Association between comorbidity and clinical characteristics of MS.

BACKGROUND: Comorbidity may be associated with the clinical phenotype of disease and may affect prognostication and treatment decisions. Using the North American Research Committee on Multiple Sclerosis Registry, we described comorbidities present at onset and diagnosis of multiple sclerosis (MS) and examined whether comorbidities present at onset were associated with clinical course or age of MS symptom onset. METHODS: In 2006, 8983 participants reported their physical and mental comorbidities; smoking status; height; and past and present weight. We compared clinical course at onset and age of symptom onset by comorbidity status. RESULTS: At MS onset, a substantial proportion of participants had physical (24%) or mental (8.4%) comorbidities. The mean (SD) age of MS onset was 31.2 (9.0) years. Vascular, autoimmune, cancer, visual, and musculoskeletal comorbidities were associated with a later age of symptom onset. Among men and women, the odds of a relapsing course at onset were increased if mental comorbidities (OR 1.48; 1.08-2.01) were present at symptom onset. In women, gastrointestinal comorbidities (OR 1.78; 1.25-2.52) and obesity (OR 2.08 1.53-2.82) at MS onset were also associated with a relapsing course at onset. CONCLUSIONS: Comorbidity is frequently present at onset of MS and is associated with differences in clinical characteristics.

Adherence to treatment and health outcomes.

Adherence (or compliance) is the extent to which a person's behavior coincides with medical or health advice. Recent evidence indicates that patients who adhere to treatment, even when that treatment is a placebo, have better health outcomes than poorly adherent patients. Based on this evidence, we now believe that the outcomes of treatment are not solely attributable to the specific action of a drug, but may also depend on other nonspecific therapeutic effects. We consider the implications of these findings for the design and interpretation of clinical research as well as for the care of patients.

Analysis of clinical susceptibility bias in case-control studies. Analysis as illustrated by the menopausal syndrome and the risk of endometrial cancer.

Epidemiologic studies of causes of disease rarely contain adjustments for inequalities in diseases susceptibility caused by baseline differences in clinical phenomena. In the controversial association between estrogens and endometrial cancer, the menopausal syndrome was suspected as an independent risk factor for the development of endometrial cancer, irrespective of estrogen use. To investigate this suspicion, personal interview data from a case-control investigation were collected and analyzed. The odds ratio for the association between menopausal symptoms and endometrial cancer was 1.12 and 0.85 for two different sets of cases and controls assembled at the same institution. When the data were partitioned according to estrogen usage, the odds ratios became consistently less than one. The results suggest that the menopausal syndrome is not a risk factor for endometrial cancer.

Evidence against the association between alcohol use and ischemic stroke risk.

To examine the relationship between alcohol consumption and ischemic stroke risk, we used data from our case-control study of stroke risk. Eighty-nine patients admitted to the hospital with ischemic stroke documented by computed tomography of the head were matched to 178 controls. Alcohol use was defined by an estimate of customary use (heavy, moderate, light, or none). We found no consistent or significant association between any level of alcohol use and ischemic stroke risk (odds ratios: any, 1.3; heavy, 0.5; moderate, 1.5; and light, 1.5). We repeated the analysis of our study using a control group assembled according to the study criteria of another case-control study that reported a significant association in men with heavy alcohol use (odds ratio, 4.2). We demonstrated that the association in the prior study may be spurious due to methodological problems.

Exclusion bias and the false relationship of reserpine and breast cancer.

Although reserpine has an important role in treating patients with hypertension, its appeal was sharply reduced a decade ago when an alleged relationship to breast cancer was reported in case-control studies. Since the relationship was not confirmed in subsequent research and analyses, the original association is now regarded as erroneous. Since patients with cardiovascular disease were rejected as possible controls in the original reserpine-breast cancer case-control study, we suspected that the false association may have been produced by a phenomenon called exclusion bias. This bias can arise in case-control studies if patients with a particularly high (or low) rate of prior exposure to the alleged etiologic agent are excluded from the selection of either cases or controls, but not from both. To test that suspicion, we recapitulated the original study, in another medical setting. The cases were 257 women with breast cancer; and the controls were 257 hospitalized women matched according to date of admission, age, and race. The overall data showed no association between reserpine and breast cancer (odds ratio [OR] = 1.1), but when we excluded 101 women with cardiovascular disease from the control group, the OR rose to 2.5. The results suggest that exclusion bias played an important role in creating the false association between reserpine and breast cancer.

