上海市大气污染与居民每日死亡关系的病例交叉研究

目的 以病例交叉的研究方法，估计大气污染急性暴露对上海市居民每日死亡的影响，并探讨该设计用于大气污染急性健康效应研究的可行性。方法 采用病例交叉设计的方法分析上海市2000年6月1日至2001年12月31日大气污染与居民每日总死亡和分疾病别死亡的关系，同时比较双向对照设计和单向回顾性对照设计研究结果的差异。结果 采用不同的对照选择方案，病例交叉设计的研究结果变化较大；采用双向1：6的对照设计，大气可吸入颗粒物(PMl0)、二氧化硫(SO2)、二氧化氮(NO2)48h平均浓度每增加10μg／m^3，上海市城区居民总死亡发生的相对危险度分别为1．003(95％CI：1．001～1．005)、1．016(95％CI：1．011～1．021)、1．020(95％CI：1．012～1．027)。结论 上海市城区目前的PMl0、SO2、NO2水平对居民死亡确有影响；病例交叉设计是一种研究大气污染急性健康效应的有效工具。     

大气污染物与呼吸系统疾病急诊就诊关系的病例交叉研究

目的 分析大气污染急性暴露对呼吸系统疾病急诊人次的影响.方法 收集2004年1月1日至2005年12月31日北京大学第三医院急诊科呼吸系统疾病急诊资料和北京市环境监测中心大气污染物数据,应用时间分层的病例交叉设计研究方法进行数据分析,同时比较单向回顾性对照设计和双向对照设计研究结果的差异.结果 在调整气象因素并采用单向回顾性(多污染物)模型中,无滞后大气可吸入颗粒物(PM10)、二氧化硫(SO2)、滞后2 d二氧化氮(NO2)日平均浓度每增加10 μg/m3,呼吸系统疾病总急诊的OR值(95%CI)分别为1.010(1.005～1.014)、1.010(1.001～1.018)、0.996(0.983～1.009);双向对称性(多污染物)模型中,其相应OR值(95%CI)分别为1.002(0.998～1.005)、1.011(1.003～1.018)、1.012(1.001～1.022).采用不同对照选择方案,病例交叉设计的研究结果有变化.结论 区域内大气污染物暴露对居民呼吸系统疾病急诊人次有急性效应.     

Effects of air pollution on postneonatal infant mortality among firstborn infants in Seoul, Korea: case-crossover and time-series analyses

Infants are known to be susceptible to the adverse health effects of ambient air pollution. The authors examined the relationship between air pollution and postneonatal mortality from all causes among firstborn infants in Seoul, Korea, during 1999-2003, using both case-crossover and time-series analyses. Using a bidirectional control-sampling approach, the authors compared the effects of various types of air pollution on postneonatal mortality. The relative risk of postneonatal mortality from all causes was 1.000 (95% confidence interval [CI] = 0.998-1.002) for particulate matter with a diameter <10 mum, 1.002 (95% CI = 0.994-1.009) for nitrogen dioxide, 1.015 (95% CI = 0.973-1.058) for sulfur dioxide, 1.029 (95% CI = 0.833-1.271) for carbon monoxide, and 0.984 (95% CI = 0.977-0.992) for ozone for each 1-unit increase of air pollution level in the 1:6 control selection scheme. The authors observed a positive association between air pollution and infant daily mortality except for the studied particulate matter and ozone, although it was not statistically significant. They obtained similar results in the time-series analysis. The risk of postneonatal infant death from all causes was positively associated with all studied air pollutants except ozone. The authors also confirmed that the bidirectional method with many controls will give a more efficient estimator than will a method with fewer controls.     

Contribution of case-crossover design to the analysis of short-term health effects of air pollution: reanalysis of air pollution and health data

BACKGROUND: During the last decades, numerous studies have shown significant links between short-term exposure to air pollution and health. Time series design have been widely used in order to study these associations. In recent years, the case-crossover design has been applied to the analysis of acute effects of environmental exposures, especially air pollution. The aims of this paper are to describe the case-crossover design and to compare this approach with time series design to assess the association between air pollution and health. METHODS: In the case-crossover approach, a case-control study is conducted whereby each person who had a health event (case period) is matched with himself/herself on a nearby time period where he/she did not have the event (control period). Review of the literature shows that the referent selection strategies can be associated to a bias in the estimation of the health effect of air pollution. In comparison with time series design, the case-crossover design is easier to conduct, and individual factors can be taken into account. Nevertheless, it is not possible to take into account the overdispersion in the health indicator with this approach. RESULTS AND CONCLUSION: In conclusion, we suggest to use time series analysis with population data and case-crossover design with individual data.     

