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Inhaled corticosteroids are now recommended as first-line therapy for asthma. Although these drugs clearly improve the symptoms of the disease and the associated physiologic abnormalities, epidemiologic studies provide important information on their effectiveness in preventing asthma morbidity and mortality. We review the evidence regarding the role of inhaled corticosteroids in the prevention of asthma fatality and hospitalization. In the process, we discuss the methodologic complexities of the nonexperimental studies and the implications of the methodologic issues on the evaluation of the impact of these drugs. Eight of the cohort and ecologic studies conducted to date strongly suggest that inhaled corticosteroids, when taken regularly, decrease the number of hospitalizations for asthma by up to 80%. For asthma death, the results of 11 investigations appear less consistent, especially those of several cohort and case-control studies whose principal objective was to examine not the benefit of inhaled corticosteroids but the adverse effects of other drug classes. Much of the inconsistency in the results, however, can be explained by weaknesses in study design and analysis-in particular, the failure to consider exposure in terms of regular use of inhaled corticosteroids. When the most recent study involving the use of the Saskatchewan databases is considered, it is evident that regular treatment with conventional or low-dose inhaled cortico-steroids results in a significant reduction in fatalities due to asthma. In all, the evidence to date strongly indicates that regular use of inhaled corticosteroids, even at low doses, would prevent the major portion of asthma hospitalizations and deaths.

Whiplash, a common injury following motor vehicle crashes, is associated with high costs and a prognosis that is variable and difficult to predict. We studied the profile of recovery from whiplash and assessed whether presenting signs and symptoms directly after the crash were predictive of whiplash prognosis. We formed a population-based incident cohort of all 2627 individuals who sustained a whiplash injury resulting from a motor vehicle crash in the province of Québec, Canada, in 1987, and followed these patients for up to 7 years. The data on signs and symptoms were obtained from the medical charts kept by the universal automobile insurance plan (Société de l'assurance automobile du Québec), which covers all 7 million residents of the province, while data on the outcome--the recovery time from whiplash--was obtained from their databases. The median recovery time was 32 days, and 12% of subjects had still not recovered after 6 months. The signs and symptoms that were found to be independently associated with a slower recovery from whiplash, besides female gender and older age, are neck pain on palpation, muscle pain, pain or numbness radiating from the neck to arms, hands or shoulders, and headache. Together, these factors in older females (age 60) predicted a median recovery time of 262 days, compared with 17 days for younger males (age 20) who do not have this profile. In contrast, using a classification of injury severity previously proposed by the Québec Whiplash Associated Disorders Task Force, the median recovery time varied from 17 to only 123 days. We conclude that whiplash patients presenting with several specific musculoskeletal and neurological signs and symptoms will have a longer recovery period. These patients can easily be identified and closely monitored and targeted for the evaluation of early intervention programmes aimed at managing whiplash patients with a poor prognosis.

Background: There has been some concern that vaccination may precipitate the onset of multiple sclerosis or lead to relapses. Since the recent hepatitis B vaccination program in France, there have been new reports of an increased risk of active multiple sclerosis after vaccination., Methods: We conducted a case-crossover study to assess whether vaccinations increase the risk of relapse in multiple sclerosis. The subjects were patients included in the European Database for Multiple Sclerosis who had a relapse between 1993 and 1997. The index relapse was the first relapse confirmed by a visit to a neurologist and preceded by a relapse-free period of at least 12 months. Information on vaccinations was obtained in a standardized telephone interview and confirmed by means of medical records. Exposure to vaccination in the two-month risk period immediately preceding the relapse was compared with that in the four previous two-month control periods for the calculation of relative risks, which were estimated with the use of conditional logistic regression., Results: Of 643 patients with relapses of multiple sclerosis, 15 percent reported having been vaccinated during the preceding 12 months. The reports of 94 percent of these vaccinations were confirmed. Of all the patients, 2.3 percent had been vaccinated during the preceding two-month risk period as compared with 2.8 to 4.0 percent who were vaccinated during one or more of the four control periods. The relative risk of relapse associated with exposure to any vaccination during the previous two months was 0.71 (95 percent confidence interval, 0.40 to 1.26). There was no increase in the specific risk of relapse associated with tetanus, hepatitis B, or influenza vaccination (range of relative risks, 0.22 to 1.08). Analyses based on risk periods of one and three months yielded similar results., Conclusions: Vaccination does not appear to increase the short-term risk of relapse in multiple sclerosis.

Background: Treatment guidelines recommend concomitant use of ipratropium bromide and inhaled beta2-agonists as severity of COPD progresses. While the use of these two agents in a single inhaler may enhance patient compliance and result in cost savings, it may, by itself, increase medication use. We assessed whether the introduction of a combined inhaled bronchodilator in the treatment of COPD modifies the use and costs related to prescribed medications., Method: A cohort of subjects > or =45 years old initiating treatment with either a combined inhaled bronchodilator (641 subjects) or ipratropium bromide and inhaled beta2 -agonist (411 subjects) between July 1, 1996, and June 30, 1997, was identified using the Saskatchewan Health databases. The primary outcomes were prescribed medication usage and the subsequent related costs during a 1-year follow-up period. Poisson regression analysis was used to estimate rate ratios (RRs) adjusted for drug use and hospitalization during the year prior to cohort entry., Results: The adjusted RR of inhaled bronchodilator use was elevated for combined inhaled bronchodilator therapy (adjusted RR, 1.16; 95% confidence interval [CI], 1.07 to 1.26). However, the overall costs associated with these inhaled bronchodilators were reduced with combined inhaled bronchodilator therapy (adjusted mean ratio, 0.83; 95% CI, 0.76 to 0.92). The rate of use of other respiratory drugs and antibiotics was similar (adjusted RR, 1.03; 95% CI, 0.93 to 1.16). Applying the rate ratio for cost savings to all new, combined inhaled bronchodilator users led to estimated annual savings in Canadian dollars of 103,468 dollars (95% CI, 48,694 dollars to 146,082 dollars) in this province., Conclusion: The introduction of a simpler bronchodilator dosing regimen did not significantly alter the treatment of COPD and resulted in appreciable cost savings.