Problems in the conduct and analysis of randomized clinical trials. Are we getting the right answers to the wrong questions?

To achieve the goal of validity, the randomized clinical trial has emerged as the scientific "gold standard" for evaluating therapies in clinical medicine. Regardless of how well randomized clinical trials are designed, however, problems often occur during the conduct of the trials that give rise to methodologic challenges in the analysis of results. Primarily two types of problems, changes in intended treatment and the failure to ascertain the study outcomes, occur during the conduct of randomized clinical trials. We studied the current analytic strategies that are used to deal with these problems and how the use of these analytic strategies can change the focus of the research so that the trial no longer answers the relevant question. To ensure that the right question is answered, new methods of design and analysis are required that balance the goals of validity and clinical pertinence.

A reappraisal of the United Kingdom epidemic of fatal asthma. Can general mortality data implicate a therapeutic agent?

The 1960s epidemic of asthma deaths that affected young persons in England and Wales, as well as in other countries, was attributed to the effect of newly available pressurized aerosols containing sympathomimetic bronchodilators. The subsequent decision to ban the nonprescription sale of these agents in the United Kingdom represented a unique use of national and international mortality data. The application of such data for decisions about therapeutic agents has implications for the current rise of asthma deaths in New Zealand, for the recent United States regulatory action regarding the nonprescription sale of aerosolized bronchodilators, and for the appraisal of adverse reactions to other pharmaceutical substances. This article is concerned with the quality of the scientific evidence used to implicate bronchodilators in the 1960s epidemic, and also with the strengths and weaknesses of the ecologic studies on which the implication depended. After concluding that the causal link between asthma deaths and bronchodilators was not supported by satisfactory scientific evidence, we present new data and an alternative diagnostic-exchange hypothesis that may, in part, help explain the original association.

An ecogenetic hypothesis for lung cancer in women.

Epidemiologic studies have established a strong association between cigarette smoking and lung cancer, but the risk estimates for women are less impressive than for men. We assessed the possible role of family history and its interrelationship with cigarette smoking as risk factors for lung cancer in women by conducting a case-control study. Among 112 cases, 7% had a primary family member with lung cancer compared with only 3% of 224 controls for an odds ratio of 2.8. Cigarette smoking was present for 87% of the cases and 41% of the controls for an odds ratio of 11.3. The ecogenetic interrelationship of cigarette smoking and family history was supported by the gradient in the odds ratio for lung cancer created by the two variables: patients who never smoked but had a positive family history had an odds ratio of 5.7; patients who smoked but had a negative family history had an odds ratio of 15.1; and patients who smoked and had a positive family history had an odds ratio of almost 30. We conclude that family history may be an important risk factor for lung cancer in women, and that the ecogenetic interrelationship of family history with cigarette smoking may help explain the occurrence of this disease in women.

The efficacy of atenolol in the outpatient management of the alcohol withdrawal syndrome. Results of a randomized clinical trial.

We conducted a randomized, double-blind, clinical trial of atenolol compared with placebo in the outpatient management of patients with the alcohol withdrawal syndrome. In addition to receiving customary therapy, 88 patients were randomly assigned to receive atenolol and 92 to receive placebo. Outcome during the next 14 days was assessed using two main measures: the patient's clinical course as assessed by an alcohol withdrawal severity index; and the occurrence of treatment failure (composite measure including return to drinking, dropouts, and withdrawal lasting longer than 5 days). In addition, levels of craving for alcohol were assessed as an associated response variable. Overall, treatment failure occurred for 37% of the patients receiving atenolol and 52% of those receiving placebo. Among patients who had withdrawal symptoms at baseline, vital signs became normal more rapidly in the patients receiving atenolol, and their abnormal behavioral characteristics also resolved more rapidly. Levels of craving for alcohol were strongly associated with treatment failure; the group of patients who received atenolol included significantly fewer who reported high levels of craving 24 hours after treatment began (7% of patients receiving atenolol and 20% of those receiving placebo). We conclude that the outpatient management and treatment outcomes of the alcohol withdrawal syndrome are improved in patients who receive atenolol, and that the beneficial effects are associated with reduced levels of craving for alcohol. If these results are confirmed by other investigators, atenolol may prove to play an important role in the outpatient management of the alcohol withdrawal syndrome.