Extreme air pollution events from bushfires and dust storms and their association with mortality in Sydney, Australia 1994-2007

Introduction

Extreme air pollution events due to bushfire smoke and dust storms are expected to increase as a consequence of climate change, yet little has been published about their population health impacts. We examined the association between air pollution events and mortality in Sydney from 1997 to 2004.

Methods

Events were defined as days for which the 24 h city-wide concentration of PM₁₀ exceeded the 99th percentile. All events were researched and categorised as being caused by either smoke or dust. We used a time-stratified case-crossover design with conditional logistic regression modelling adjusted for influenza epidemics, same day and lagged temperature and humidity. Reported odds ratios (OR) and 95% confidence intervals are for mortality on event days compared with non-event days. The contribution of elevated average temperatures to mortality during smoke events was explored.

Results

There were 52 event days, 48 attributable to bushfire smoke, six to dust and two affected by both. Smoke events were associated with a 5% increase in non-accidental mortality at a lag of 1 day OR (95% confidence interval (CI)) 1.05 (95%CI: 1.00–1.10). When same day temperature was removed from the model, additional same day associations were observed with non-accidental mortality OR 1.05 (95%CI: 1.00–1.09), and with cardiovascular mortality OR (95%CI) 1.10 (95%CI: 1.00–1.20). Dust events were associated with a 15% increase in non-accidental mortality at a lag of 3 days, OR (95%CI) 1.16 (95%CI: 1.03–1.30).

Conclusions

The magnitude and temporal patterns of association with mortality were different for smoke and dust events. Public health advisories during bushfire smoke pollution episodes should include advice about hot weather in addition to air pollution.     

Reanalysis of the effects of air pollution on daily mortality in Seoul, Korea: A case-crossover design.

We used the case-crossover design to identify any increase in mortality in Seoul, Korea, when there were higher levels of ambient air pollution on case-days than would be expected solely as a result of chance. This empirical study showed that either unidirectional retrospective (selecting only control days prior to death) or prospective (selecting only control days after death) control sampling could cause risk estimates to be confounded by seasonal waves as well as time trends in air pollution levels. In bidirectional control sampling in which exposures at death were compared with exposures both before and after death, the estimated mortality was resistant to confounding by time patterns of air pollution. Using a bidirectional control sampling approach, the results from a conditional logistic regression model controlling for weather conditions showed that the nonaccidental mortality associated with a 50-ppb increment over a 3-day moving average of SO(2) concentrations, including the concurrent day and preceding 2 days, was 1.023 [95% confidence interval (CI), 1.016-1.084]. The relative risk of death was 1.023 (CI, 0.999-1.048) per 50 ppb for 1-hr maximum O(3) and 1.010 (CI, 0.988-1.032) per 100 microg/m(3 )or total suspended particulates. In conclusion, the findings of this study were 2-fold: given the consistency of the observed association between SO(2) and daily mortality across different analysis methods, the association reported here indicates that air pollution is a probable contributor to premature death; and bidirectional control sampling is needed in a case-crossover design applied to air pollution epidemiologic studies to control confounding by seasonal patterns of air pollution as well as time trends.     

Patients with chronic obstructive pulmonary disease are at increased risk of death associated with urban particle air pollution: a case-crossover analysis

The authors assessed the acute association between particulate air pollution and mortality among subjects suffering from chronic obstructive pulmonary disease by using a case-crossover analysis. This design avoided the common concerns about the methods used to assess the acute effects of air pollution. The 1,845 men and the 460 women included were residents of Barcelona, Spain, who were over age 35 years, had died during the period 1990-1995, and had visited emergency rooms because of a chronic obstructive pulmonary disease exacerbation during the period 1985-1989. Particle levels (measured as black smoke at the city monitoring stations) were associated with mortality for all causes (odds ratio (OR) for an increase of 20 microg/m3, the interquartile change, adjusted for temperature, humidity, and influenza = 1.112, 95 percent confidence interval (CI): 1.017, 1.215). The association was stronger for respiratory causes (OR = 1.182, 95 percent CI: 1.025, 1.365), but was not significant for cardiovascular causes (OR = 1.077, 95 percent CI: 0.917, 1.264). Older women, patients admitted to intensive care units, and patients with a higher rate of emergency room visits were at greater risk of dying associated with black smoke. The results reinforced the deleterious role of urban pollution and provided information on factors possibly conferring susceptibility to the acute role of air pollution.     