Background: The debate on the association between nonphenacetin-containing combined analgesics and renal disease has lasted for several years., Method: A peer review committee of scientists, selected jointly by the regulatory authorities of Germany, Switzerland, and Austria and the pharmaceutical industry was asked to critically review data on the relationship between nonphenacetin combined analgesics and nephropathy., Results: The committee regarded epidemiologic evidence on nonphenacetin combined analgesics as inconclusive because of sparse information and substantial methodological problems. The committee also noted that a diagnosis of analgesic-associated nephropathy (AAN) in clinical practice usually depends on information about exposure before or in the early stages of the disease and is seldom accompanied by specific histologic evidence. The morphologic finding of papillary calcification can arise from other conditions and is not specific for AAN. For these reasons, the identification criteria for AAN should be reappraised with scientific methods to validate the diagnostic procedure. In the limited amount of experimental pharmacological data in humans and animals, the committee found no convincing evidence to confirm or refute the hypothesis that nonphenacetin combined analgesics are more nephrotoxic than single formulations. For caffeine taken with combined analgesics, the currently available information is not sufficient to postulate a harmful toxicological effect., Conclusion: The committee's two main conclusions were that sufficient evidence is absent to associate nonphenacetin combined analgesics with nephropathy and that new studies should be done to provide appropriate data for resolving the question.

Background: Although inhaled corticosteroids are effective for the treatment of asthma, it is uncertain whether their use can prevent death from asthma., Methods: We used the Saskatchewan Health data bases to form a population-based cohort of all subjects from 5 through 44 years of age who were using antiasthma drugs during the period from 1975 through 1991. We followed subjects until the end of 1997, their 55th birthday, death, emigration, or termination of health insurance coverage; whichever came first. We conducted a nested case-control study in which subjects who died of asthma were matched with controls within the cohort according to the length of follow-up at the time of death of the case patient (the index date), the date of study entry, and the severity of asthma. We calculated rate ratios after adjustment for the subject's age and sex; the number of prescriptions of theophylline, nebulized and oral beta-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled beta-adrenergic agonists used in the year before the index date; and the number of hospitalizations for asthma in the two years before the index date., Results: The cohort consisted of 30,569 subjects. Of the 562 deaths, 77 were classified as due to asthma. We matched the 66 subjects who died of asthma for whom there were complete data with 2681 controls. Fifty-three percent of the case patients and 46 percent of the control patients had used inhaled corticosteroids in the previous year, most commonly low-dose beclomethasone. The mean number of canisters was 1.18 for the patients who died and 1.57 for the controls. On the basis of a continuous dose-response analysis, we calculated that the rate of death from asthma decreased by 21 percent with each additional canister of inhaled corticosteroids used in the previous year (adjusted rate ratio, 0.79; 95 percent confidence interval, 0.65 to 0.97). The rate of death from asthma during the first three months after discontinuation of inhaled corticosteroids was higher than the rate among patients who continued to use the drugs., Conclusions: The regular use of low-dose inhaled corticosteroids is associated with a decreased risk of death from asthma.

Objective: To determine whether the pain, contracture, and disability associated with idiopathic frozen shoulder are diminished by a series of 3 indirect bupivacaine suprascapular nerve blocks delivered in an ambulatory care clinic., Methods: A double blind randomized controlled trial of patients referred by primary care and specialty clinics in Montreal to an ambulatory tertiary care academic facility. Patients and controls underwent a series of 3 indirect suprascapular nerve blocks at 7 day intervals using either 10 c.c. bupivacaine 0.5 (Marcaine) in the treatment group or 10 c.c. of physiological saline in controls. Subjects in both groups were taught a program of shoulder range of motion exercises to be done at home. The primary outcome measure was the McGill-Melzack Pain Questionnaire (MPQ) short form at 1 month post-randomization (2 weeks after last injection). The secondary outcome measures were disability measured by the simple shoulder test and glenohumeral joint contracture measured by shoulder range of motion measurements., Results: Thirty-four subjects were randomized from 58 screened. Average age of subjects was 52 years. Mean duration of pain prior to randomization was one year. Dropout rate was 11% in the treatment group, 30% in the placebo group. A 64% reduction in pain in the treatment group versus 13% in the placebo group was observed at one month as measured by the MPQ multidimensional pain descriptors score (p = 0.03). A nonsignificant 15.8% improvement in shoulder function in the treatment group versus 4% in the placebo group (p = 0.24) was also noted. No improvement in shoulder range of movement was noted. No side effects other than transient vagal symptoms and local tenderness at the injection site were reported., Conclusion: The use of bupivacaine suprascapular nerve blocks was effective in reducing the pain of frozen shoulder at one month. Clinical studies with a larger number of subjects and a longer study period will help determine the duration and nature of the effect of bupivacaine suprascapular nerve blocks in treating the pain, disability, and glenohumeral joint contracture of frozen shoulder.

The role of psychological factors in recovery from first lifetime low back pain (LBP) was explored in this study. Consecutive clients from one physiatry clinic in Montreal who had LBP of less than 3 months' duration, were on sick leave and receiving workers' compensation benefits, and reported the current event as first lifetime LBP were enrolled. Psychological factors that fluctuate with current events (Psychiatric Symptom Index) and remain stable over time (General Well Being Scale) were assessed. Outcomes were late return to work (> 31 days) and 1 year incidence of compensated recurrence. Results from two multivariate models indicated lower psychological distress predicted late return to work, and higher well being, higher aggressiveness, and lower anxiety predicted compensated recurrence. Researchers concluded psychological factors do not impact clients with all types of LBP in the same way. For individuals lacking prior LBP experience, better psychological functioning increased lengthy work absence. Thus, awareness of the clients' psychological profiles and previous LBP experiences may benefit recovery.

The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use.

The role of maternal smoking as a causal factor for the incidence of childhood asthma is still not clearly established. It was investigated among 3- and 4-year-old-child incident cases confirmed by a 6-year follow-up (n = 294) and cases who no longer had symptoms after diagnosis (n = 110). The study took place in Montréal, Canada, between 1988 and 1997. Persistent and transient cases were compared with their respective controls from the original case-control study of incidence. The odds ratio for heavy maternal smoking adjusted for known risk factors for asthma was 3.84 (95% confidence interval: 1.68, 8.76) among persistent cases and close to one among transient cases.

