. Similar results were obtained after adjustment for other potential confounding factors. Although these prospective results do not prove a cause-and-effect relation, they suggest that smoking is associated with an increased risk of MS.