The association of daily diabetes mortality and outdoor air pollution in Shanghai, China

The objective of the study reported here was to assess the association between air pollution and daily diabetes mortality in Shanghai. Death records were collected for all individuals who lived in the Zhabei district of Shanghai and died from diabetes from January 1, 2001, to December 31, 2002. The authors used a time-series approach to study the acute effects of air pollution on diabetes mortality after controlling for long-term trends, weather variables, and day of the week. Each increase of 10 microg/m3 in PM10, SO2, or NO2 was found to correspond, respectively, to a 1.006 (95 percent CI: 1.000-1.012), 1.011 (95 percent CI: 0.990-1.032), or 1.013 (95 percent CI: 1.000-1.026) relative risk of diabetes mortality in Shanghai. The air pollutants also were observed to have a greater effect on diabetics than on nondiabetics. These findings provide new evidence for the association between air pollution and diabetes mortality risk, and suggest that diabetics are more susceptible to air pollution than are nondiabetics.     

太原市大气污染对妊娠结局的影响

目的探讨大气污染对妊娠结局的影响。方法收集太原市1997—2004年6个国控监测点大气PM10和SO2浓度资料以及同期妊娠结局的资料,对妊娠结局的相关危险因素及不同妊娠时期大气中PM10和SO2浓度对妊娠结局的影响进行分析。结果空气中PM10和SO2浓度每增加100μg/m3与妊娠结局的Logistic回归结果表明,PM10空气污染对早产、出生缺陷和死胎死产有显著影响,早产的OR值为1.17～1.76,最高OR值为1.76(95%CI:1.64～1.90),出现在怀孕前3个月;出生缺陷的OR值为1.37～1.67,最高OR值为1.67(95%CI:1.28～2.17),出现于第3个孕月。关于SO2空气污染,只观察到对早产的显著影响,且发生于第1、2个孕月,相应的OR值分别为1.27(95%CI:1.21～1.34)和1.07(95%CI:1.01～1.14)。结论太原市空气污染已对妊娠结局造成一定影响,应采取严格的空气污染控制措施,降低不良妊娠结局发生率。     

上海市某区居民脑卒中死亡与大气污染关系的时间序列研究

目的　分析大气污染急性暴露对居民每日脑卒中死亡的影响。方法　采用时间序列的半参数广义相加模型 ,在控制死亡的长期趋势、气象因素、“星期几效应”等混杂因素的基础上 ,分析了上海市某区 2 0 0 1年 1月 1日～ 12月 31日大气污染与居民每日脑卒中死亡的关系。结果　大气PM10 ,SO2 和NO2 4 8h平均浓度每增加 10 μg m3 ,居民因脑卒中而死亡的相对危险度分别为 1 0 0 8(95 %CI 1 0 0 0～ 1 0 16 ) ,1 0 17(95 %CI 0 998～ 1 0 36 )和 1 0 2 9(95 %CI1 0 0 1～ 1 0 5 7)。结论　上海市某区目前的PM10 和NO2 水平对居民脑卒中死亡有影响。     

Comparison of four case-crossover study designs to analyze the association between air pollution exposure and acute myocardial infarction

The case-crossover design is frequently used for analyzing the acute health effects of air pollution. Nevertheless, only a few studies compared different methods for selecting control periods. In this study, the bidirectional method and three time-stratified methods were used to estimate the association between air pollution and acute myocardial infarction (AMI) in Charleroi, Belgium, during 1999–2008. The strongest associations between air pollution and AMI were observed for PM₁₀ and NO₂ during the warm period, OR = 1.095 (95?% CI: 1.003–1.169) and OR = 1.120 (95?% CI: 1.001–1.255), respectively. The results of this study reinforce the evidence of the acute effects of air pollution on AMI, especially during the warm season. This study suggests that the different methods of case-crossover study design are suitable to studying the association between acute events and air pollution. The temperature-stratified design is useful to exclude temperature as a potential confounder.     