Background: Reference-based pricing is a cost-containment policy applied to prescription drugs that are in the same class and deemed to be therapeutically equivalent. Recent reference-based pricing measures have targeted several drug classes, including angiotensin-converting-enzyme (ACE) inhibitors. The objective of this study was to assess whether patients treated for hypertension with various ACE inhibitors differed in their utilization of health care services and hence, whether the various ACE inhibitors should be considered therapeutically equivalent., Methods: A retrospective cohort was formed from 4709 Saskatchewan residents aged 40-79 years who initiated treatment for hypertension with 1 of the 3 most frequently prescribed ACE inhibitors (captopril, enalapril or lisinopril) between Jan. 1, 1991, and Dec. 31, 1993. Information obtained from universal insurance databases included prescription drug use, the number of visits to a general practitioner (GP) or specialist and the number of hospital admissions during the year before treatment was initiated and during a follow-up period of up to 4 years. Rates were statistically adjusted for potential confounding variables and compared across treatment groups., Results: Of the 4709 patients, 529 were prescribed captopril initially, 2939 enalapril and 1241 lisinopril. After treatment was initiated patients prescribed captopril were dispensed more medications on average, with an overall rate of 18.6 prescriptions per patient per year (v. 16.4 and 14.7 for enalapril and lisinopril users respectively); they were admitted to hospital more often, and they made more visits to GPs and specialists. The adjusted rate ratio of the number of visits to a GP for patients receiving enalapril, relative to captopril, was 0.84 (95% confidence interval [CI] 0.80-0.88), and for those receiving lisinopril it was 0.79 (95% CI 0.74-0.83). The adjusted rate ratios for the number of visits to a specialist were similar but lower, and for the number of hospital admissions they were 0.82 for patients prescribed enalapril initially (95% CI 0.73-0.93) and 0.65 (95% CI 0.56-0.75) for those prescribed lisinopril., Interpretation: Patients with hypertension who are initially prescribed captopril used health care services more than those initially prescribed enalapril or lisinopril. This suggests that ACE inhibitors may not be therapeutically equivalent.

The proverbial relative risk may not always be the most suitable measure to compare the risk of two exposures, since it inherently includes a background effect. An alternative comparative measure, the relative excess risk, is introduced. It applies to situations in which an "unexposed" reference group is included in addition to the two exposures under evaluation. This comparative measure is based solely on the component of risk due to the exposures, since it removes the background risk. Estimators of the relative excess risk are presented, along with formulas for the confidence intervals under cohort and case-control designs, using both crude and adjusted rate ratios. This new measure is illustrated with data from epidemiologic studies of the risks of oral contraceptives and antidiabetic drugs.

Background: Early treatment with inhaled corticosteroids appears to improve clinical symptoms in asthma. Whether a first treatment initiated in the year following the recognition of asthma can prevent major outcomes such as admission to hospital has yet to be studied., Methods: A case-control study nested within a cohort of 13,563 newly treated asthmatic subjects selected from the databases of Saskatchewan Health (1977-1993) was undertaken to investigate the effectiveness of a first treatment with inhaled corticosteroids in preventing admissions to hospital for asthma. Study subjects were aged between five and 44 years at cohort entry. First time users of inhaled corticosteroids were compared with first time users of theophylline for a maximum of 12 months of treatment. The two treatments under study were further classified into initial and subsequent therapy to minimize selection bias and confounding by indication. Odds ratios associated with hospital admissions for asthma were estimated using conditional logistic regression. Markers of asthma severity, as well as age and sex, were considered as potential confounders., Results: Three hundred and three patients admitted to hospital with asthma were identified and 2636 matched controls were selected. subjects initially treated with regular inhaled corticosteroids were 40% less likely to be admitted to hospital for asthma than regular users of theophylline (odds ratio 0.6; 95% CI 0.4 to 1.0). The odds ratio decreased to 0.2 (95% CI 0.1 to 0.5) when inhaled corticosteroids and theophylline were given subsequently., Conclusion: The first regular treatment with inhaled corticosteroids initiated in the year following the recognition of asthma can reduce the risk of admission to hospital for asthma by up to 80% compared with regular treatment with theophylline. This is probably due, at least in part, to reducing the likelihood of a worsening in the severity of asthma.

Objective: To determine whether exposure to allopurinol is associated with an increased risk of cataract extraction in elderly patients., Methods: We conducted a case-control study using data from the Quebec universal health insurance program for all elderly patients. The 3677 cases were patients with a cataract extraction between 1992 and 1994. The 21,868 controls were randomly selected among patients not diagnosed with cataract and matched to cases on the date of the extraction. We determined the odds ratio of cataract extraction according to the cumulative dose and duration of allopurinol use relative to nonusers, using conditional logistic regression analysis. The analysis was adjusted for the effects of age, sex, diabetes mellitus, hypertension, glaucoma, and ophthalmic and oral corticosteroid exposure., Results: A cumulative dose of allopurinol of more than 400 g or a duration of use of longer than 3 years were associated with an increased risk of cataract extraction, with odds ratios of 1.82 (95% confidence interval [CI], 1.18-2.80) and 1.53 (95% CI, 1.12-2.08), respectively. No increase in risk was observed for lower cumulative doses or shorter exposure periods., Conclusion: Long-term administration of allopurinol increases the risk of cataract extraction in elderly patients.

Purpose: Calcium channel blockers have been reported to increase the risk of gastrointestinal bleeding. We tested this hypothesis, and also assessed whether beta blockers decrease this risk., Subjects and Methods: A nested case-control design within a population-based cohort of all 34,074 new users of beta blockers, angiotensin-converting enzyme (ACE) inhibitors, or calcium channel blockers in Saskatchewan, from 1990 to 1993 and followed up to March 1995, was used. We identified all 311 subjects hospitalized because of gastrointestinal bleeding during this period, each of whom was matched to 10 randomly selected controls., Results: The rate of hospitalization for gastrointestinal bleeding was 3.0 per 1,000 per year. The adjusted rate ratio of gastrointestinal bleeding for current use of calcium channel blockers was 1.1 (95% confidence interval [CI] 0.8 to 1.4) and 0.66 (95% CI 0.44 to 0.98) for beta blockers compared with no current use of anti-hypertensive drugs. The adjusted rate ratio for ACE inhibitor use was 1.0 (95% CI 0.7 to 1.3) while that for diuretic use was 1.4 (95% CI 1.0 to 2.0)., Conclusions: The use of calcium channel blockers does not appear to increase the risk of gastrointestinal bleeding in the first five years of treatment, while beta blockers may prevent this adverse event. The unexpected elevated risk associated with the use of diuretics needs to be investigated further.