Case-control research. Temporal precedence and other problems of the exposure-disease relationship.

We assessed the principle of temporal precedence in recent case-control studies demonstrating the alleged associations between tampon use and toxic shock syndrome and between aspirin use and Reye's syndrome. For both relationships, we considered four components of the exposure-disease association, including: (1) establishing that the agent preceded the disease, (2) selecting an index time, (3) defining criteria for classifying a patient as "exposed," and (4) avoiding the bias that occurs when use of the etiologic agent was influenced by an early manifestation of the disease. The problems can be minimized by interviewing patients early during the course of their illness and by improving strategies for data analysis.

Zidovudine (AZT) for treatment of patients infected with human immunodeficiency virus type 1. An evaluation of effectiveness in clinical practice.

To learn about the patterns of use and the effectiveness of zidovudine therapy in clinical practice, we conducted an observational cohort study of 86 patients with human immunodeficiency virus type 1 infection. All patients were followed up for at least 6 months after starting zidovudine (AZT) therapy. Of the 86 patients, 78 (91%) initially received full-dosage zidovudine (1200 mg/d), and eight received a reduced dosage (600 mg/d). During follow-up, the number able to maintain full-dosage zidovudine therapy decreased to 54 (63%) at 3 months and 40 (47%) at 6 months. Thirty-five patients required dosage reductions that lasted at least 7 days and were not preceded by an adverse outcome (death or opportunistic infection). Overall, adverse outcomes occurred for nine (26%) of those with dosage reductions compared with 22 (43%) of 51 patients with no previous dosage change. Even after adjusting for baseline cytopenias and the time of the dosage reductions, adverse outcomes did not occur significantly more often in patients who received reductions in their zidovudine dosage. Our results indicate that full-dosage zidovudine therapy cannot be maintained for most patients infected with human immunodeficiency virus, but that clinicians need not be pessimistic about treatment outcomes when dosage reductions are needed.

A simple index to identify occult bacterial infection in adults with acute unexplained fever.

Patients with acute fever (less than three weeks' duration) and no localizing symptoms or physical findings to suggest a source (unexplained fever) may have self-limited illness or occult bacterial infection requiring prompt treatment. To develop a management strategy for patients with unexplained fever, we studied 880 adults who were evaluated for acute fever in an emergency room. At presentation, 135 (15%) patients had unexplained fever. Occult bacterial infection was found in 48 (35%) of these 135 patients, and 21 (44%) of 48 infected patients had bacteremia. Four bacteremic patients were incorrectly discharged from the emergency room without antimicrobial therapy. Neither a "toxic" appearance of the patient nor an initial temperature of greater than or equal to 39.4 degrees C (103 degrees F) were predictive of occult bacterial infection. An index of predictive features was developed that included: age 50 years or older; diabetes mellitus; a white blood cell count greater than or equal to 15,000/mm3 (15 X 10(9)/L); a neutrophil band cell count greater than or equal to 1500/mm3 (1.5 X 10(9)/L); and a Wintrobe erythrocyte sedimentation rate greater than or equal to 30 mm/h. In patients with 0, 1, 2, or 3 or more index features present, the proportions having occult bacterial infection were 5% (1/21), 33% (15/45), 39% (15/38), and 55% (17/31), respectively. All four bacteremic patients incorrectly discharged had two or more of the index features. Adults presenting with acute unexplained fever often have life-threatening bacterial infection. A simple clinical index can be used to estimate the likelihood of occult infection and may reduce the frequency of diagnostic error.