Temperature and mortality among the elderly in the United States: a comparison of epidemiologic methods

BACKGROUND: Time-series analyses have been used for decades to investigate time-varying environmental exposures. Recently, the case-crossover design has been applied to assess acute effects of air pollution. Our objective was to compare time-series and case-crossover analyses using varying referent periods (ie, unidirectional, ambidirectional, and time-stratified). METHODS: We examined the association between temperature and cardiorespiratory mortality among the elderly population in the 20 largest metropolitan areas of the United States. Risks were estimated by season and geographic region in 1992. We obtained weather data from the National Climatic Data Center and mortality data from the Division of Vital Statistics. Conditional logistic regression (case-crossover) and Poisson regression (time-series) were used to estimate the increased risk of cardiorespiratory mortality associated with a 10 degrees F increase in daily temperature, accounting for dew-point temperature and other potential confounding factors. RESULTS: In the time-stratified case-crossover analysis, the strongest associations were found in the summer; in the Southwest, Southeast, Northwest, Northeast, and Midwest, the odds ratios were 1.15 (95% confidence interval=1.07-1.24), 1.10 (0.96-1.27), 1.08 (0.92-1.26), 1.08 (1.02-1.15), and 1.01 (0.92-1.11), respectively. Mostly null or negative associations were found in the winter, spring, and fall. The ambidirectional case-crossover and the time-series analyses produced quantitatively similar results to those from the time-stratified analysis. The unidirectional analysis produced conflicting results. CONCLUSIONS: Inferences from studies of weather and mortality using the ambidirectional or time-stratified case-crossover approaches and the time-series analyses are comparable and provide consistent findings in this study.     

Case-crossover analyses of air pollution exposure data: referent selection strategies and their implications for bias

The case-crossover design has been widely used to study the association between short-term air pollution exposure and the risk of an acute adverse health event. The design uses cases only; for each individual case, exposure just before the event is compared with exposure at other control (or "referent") times. Time-invariant confounders are controlled by making within-subject comparisons. Even more important in the air pollution setting is that time-varying confounders can also be controlled by design by matching referents to the index time. The referent selection strategy is important for reasons in addition to control of confounding. The case-crossover design makes the implicit assumption that there is no trend in exposure across the referent times. In addition, the statistical method that is used-conditional logistic regression-is unbiased only with certain referent strategies. We review here the case-crossover literature in the air pollution context, focusing on key issues regarding referent selection. We conclude with a set of recommendations for choosing a referent strategy with air pollution exposure data. Specifically, we advocate the time-stratified approach to referent selection because it ensures unbiased conditional logistic regression estimates, avoids bias resulting from time trend in the exposure series, and can be tailored to match on specific time-varying confounders.     

Season, sex, age, and education as modifiers of the effects of outdoor air pollution on daily mortality in Shanghai, China: The Public Health and Air Pollution in Asia (PAPA) Study

BACKGROUND: Various factors can modify the health effects of outdoor air pollution. Prior findings about modifiers are inconsistent, and most of these studies were conducted in developed countries. OBJECTIVES: We conducted a time-series analysis to examine the modifying effect of season, sex, age, and education on the association between outdoor air pollutants [particulate matter < 10 microm in aerodynamic diameter (PM(10)), sulfur dioxide, nitrogen dioxide, and ozone] and daily mortality in Shanghai, China, using 4 years of daily data (2001-2004). METHODS: Using a natural spline model to analyze the data, we examined effects of air pollution for the warm season (April-September) and cool season (October-March) separately. For total mortality, we examined the association stratified by sex and age. Stratified analysis by educational attainment was conducted for total, cardiovascular, and respiratory mortality. RESULTS: Outdoor air pollution was associated with mortality from all causes and from cardiorespiratory diseases in Shanghai. An increase of 10 mug/m(3) in a 2-day average concentration of PM(10), SO(2), NO(2), and O(3) corresponds to increases in all-cause mortality of 0.25% [95% confidence interval (CI), 0.14-0.37), 0.95% (95% CI, 0.62-1.28), 0.97% (95% CI, 0.66-1.27), and 0.31% (95% CI, 0.04-0.58), respectively. The effects of air pollutants were more evident in the cool season than in the warm season, and females and the elderly were more vulnerable to outdoor air pollution. Effects of air pollution were generally greater in residents with low educational attainment (illiterate or primary school) compared with those with high educational attainment (middle school or above). CONCLUSIONS: Season, sex, age, and education may modify the health effects of outdoor air pollution in Shanghai. These findings provide new information about the effects of modifiers on the relationship between daily mortality and air pollution in developing countries and may have implications for local environmental and social policies.     