Context: The use of systemic corticosteroids is a known risk factor for the development of cataracts., Objective: To determine whether treatment with inhaled corticosteroids is associated with cataract extraction in the elderly., Design: Case-control study., Setting: Quebec universal health insurance program for all elderly (provincial health insurance plan database [RAMQ database])., Patients: RAMQ enrollees 70 years and older. The 3677 cases were patients with a cataract extraction between 1992 and 1994. The 21868 controls were randomly selected from patients who did not have a diagnosis of cataract and matched to cases on the index date of the case., Main Outcome Measures: Odds ratio of cataract extraction in patients with prolonged cumulative exposure to inhaled corticosteroids compared with nonusers., Results: Excluding patients with systemic steroid treatment and after adjusting for age, sex, diabetes, systemic hypertension, glaucoma, ophthalmic steroids, and the number of physician claims for services, use of inhaled corticosteroids for more than 3 years was associated with undergoing cataract extraction (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.53-6.13). For high average daily doses of beclomethasone or budesonide (>1 mg), the OR was elevated after more than 2 years of treatment (OR, 3.40; 95% CI, 1.49-7.76), whereas for low to medium doses (< or =1 mg) of these drugs, the OR was 1.63 (95% CI, 0.85-3.13) after 2 years., Conclusion: Prolonged administration of high doses of inhaled corticosteroids increases the likelihood of undergoing cataract extraction in elderly patients. Further studies are needed to investigate the risk of developing cataracts for low to medium doses over longer periods.

Despite the proven efficacy of inhaled corticosteroids in reducing airway inflammation and their increasing use for the treatment of asthma since the mid 1980s, hospitalization for asthma has been increasing in frequency in several countries. Only few studies, reporting contradictory results, have investigated the role of inhaled corticosteroids in the prevention of hospitalizations for asthma. Using a cohort of 2,059 hospitalized asthmatic patients between 5 and 54 yr of age, we estimated the effectiveness of inhaled corticosteroids in preventing a readmission to hospital for asthma as a function of the duration of therapy. The cohort was selected from the databases of Saskatchewan Health from 1977 to 1993. The rate ratio (RR) of a readmission for asthma varied with duration of regular therapy with inhaled corticosteroids. During the first 15 d of regular therapy, users of inhaled corticosteroids were as likely as nonusers of these medications to be readmitted for asthma with a RR of 1.2 (95% CI: 0.8-1.8). Subjects treated regularly with inhaled corticosteroids for at least 16 d and as long as 6 mo were 40% less likely to be readmitted for asthma (RR = 0.6; 95% CI: 0.4-0.9), while after 6 mo of regular treatment the protective effect disappeared (RR = 1.3; 95% CI: 0.7-2.4). We conclude that regular therapy with inhaled corticosteroids can substantially reduce the risk of a readmission for asthma after only 15 d of use. Confounding by severity appears as the most likely explanation for the disappearance of the beneficial effect after 6 mo of regular therapy.

The case-time-control design is a strategy that was developed to tackle the problem of confounding by indication in the nonexperimental assessment of intended or known effects of drugs. By using subjects as their own controls, the case-time-control design, under an explicitly defined model, eliminates the biasing effect of unmeasured confounding factors in the situation where exposure varies over time. The correct application of this design is based on a specific model that contains inherent assumptions and imposes certain conditions for the approach to be valid. In a recent article, Greenland questioned the validity of the case-time-control design by presenting several "counterexamples." In this paper, we review the assumptions inherent to the validity of the case-time-control model. We show that the presumed counterexamples are not what they are claimed to be, simply because they do not conform to the logistic model explicitly underlying the case-time-control approach. These examples are shown to arise from an alternative model that includes a confounder by period interaction, a term expressly avoided in the case-time-control model. When the data from these examples are modified to satisfy the correct model, the resulting case-time-control estimates of the treatment odds ratio are exactly 2, the true treatment effect. We clarify the necessity of this assumption in the context of matching in epidemiology. We also discuss briefly the assumptions of conditional independence and carryover effects.

Whiplash injury, common after a motor vehicle crash, has a variable prognosis that is difficult to predict. To assess the role of various factors on this prognosis, we assembled a historical cohort of 3014 individuals who sustained a whiplash injury resulting from a motor vehicle crash in the Province of Quebec, Canada, in 1987 and were followed for 6 years. The data were obtained from the computerized databases created by the province's universal automobile insurance plan and police accident reports. The recovery time from whiplash, as measured by duration of compensation, was the primary outcome. Socio-demographic and crash-related factors measured at the time of the crash were investigated. The median recovery time for the cohort was 31 days, with 22% recovering within a week and 3% still not recovered after 1 year. For the 1551 subjects with a whiplash injury only, the socio-demographic factors that were found to be independently associated with a slower recovery from whiplash in this cohort are female gender, older age, having dependents, and not having full-time employment. The significant crash-related factors are occupancy in a truck or bus, being a passenger in the vehicle, colliding with a moving object, and being in a head-on or perpendicular collision. We classified the subjects according to a prediction score ranging from 0 to 11, devised from these factors. Subjects with a score of 0 to 2, that is those who had at most two risk factors present, had the fastest median recovery time of 19 days compared with 71 days for subjects who had a score of 6 or more. We conclude that several sociodemographic and crash-related factors are independently associated with a slow and costly recovery from whiplash injury. They are easily measurable at the time of the crash and combined so as to be simply incorporated in intervention programs aimed at early identification and management of whiplash patients with a poor prognosis.

In case-control studies conducted using computerized databases, controls are often selected as a random sample from the base population. This representative choice of controls is intended to guard against selection bias. We show, using data from a database case-control study, that such a definition of controls may also lead to selection bias under two conditions: (1) if the target disease has a prolonged asymptomatic clinical course with its detection depending on a specific physical examination and (2) if exposed patients have a higher likelihood of having the disease detected than unexposed patients. The extent of the bias that could result from the use of randomly selected controls was investigated in the context of a case-control study of the risk of ocular hypertension or glaucoma associated with the use of glucocorticoids, conducted using the Quebec universal health insurance computerized databases. This article also illustrates that a computerized database can be useful to empirically explore opportunities for bias.