Price of adaptation--allostatic load and its health consequences. MacArthur studies of successful aging.

BACKGROUND: Exponential growth in the population of older adults presents clinicians with special concerns about factors affecting risks for declines in cognitive and physical functioning. OBJECTIVES: To examine the hypothesis that risks for such declines and for disease outcomes, such as cardiovascular disease, are related to differences in allostatic load, the cumulative physiologic toll exacted on the body over time by efforts to adapt to life experiences. To present an operational definition of allostatic load, along with preliminary evidence of its predictive validity in relation to salient outcomes of aging. METHODS: Data from a longitudinal, community-based study of successful aging were used to develop a measure of allostatic load based on 10 parameters reflecting levels of physiologic activity across a range of important regulatory systems. Allostatic load is the sum of the number of parameters for which the subject was rated in the highest-risk quartile. RESULTS: Higher allostatic load scores were associated with poorer cognitive and physical functioning and predicted larger decrements in cognitive and physical functioning as well as being associated with an increased risk for the incidence of cardiovascular disease, independent of sociodemographic and health status risk factors. CONCLUSIONS: Findings are consistent with the conceptualization of allostatic load as an index of wear and tear on the body, with elevations in allostatic load predicting an increased risk for a decline in cognitive and physical functioning as well as cardiovascular disease in a cohort of older men and women. From a clinical perspective, the concept of allostatic load may provide the basis for a more comprehensive assessment of major risks in the aging process.

Comorbid and clinical determinants of prognosis in endometrial cancer.

In cancers of the lung, larynx, rectum, and breast, the patients' initial clinical manifestations and comorbid diseases have shown important prognostic distinctions that are not evident in the customary systems of anatomic staging. This study was done to see whether the same phenomena occurred for cancer of the endometrium. In 142 consecutive cases of endometrial carcinoma, strikingly high five-year survival rates were found in women who had no symptoms attributable to the cancer or whose only symptoms might have been caused either by concomitant uterine or cervical disease or by replacement estrogen therapy. A distinct decline in survival was associated with systemic symptoms and with major comorbid ailments. Estimation of prognosis and evaluation of therapy can be improved with a new composite staging system, formed by combining the new clinical categories and the standard morphologic stages of the International Federation of Gynecology and Obstetrics (FIGO) system.

The role of susceptibility bias in epidemiologic research.

Because prognostic adjustment in epidemiologic studies of disease etiology has usually been limited to matchings or stratifications based on demographic characteristics, clinical sources of susceptibility bias have received little attention. This may have led to an incorrect association in two prominent epidemiologic relationships: that between clear-cell vaginal carcinoma and the use of diethylstilbestrol to treat women with bleeding or previous pregnancy loss; and that in the conflicting results of the studies linking sex steroids to the risk of birth defects. The recognition and management of susceptibility bias requires attention to the patients' clinical status at the time of exposure to the alleged causative agent, and also requires collecting and analyzing clinical data excluded or ignored in most epidemiologic studies. To avoid susceptibility bias, data about bleeding, threatened abortion, and other clinical reasons for prescribing therapy are needed for the appropriate matchings or stratifications.

Functional disability before myocardial infarction in the elderly as a determinant of infarction severity and postinfarction mortality.

BACKGROUND: Functional disability is a common condition among elderly patients. However, to our knowledge, its effect on outcome of myocardial infarction (MI) has not been assessed. Our objectives were to determine whether disability in the activities of daily living measured before MI is a predictor of MI severity and mortality. METHODS: Disability in activities of daily living was measured prospectively in a cohort of 222 patients who were hospitalized with acute MI. Outcome measures were severity characteristics on admission to the hospital (higher Killip class, presence of new Q waves in the first electrocardiogram, and lower systolic blood pressure), and 6-month mortality. RESULTS: Patients with disability before hospitalization were older and had more comorbidity. After adjusting for these factors and for delay in hospital arrival, disability was still significantly associated with clinical severity on admission to the hospital and with mortality (adjusted relative risk of death for patients with disability vs patients without disability, 2.01; 95% confidence interval, 1.23-3.28). Clinical severity and hospital treatment explained the higher mortality of patients with disability. When these factors were added to the previous model, the relative risk of mortality for patients with disability vs patients without disability was 1.24, and the 95% confidence interval was 0.73 to 2.12. CONCLUSIONS: Functional disability in activities of daily living before MI is an important predictor of clinical severity and mortality in elderly patients with MI. This effect is only minimally explained by the older age and higher comorbidity of patients with disability. However, higher clinical severity and lower use of treatment interventions are major determinants of their higher mortality compared with patients without disability.