上海市卢湾区居民日死亡数与大气污染关系的时间序列研究

[目的]分析上海市卢湾区大气污染急性暴露对居民每日死亡数的影响。[方法]分别采用时间序列的半参数广义相加模型(GAM)和广义线性模型(GLM),在控制死亡的长期趋势、气象因素、“星期几效应”等混杂因素的基础上,分析上海市卢湾区2001年1月1日~2004年12月31日大气污染与居民每日死亡数的关系。[结果]在GAM中大气可吸入颗粒物(PM10),SO2和NO2,48h平均浓度每增加10μg/m3,居民死亡的相对危险度分别为1.0003(95%CI1.0000~1.0007)、1.0009(95%CI0.9998~1.0019)和1.0012(95%CI1.0003~1.0021);在GLM中大气PM10,SO2和NO2,48h平均浓度每增加10μg/m3,居民死亡的相对危险度分别为1.0004(95%CI1.0001~1.0008)、1.0008(95%CI0.9998~1.0019)和1.0012(95%CI1.0002~1.0022)。[结论]GAM、GLM拟和结果相似,上海市卢湾区目前的PM10和NO2水平对居民日死亡数有影响。     

Is the association of airborne particles with daily deaths confounded by gaseous air pollutants? An approach to control by matching.

Although particulate air pollution has been associated with increased numbers of daily deaths in dozens of cities around the world, issues still remain about the association. Some have questioned the complex modeling used to control for season in Poisson regression or the role of gaseous air pollutants as potential confounders of the association. I examined the association between deaths and particulate matter with an aerodynamic diameter less than or equal to 10 microm (PM10) using a case-crossover design. In this approach, the pollution on the day of each death is contrasted with the pollution level on control days when the subject did not die. Season and gaseous air pollutants were controlled by matching. Control days were chosen within the same month of the same year to control for season, and matched on either sulfur dioxide (SO2; within 1 ppb), nitrogen dioxide (within 1 ppb), maximum ozone (within 2 ppb), or carbon monoxide (within 0.03 ppm). The analysis was conducted in 14 U.S. cities that have daily PM10 monitoring. After matching, there were about 400,000 deaths in each analysis. Results were combined across cities using a maximum likelihood method. PM10 was a significant predictor of mortality when controlling for gaseous air pollutants, with effect sizes ranging from a 0.45% increase per 10 microg/m3 increment of PM10 [95% confidence interval (CI), 0.12-0.79%] when matched on maximum hourly ozone levels, to a 0.81% increase per 10 microg/m3 increment of PM10 (95% CI, 0.47-1.16%) when matched on 24-hr average SO2.     

A case-crossover analysis of air pollution and mortality in Philadelphia.

This study reassessed Schwartz and Dockery's analysis of daily mortality from nonexternal causes among residents of Philadelphia, Pennsylvania, over 8 years, from 1973 to 1980 [American Review of Respiratory Disease 145:600-604 (1992)]. A Poisson regression analysis using the same model found that a 100-microg/m(3) increment in the 48-hr mean concentration of total suspended particulates (TSP) was associated with increased all-cause mortality [rate ratio = 1.069; 95% confidence interval (CI), 1.043-1.096) after adjustment for quadratic trend, season, year, previous day's mean temperature, dew point, winter temperature, and indicators of hot (temperature > 80 degrees F) and humid days (dew point > 66 degrees F). Critics suggested that time-varying factors such as season and day of week were not sufficiently controlled in this analysis and subsequent studies in other locations. We used a conditional logistic regression analysis with a case-crossover design to reanalyze the data, with air pollution in the prior and subsequent weeks to the day of death serving as referent periods. The case-crossover approach controls for season and day of week by design rather than modeling. We found that a 100-microg/m(3) increment in the 48-hr mean level of TSP was associated with increased all-cause mortality [odds ratio (OR) = 1.056; CI, 1.027-1.086) after adjustment for the same weather variables as above. Similar associations were observed for deaths in individuals over 65 years of age (OR = 1.074; CI, 1. 037-1.111) and for deaths due to cardiovascular disease (OR = 1.063; CI, 1.021-1.107). The current case-crossover analysis confirms the general conclusion of the previous Poisson regression analysis of an association of TSP with daily mortality in Philadelphia, Pennsylvania.     