The nested case-control design, used to sample within cohorts, is usually employed for internal comparisons. We propose to use this design for external comparisons. We present two probability-weighted estimators of the expected number of cases under a given exposure, based on external rates, for two versions of the nested case-control design. These estimators are used, along with their variance estimators, to form confidence intervals for standardized mortality ratios. The estimators are practically unbiased, whereas the naive estimator that treats the nested case-control sample as a random sample of the cohort is clearly biased. An estimator from the alternative Cox model-based approach is found to be substantially biased when applied in this context. Comparing the proposed estimators for nested case-control designs to a corresponding estimator for the case-cohort design, we found that the correlation between follow-up time and exposure time (that is, the amount of time under the exposure effect) has an impact on which type of design is more efficient for external comparisons. A small correlation favors the case-cohort design and a large correlation the nested case-control design. We examine empirical properties of these estimators through computer simulations, using a cohort study of the incidence of second cancer in 2,189 patients with Hodgkin's disease.

Study Design: Population-based randomized clinical trial., Objectives: To develop and test a model of management of subacute back pain, to prevent prolonged disability., Summary of Background Data: The present management of back pain seems inadequate, and development of innovative models has been urged., Methods: A model for the treatment of subacute work-related back pain has been developed and evaluated in a population-based randomized clinical trial. Workers (n = 130) from eligible workplaces in the Sherbrooke area (N = 31), who had been absent from work for more than 4 weeks for back pain, were randomized, based on their workplace, in one of four treatment groups: usual care, clinical intervention, occupational intervention, and full intervention (a combination of the last two). The duration of absence from regular work and from any work was evaluated using survival analysis. Functional status and pain were compared at study entry and after 1 year of follow-up., Results: The full intervention group returned to regular work 2.41 times faster than the usual care intervention group (95% confidence interval 1.19-4.89; P < 0.01). The specific effect of the occupational intervention accounted for the most important part of this result, with a rate ratio of return to regular work of 1.91 (95% confidence interval = 1.18-3.10; P < 0.01). Pain and disability scales demonstrated either a statistically significant reduction or a trend toward reduction in the three intervention groups, compared with the trend in the usual care intervention group., Conclusions: Close association of occupational intervention with clinical care is of primary importance in impeding progression toward chronicity of low back pain.

Background: Ocular hypertension and open-angle glaucoma are well-known side-effects of treatment with topical ophthalmic glucocorticoids. There is uncertainty about the risk of these disorders with oral glucocorticoid therapy., Methods: Data from the Quebec universal health insurance programme for the elderly were used to identify 9793 patients with a new diagnosis of ocular hypertension or open-angle glaucoma, or on newly prescribed treatment for these disorders (cases). 38,325 controls were randomly selected from ophthalmology patients seen in the same month and year as the case (index date). Current use of oral glucocorticoids was defined as that within 14 days of the index date. All glucocorticoid doses were converted to the equivalent amount of hydrocortisone. The case-control analysis was done by conditional logistic regression and adjusted for age, sex, systemic hypertension, diabetes mellitus, ophthalmic glucocorticoids, glucocorticoid injections, and variables related to general health., Findings: The mean ages of cases and controls were similar (74.9 [SD 6.3] vs 74.7 [6.4]). The adjusted odds ratio of ocular hypertension or open-angle glaucoma for current users of oral glucocorticoids compared with non-users was 1.41 (95% CI 1.22-1.63). There was a dose-related increase in the adjusted odds ratios for current users: 1.26 (1.01-1.56) for less than 40 mg per day of hydrocortisone, 1.37 (1.06-1.76) for patients on 40-79 mg per day, and 1.88 (1.40-2.53) for patients on 80 mg or more per day. The odds ratios also increased with the duration of treatment over the first 11 months of exposure., Interpretation: The use of oral glucocorticoids increases the risk of ocular hypertension or open-angle glaucoma in elderly patients. In patients in this age-group who need long-term treatment with high doses of oral glucocorticoids, monitoring of intraocular pressure may be justified.

The abundance of health-related statistics routinely collected worldwide invites their misuse from haphazard associations between secular trends of these data. This misuse is often compounded by assessing these associations simply on the basis of a visual inspection of the data. The visual approach to data analysis, known to have several pitfalls, is particularly tempting in the context of asthma where it has often been used. For example, the epidemic of asthma deaths that occurred in New Zealand during the last two decades has been imputed to fenoterol, a medication for asthma, on the basis of a visual assessment of ecological data. The simultaneity of time trends in the asthma death rate and fenoterol market share in that country formed an important part of the statistical basis of the evidence. We verified whether the results of such visual analyses are corroborated by more objective quantitative statistical methods of analysis. We reanalyzed these same data, namely the time trend data of New Zealand asthma death rates, fenoterol market share, sales of beta-agonists and inhaled corticosteroids, measured yearly for the 16-year span 1976-1991, using Poisson weighted loglinear regression. We found that the protective effect of inhaled corticosteroids (rate ratio 0.5 per canister per month; 95% confidence interval 0.4 to 0.7; p = 0.0001) was more closely associated with changes in asthma mortality than either fenoterol (RR 2.7 per canister per month; 95% CI: 0.9 to 7.5; p = 0.06) or all beta-agonists combined (RR 1.6; 95% CI: 0.8 to 3.0; p = .19). We conclude from this quantitative analysis that these ecological asthma mortality data provide evidence of a stronger association with inhaled corticosteroids, little used in New Zealand at the onset of the epidemic but used abundantly at its termination, than with fenoterol. This conclusion is diametrically opposite to that found by the visual approach. The quantitative analysis demonstrates that the visual approach to the analysis of ecological data, although seemingly convincing, can be misleading by creating an optical illusion. This purely visual approach to data analysis may thus have serious implications when the resulting scientific information is used to make vital public health and policy decisions.

Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third generation oral contraceptives than with second generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of oral contraceptive use particularly among first-time users, are inconsistent. We reanalyzed data from the Transnational case-control study to assess the risk of VTE associated with first-time use of oral contraceptives as a function of its duration of use. Over the period 1993 to 1995, 471 cases of venous thromboembolism were identified in Germany and the United Kingdom. For each case, up to four controls were obtained, for a total of 1772 controls. Data on oral contraceptive use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second or third generation agents, or never users of oral contraception. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of oral contraceptive use by logistic regression and quadratic spline models. We found, for first-time users, that the adjusted rate ratio of VTE as a function of the duration of oral contraceptive use is essentially identical for second and third generation pills relative to never users. This rate ratio increases to around 10 in the first year of use and decreases to around two after 2 years of use, remaining at this risk level thereafter for both second and third generation agents. We conclude that second and third generation agents are associated with identical risks of venous thromboembolism when they are prescribed to women who are using oral contraceptives for the first time ever.

Context: Benzodiazepines, used by a sizable number of the elderly population, may affect the ability to drive and thus increase the risk of a motor vehicle crash. Epidemiologic studies of this question have produced inconsistent results that may be due to the different effects of long- and short-half-life benzodiazepines and variations in their duration of use., Objective: To determine whether the use of benzodiazepines of either long- or short-elimination half-life is associated with the risk of injurious motor vehicle crash in the elderly., Design and Setting: Nested case-control design within a cohort of 224,734 drivers from the Canadian province of Quebec, aged 67 to 84 years, followed up from 1990 to 1993. Computerized data for the study were obtained from provincial driver's license files, police reports of injurious crashes, and health insurance records., Patients: We identified all 5579 drivers involved in an injurious crash (cases) and a random sample of 10 controls per case selected from a subcohort of 13,256 subjects., Main Outcome: Involvement of a cohort member as a driver in a motor vehicle crash in which at least 1 person (not necessarily the driver) sustained bodily injury., Results: The adjusted rate ratio of crash involvement within the first week of long-half-life benzodiazepine use was 1.45 (95% confidence interval [CI], 1.04-2.03). The rate ratio for continuous use of longer duration up to 1 year was slightly lower but remained significant (rate ratio, 1.26; 95% CI, 1.09-1.45). In contrast, there was no increased risk after the initiation of treatment with short-half-life benzodiazepines (rate ratio, 1.04; 95% CI, 0.81-1.34) or with their continued use (rate ratio, 0.91; 95% CI, 0.82-1.01)., Conclusions: Brief or extended periods of exposure to long-half-life benzodiazepines are associated with an increased risk of motor vehicle crash involvement in the elderly population. There is no such elevated risk for short-half-life benzodiazepines.

Nonexperimental studies using computerized databases often give rise to missing or partially available information on confounders. A frequent situation occurs when data on exposure are available for all subjects of a case-control study, but data on confounders are available only for the cases but not for the controls. In that situation, the fact of confounding can be verified by assessing the association between exposure and a confounder in the cases, but the data are insufficient to produce an adjusted estimate of the relative risk if confounding is found to be present. We propose simple conditions under which an adjusted estimate of the relative risk can be obtained when data on a confounder are available only for the cases, and we derive formulae for the estimator and its confidence limits. The method requires an external estimate of the confounder prevalence or, additionally, of the confounder-exposure odds ratio. We illustrate the technique with data from a nested case-control study of the risk of acute cardiac death associated with the use of bronchodilator drugs within a cohort of 12,301 asthmatics, with smoking as the confounder of interest.

Objective: To determine whether the use of inhaled and nasal glucocorticoids is associated with an increased risk of ocular hypertension or open-angle glaucoma., Design: Case-control study., Setting: Québec universal health insurance program for all elderly (registered in the Régie de l'assurance maladie du Québec [RAMQ] database)., Patients: Enrollees in the RAMQ database aged 66 years and older. The 9793 case patients were ophthalmology patients with a new diagnosis of borderline glaucoma or open-angle glaucoma or were newly started on treatment for ocular hypertension or glaucoma between 1988 and 1994. The 38,325 control patients were randomly selected among noncases with ophthalmologist visits in the same month and year as the case event (index date)., Main Outcome Measures: The odds ratio (OR) of ocular hypertension or open-angle glaucoma was determined in patients using inhaled or nasal glucocorticoids relative to nonusers, using conditional logistic regression analysis. The OR was adjusted for age, sex, diabetes mellitus, systemic hypertension, use of ophthalmic and oral glucocorticoids, and characteristics of health care system use in the year before the index date., Results: Overall, current use of inhaled and nasal glucocorticoids was not associated with an increased risk of ocular hypertension or open-angle glaucoma. Current users of high doses of inhaled steroids prescribed regularly for 3 or more months were at an increased risk with an OR of 1.44 (95% confidence interval, 1.01-2.06)., Conclusion: Prolonged administration of high doses of inhaled glucocorticoids increases the risk of ocular hypertension or open-angle glaucoma. This finding suggests that in these patients intraocular pressure monitoring may be warranted.

Background: The increasing costs of managing asthma are due in part to the introduction of new medications, such as leukotriene receptor antagonists. These antagonists interfere with the action of leukotrienes, which are implicated in bronchoconstriction and the formation of airway edema in patients with asthma. Leukotriene receptor antagonists must be shown to be clinically and economically effective for their clinical use to be justified., Objective: To assess the clinical and economic effectiveness of zafirlukast, a leukotriene receptor antagonist, in patients with mild-to-moderate asthma who might benefit from regular anti-inflammatory therapy., Design: Randomized, double-blind, multicenter, placebo-controlled trial., Setting: 28 outpatient clinics., Patients: 146 patients with mild-to-moderate asthma who were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, had an FEV1 at least 55% of the predicted value with no upper limit, had demonstrated bronchial hyperresponsiveness, and were symptomatic during the 7-day run-in period. All patients were seen every 2 to 3 weeks for 13 weeks., Intervention: 103 patients received zafirlukast (20 mg twice daily), and 43 patients received placebo (twice daily). All patients received inhaled beta-agonists as needed., Measurements: Data were obtained from medical examinations, patient questionnaires, and daily diaries. The clinical effectiveness outcomes were days per month without asthma symptoms, limitation of activity, use of beta-agonists, sleep disturbance, and episodes of asthma (the latter was a composite measure made up of the first four outcomes plus the occurrence of adverse events). The economic effectiveness outcomes were frequency and type of unscheduled health care contacts, use of beta-agonist inhalers, consumption of nonasthma medications, and days of absence from work or school., Results: The zafirlukast group had 89% more days without symptoms (adjusted rates, 7.0 compared with 3.7 days per month; P = 0.03), 89% more days without use of beta-agonists (adjusted rates, 11.3 compared with 6.0 days per month; P = 0.001), and 98% more days without episodes of asthma (adjusted rates, 10.1 compared with 5.1 days per month; P = 0.003). They also had 55% (95% CI, 19% to 74%) fewer health care contacts (18.5 compared with 40.7 per 100 per month; P = 0.007) and 55% (CI, 3% to 79%) fewer days of absence from work or school (15.6 compared with 35.0 per 100 per month; P = 0.04). They used 17% fewer canisters of inhaled beta-agonists (P = 0.17) and 19% less nonasthma medication (P < 0.2)., Conclusions: A daily regimen of zafirlukast added to as-needed inhaled beta-agonists is more effective than beta-agonists alone in treating mild-to-moderate asthma. The clinical and economic effectiveness of zafirlukast, a potential alternative to inhaled corticosteroids, provides further impetus to use regular "preventive" therapy in patients with mild-to-moderate asthma.