Sex differences in mortality after myocardial infarction: evidence for a sex-age interaction.

BACKGROUND: Studies of sex differences in mortality after myocardial infarction (MI) have shown conflicting results. OBJECTIVES: To test the hypothesis that sex differences in mortality after MI vary according to patients' age, with younger women, but not older women, having a higher mortality compared with men. METHODS: We performed a retrospective cohort study of 1025 consecutive patients who met accepted criteria for MI in 1992 and 1993 in 15 Connecticut hospitals. Data for the study were abstracted from medical records. RESULTS: Women had a 40% higher hospital mortality rate than men. Simple age adjustment eliminated the sex difference in mortality rate (odds ratio, 0.99; 95% confidence interval, 0.66-1.48). However, when the sample was subdivided into 2 age groups, women younger than 75 years showed twice as high a mortality rate as men in the same age group, while among older patients no difference in mortality was found. In multivariate analyses the interaction of sex with age was highly significant, even after adjusting for comorbid conditions, clinical severity, process of care, and hospital characteristics. In the fully adjusted model, this interaction indicated that among patients younger than 75 years women had 49% higher odds of hospital death than men, while in the age group 75 years or older women had 46% lower odds of death compared with men. CONCLUSIONS: A higher mortality of women compared with men after MI is confined to the younger age groups. The sex-age interaction should be considered when examining sex differences in mortality after MI.

A quality-of-life instrument for young hemorrhagic stroke patients.

BACKGROUND AND PURPOSE: Hemorrhagic stroke has a high initial mortality rate. While survivors often recover motor function, many experience significant changes in their quality of life (QOL). Available outcome measures assess neurological impairment, disability, or handicap, yet often inadequately characterize the full impact of a stroke on patients' lives. In this study, we develop and validate a QOL instrument specific for young patients with hemorrhagic strokes. METHODS: Methodological guidelines for instrument development were initially established. Based on the content of 40 open-ended patient interviews, a 54-item instrument (HSQuale) was developed. The reliability (test-retest and internal consistency) and validity (content and construct) of HSQuale were assessed in another 71 patients (18 to 49 years of age, 63% women, 77% white), at 1 year after their hemorrhagic stroke. Comparisons were made between HSQuale and other commonly used outcome measures. RESULTS: HSQuale demonstrated reproducibility (test-retest kappa, 0.40 to 0.96) and internal consistency (Cronbach alpha >/=0.80 for 5 of 7 domains). HSQuale scores had broad frequency distributions (

Placebos, active control groups, and the unpredictability paradox.

Randomized controlled trials often rely on placebo control groups to estimate treatment differences. Recently, the high frequency of negative trials and ethical concerns surrounding the use of placebos have brought the use of placebo control groups under increased scrutiny. Although many psychiatric researchers argue that placebo control groups should be replaced with active control groups, we argue that preferential use of active control groups will not reduce the number of negative trials. Rather, we suggest that some of the variation and contradiction in randomized controlled trial results arises from the clinical heterogeneity of patient characteristics, disease severity, comorbidity, and cotherapies. Further characterization of patient heterogeneity, through improved disease taxonomies, severity indices, and classification of comorbid diseases, will serve to reduce clinical heterogeneity among patients and reduce the number of negative trials produced by wide variation in treatment and control response rates.

Insulin resistance and risk for stroke.

BACKGROUND AND PURPOSE: Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance. METHODS: The authors searched Medline (1977-2001) and reviewed bibliographies to identify pertinent English-language publications. RESULTS: Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke. CONCLUSION: Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.