气温变化与心脑血管疾病急诊关系的病例交叉研究

目的 探讨北京市日平均气温与心脑血管疾病急诊(ICD-10:I00～I99)的关系,研究气温变化对心脑血管疾病的影响.方法 收集北京大学第三医院急诊科心脑血管疾病急诊资料、北京市气象资料和北京市大气污染物数据,应用时间分层的病例交叉设计研究方法分析春季(3-5月)、夏季(6-8月)、秋季(9-11月)、冬季(12-2月)日平均气温与心脑血管疾病急诊的关系.结果 在控制二氧化硫(SO2)、二氧化氮(NO2)及大气可吸入颗粒物(PM10)影响的情况下,春季、夏季、秋季、冬季当日平均气温对心脑血管疾病急诊的影响最大,平均气温每升高1℃与心脑血管疾病急诊的OR值分别为1.282(95%CI:1.250 ～1.315)、1.027(95% CI:1.001～1.055)、0.661(95% CI:0.637～0.687)、0.960(95%CI:0.937～0.984),关联有统计学意义(P<0.05).当同时调整相对湿度、风速、大气压强的影响时,春季、夏季、秋季、冬季平均气温与心脑血管疾病急诊的OR值分别为1.423(95%CI:1.377～1.471)、1.082(95%CI:1.041～1.124)、0.633(95%CI:0.607～0.660)、0.971(95%CI:0.944～1.000).关联有统计学意义(P<0.05).结论 春季、夏季日平均气温升高可以导致心脑血管疾病急诊人次增加,说明春夏季气温升高对心脑血管疾病患者是危险因素,应注意防暑;秋季、冬季气温升高可以导致心脑血管疾病急诊减少,说明秋冬季气温升高对心脑血管疾病患者是保护性因素,应注意保暖.     

大气颗粒物污染与脑卒中死亡的病例交叉研究

目的 评价大气颗粒物污染对人群脑卒中死亡的急性效应.方法 采用时间分层的病例交叉设计,分析杭州市2002-2004年间大气可吸入颗粒物(PM10)日平均浓度短期增加与人群每日脑卒中死亡的关系,同时分析其他气态污染物(NO2和SO2)的急性健康效应.结果共纳入9906例脑卒中死亡病例,粗死亡率约为83.54/10万.调整气象因素后,3 d内PM10、SO2和NO2日平均浓度每增加10μg/m3,人群脑卒中死亡则分别增加0.56%(95%CI:0.14%～0.99%)、1.62%(95%CI:0.26%～3.01%)和2.07%(95%CI:0.54%～3.62%).多污染物模型中未见有统计学意义的关联.敏感性分析结果显示进行缺失值填补后,单污染物模型中均有关联效应,多污染物模型中则无统计学意义的关联.结论大气颗粒物污染以及SO2和NO2污染物浓度短期升高均与脑卒中死亡增加存在一定关联.     

Comparison of time series and case-crossover analyses of air pollution and hospital admission data

BACKGROUND: Time series analysis is the most commonly used technique for assessing the association between counts of health events over time and exposure to ambient air pollution. Recently, case-crossover analysis has been proposed as an alternative analytical approach. While each technique has its own advantages and disadvantages, there remains considerable uncertainty as to which statistical methodology is preferable for evaluating data of this type. METHODS: The objective of this paper is to evaluate the performance of different variations of these two procedures using computer simulation. Hospital admission data were generated under realistic models with known parameters permitting estimates based on time series and case-crossover analyses to be compared with these known values. RESULTS: While accurate estimates can be achieved with both methods, both methods require some decisions to be made by the researcher during the course of the analysis. With time series analysis, it is necessary to choose the time span in the LOESS smoothing process, or degrees of freedom when using natural cubic splines. For case-crossover studies using either uni- or bi-directional control selection strategies, the choice of time intervals needs to be made. CONCLUSIONS: We prefer the times series approach because the best estimates of risk that can be obtained with time series analysis are more precise than the best estimates based on case-crossover analysis.