A previously published nested case-control study, the Saskatchewan Asthma Epidemiologic Project (SAEP) spanning 1980-1987, investigated the risk of fatal or near fatal asthma and found different risks for two inhaled beta 2-agonists, fenoterol and salbutamol. The authors assessed whether this comparison was confounded by indication because of channeling of inhaled fenoterol to more severely afflicted asthmatics. Using three subcohorts selected from a cohort of 12,301 asthmatics assembled from the computerized databases of Saskatchewan Health and followed over 7 years, the authors studied two forms of channeling and investigated whether greater asthma severity and less well-controlled disease were associated with preferential prescribing of a first prescription of inhaled fenoterol, as opposed to inhaled salbutamol, and whether they were associated with the likelihood of a switch from inhaled salbutamol to fenoterol as well as a switch from inhaled fenoterol to salbutamol. The authors found that the initial choice between fenoterol and salbutamol was independent of the severity of the asthma and disease control, but that preferential prescribing of fenoterol occurred among users of salbutamol who showed signs of increased severity or uncontrolled asthma. The switch from inhaled fenoterol to salbutamol was, however, minimally related to asthma severity. They conclude that the comparison between inhaled fenoterol and salbutamol in the SAEP may have been biased by indication. This study demonstrates that long-term information on medication use is essential to ensure that the results of such case-control studies are not biased by indication.

Bronchodilators used in the treatment of airway disease have been shown to have a variety of cardiac effects that may contribute to the occurrence of life-threatening events such as cardiac arrhythmias and cardiac arrest. We investigated whether theophylline and beta-agonists were associated with cardiovascular mortality among a cohort of subjects prescribed antiasthma medications. We used a population-based cohort of 12,301 subjects aged 5 to 54 yr, formed from health-insurance data bases from Saskatchewan, Canada, and spanning the period 1978 to 1987. Within this cohort, we identified all 30 deaths from cardiovascular causes in which acute asthma did not appear to be a contributing factor. We identified all asthma and cardiovascular drugs dispensed to these subjects shortly before their deaths and compared this therapy to that dispensed to a random sample of 4,080 person-time controls. After adjustment for age and the prior use of cardiac drugs, the rate of cardiovascular death was greater in users of theophylline, with a rate ratio (RR) of 2.7 (95% Cl:1.2 to 6.1), and in users of beta-agonists taken orally or by nebulizer (RR = 2.4; 95% Cl:1.0 to 5.4), but not in users of beta-agonists administered by metered-dose inhaler (RR = 1.2; 95% Cl:0.5 to 2.7). The great majority of cardiovascular deaths occurred among subjects with clinical or pathologic evidence of potentially lethal conditions. These results suggest that the use of theophylline and of beta-agonists administered orally or by nebulization should be avoided in subjects with significant cardiac disease or at high risk for such disease, especially acute coronary insufficiency and congestive cardiomyopathy. On the other hand, the use of beta-agonists administered by metered-dose inhalers (MDIs) was not associated with an increased risk of cardiovascular death.

Objective: To assess the efficacy of a back school program for patients with a first episode of acute work-related low back pain requiring compensation., Design: A randomized single-blind controlled trial., Setting: A private physiatrics outpatient clinic., Patients: The mean duration of low back pain was 15 days., Intervention: Eligible patients were randomized to a standard treatment program that included daily physiotherapy (n = 86) or the same program with the addition of back school (n = 82). The back school program consisted of three 90-minute sessions given by a single trained instructor at 0, 1, and 8 weeks., Main Outcome Measures: The primary outcomes were the time off work for the presenting episode of back pain and the number and duration of recurrences in the year following the study onset. Secondary outcomes included the level of pain, spinal mobility, active straight-leg raising, and functional disability assessed by the Oswestry and Roland-Morris scales., Results: Those randomized to the back school group gained significantly more knowledge, based on the multiple choice examination (p = .0001) and performed the exercise program significantly better (p = .0001) than the standard care group. There were no differences between the two treatment groups for either of the primary outcomes. The median time to return to work from randomization was 33 days for both the back school and the standard care groups (p = .48). The number of compensated recurrences of low back pain over 1 year was similar (back school = 14, standard care = 10, p = .16), as was the median duration of these episodes (back school = 25 days, standard care = 70 days, p = .21). There were no significant differences favoring the back school group for any of the secondary outcomes at the posttreatment, 6-month, or 12-month assessments., Conclusion: A back school intervention in addition to standard care resulted in no reduction in the time to return to work or the number or duration of recurrences of low back pain requiring compensation over a period of one year.

Objective: To assess the potentially increased risk of death or near death from asthma in asthmatic patients with psychosis., Design: Case-control study., Setting: The computerised health databases of the Canadian province of Saskatchewan., Subjects: 131 cases of death or near death from asthma identified within a cohort of asthmatic patients; 3930 matched non-cases. EXPOSURE AND OUTCOME MEASURES: The exposure of interest was the use of major tranquillisers in the period before an outcome event. Outcomes included death or near death from asthma., Results: Crude analyses showed that asthmatic patients who had used major tranquillisers in the previous 12 months were at a 3.2 (95% confidence interval 1.4 to 7.5) times greater risk of death or near death from asthma than asthmatic patients who did not use major tranquillisers. Past users of major tranquillisers who had recently discontinued use were at a particularly high risk (relative risk 6.6; 2.5 to 17.6). Adjustment for use of antiasthma drugs and other confounders abolished this excess risk., Conclusions: Asthmatic patients who use major tranquillisers seem to be at an increased risk of death or near death from asthma. Physicians treating asthmatic patients with a history of use of major tranquillisers should exercise greater caution with regard to management of such patients.

Objective: To quantify the effectiveness of home visiting programmes in the prevention of child injury and child abuse., Design: Systematic review of 11 randomised controlled trials of home visiting programmes. Pooled odds ratios were estimated as an inverse variance weighted average of the study specific odds ratios., Setting: Randomised trials that were available by April 1995., Subjects: The trials comprised 3433 participants., Results: Eight trials examined the effectiveness of home visiting in the prevention of childhood injury. The pooled odds ratio for the eight trials was 0.74 (95% confidence interval 0.60 to 0.92). Four studies examined the effect of home visiting on injury in the first year of life. The pooled odds ratio was 0.98 (0.62 to 1.53). Nine trials examined the effect of home visiting on the occurrence of suspected abuse, reported abuse, or out of home placement for child abuse. Because of the potential for bias in outcome reporting in these studies, pooled effect estimates were not calculated., Conclusions: Home visiting programmes have the potential to reduce significantly the rates of childhood injury. The problem of differential surveillance for child abuse between intervention and control groups precludes the use of reported abuse as a valid outcome measure in controlled trials of home visiting.

This study was designed to estimate the role of passive smoking in the occurrence of repeated acute otitis media among pre-school children. The parents of 918 children, who were part of a birth cohort, were interviewed when the children were four years old. The frequency of episodes of otitis media was determined, as well as the age at which the first such episode occurred. Information about smoking in the home had been obtained when the child was two weeks old and again at 6, 12, 18 and 40 months of age. In all, 119 mothers (13%) smoked at least 20 cigarettes a day on average, 205 (22%) smoked less than 20, and 593 (65%) stated that they did not smoke at all. Children of mothers who smoked 20 or more cigarettes per day were at significantly increased risk of having four or more episodes of acute otitis media: relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.1-3.0 and of having their first episode earlier in life RR = 1.3 (CI = 1.0-1.8), after adjustment. Moreover, the risk of recurrent (> or = four episodes) otitis media increases with the amount of cigarettes smoked. These findings clearly strengthen the case for persuading parents not to smoke in the presence of young children.

Assessing the known or intended effects of a drug using non-experimental epidemiologic designs is often infeasible because of the absence of accurate data on a major confounder, the severity of the disease treated by this drug. To circumvent this problem of confounding by indication, I propose the case-time-control design, which does not require a measure of this confounder. Instead, the design uses subjects from a conventional case-control design as their own controls and thus requires that exposure be measurable at two or more points in time. I present a logistic model to estimate relative risks under this design and illustrate the method with data from a case-control study of 129 cases of fatal or near-fatal asthma and 655 controls. The exposure of interest was quantity of use of inhaled beta-agonists, drugs prescribed for the treatment of asthma. I found that the "best" estimate of relative risk for high vs low beta-agonist use using the conventional case-control approach is 3.1 [95% confidence interval (CI) = 1.8-5.4], which inherently includes the confounding effect of unmeasured severity. The corresponding estimate of drug effect using the proposed case-time-control approach is 1.2 (95% CI = 0.5-3.0), which excludes the confounding effect of unmeasured severity. This example indicates that the class of beta-agonists may not play the leading role attributed to it in the risk of fatal or near-fatal asthma, as had been previously suspected, except perhaps at excessive doses, as indicated by the dose-response analyses.

Clinical research often involves continuous outcome measures, such as blood cholesterol, that are amenable to statistical techniques of analysis based on the mean, such as the t-test or multiple linear regression. Clinical interest, however, frequently focuses on the proportion of subjects who fall below or above a clinically relevant cut-off value, as a measure of the risk of disease. The customary approach to analyse such data is to dichotomize the continuous outcome measure and use statistical techniques based on binary data and the binomial distribution. In this paper, we use a parametric approach and the framework of generalized linear models to fit various regression models, including the logistic, on the basis of the original continuous outcome. We consider the Gaussian and the three-parameter log-normal distributions for the continuous outcome, assessing both precision and bias under various conditions. In simulation analyses, we find that we are unable to fit some of the samples with the 'dichotomous' approach, but we can with the 'continuous' approach, and that the latter yields estimates between 25 and 85 per cent more efficient than the former. We illustrate the method, programmed using GLIM macros, with data from clinical studies of the risk of hypoxaemia during open thoracic surgery and the risk of nocturnal hypoglycaemia among diabetic children.

The association between the use of inhaled beta-agonists by metered-dose inhaler and the risk of fatal or near-fatal asthma has been demonstrated. It shows that asthmatics who use one canister of beta-agonist per month more than the number used by other similar asthmatics have twice the risk of fatal or near-fatal asthma. The present investigation assesses the magnitude of this excess risk when an asthmatic increases his/her own monthly use of inhaled beta-agonists over time. From a previous nested case-control study of 129 deaths and near-deaths from asthma (cases) and 655 controls from a cohort of 12,301 asthmatics, the subset using at least 12 inhalers during the 12 month study period was identified (97 cases and 258 controls). A profile score, ranging 0-11, was formed to quantify the patterns of beta-agonist use over time for each subject, covering the entire spectrum extending from decreasing to increasing use. The relative risk was 15.2 (95% confidence interval (CI) 2.4-96.2) per unit increase of the profile score in subjects with a pattern of increasing beta-agonist use (profile score of 6.5 or more), but this relative risk was only 1.5 (95% CI 0.8-2.6) per unit when the profile score was less than 6.5 (non-increasing use). This relative risk was independent of the risk associated with the total quantity of beta-agonist use in the 12 month period, which remained around 1.6 (95% CI 1.3-2.0) per inhaler per month.(ABSTRACT TRUNCATED AT 250 WORDS)