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Applied Epidemiologic Analysis
Patricia Cohen, Ph.D.
Henian Chen, M.D., Ph. D.
Teaching Assistants
Julie Kranick
Chelsea Morroni
Applied Epidemiologic Analysis
Fall 2002
Sylvia Taylor
Judith Weissman
Lecture 4
Examining the process of data analysis for
epidemiological studies using multiple regression
analysis as a fundamental tool
Goal: To review how recently published analyses
were used to show relationship between an
exposure or other predictor of a disease indicator
and to take potential confounders or other
covariates into account.
Applied Epidemiologic Analysis
Fall 2002
Objectives
• To see how current epidemiological studies have
used multiple regression when disease measures
are scales.
• To understand how stratifying variables and
potential confounders are selected and used in
these studies.
Applied Epidemiologic Analysis
Fall 2002
First Study : Longitudinal trends in the severity
of acute myocardial infarction
Reference:
Hellermann JP, Reeder GS, Jacobsen SJ, Weston
SA, Killian JM, Roger VL. American Journal of
Epidemiology, 156, No 3., p 246-253, 2002.
Applied Epidemiologic Analysis
Fall 2002
The problem: Myocardial infarction (MI) study
There has been a decline in age-adjusted mortality
due to coronary heart disease not fully accounted
for by a decline in the incidence of hospitalized
myocardial infarction cases.
Is it due to more effective hospital care or to a
decline in severity of cases?
Applied Epidemiologic Analysis
Fall 2002
Population studied, study design, and
sample size : MI study
• Olmstead Minnesota county is served by the Mayo
Clinic Hospitals and one other hospital. Detailed
data on all admissions is kept in accordance with
protocols maintained by an epidemiology
program for that site.
• A cohort of 1300 cases presenting at one of the
two hospitals for incident myocardial infarction
are studied for changes in indicators of severity
over a 12 year period. Cases were sampled
differentially on ICD codes and weighted to reflect
these sampling fractions.
Applied Epidemiologic Analysis
Fall 2002
Measurement issues: MI study
Created values of tests taken on admission:
1) For average of 2.6 EKGs:
Segment elevation and Q wave pattern
2) For average of 4.2 enzyme draws
Peak values of indicators of problem
3) Status indicator on admission
4 ordinal levels (highest, in cardiac shock)
• No variables had more than 3% missing data except 1:
Applied Epidemiologic Analysis
not indicate how they managed missing data.
Fall does
2002
Measurement issues: MI study
Indicators of risk:
• Prior congestive heart failure
• Cardiovascular risks (hypertension, diabetes, smoking,
hyperlipidemia)
• Comorbidity index (count of risks)
Indicators of treatment:
• Time to first EKG
• Use of repurfusion therapy (thrombolytic therapy or acute
coronary angioplasty within 24 hours)
Applied Epidemiologic Analysis
Fall 2002
The effect being estimated:
Trend over time in indicators of MI severity
Basic analysis to answer study questions:
Multiple linear and multiple logistic regression analyses:
– Dependent variables: 4 cardiac status indicators: Killip
class on admission,
– Hypothesized Predictor: Year of intake (question: why
not use exact date?)
– Covariates: Time to first EKG (step 2); step 3 added
reperfusion therapy for Q wave and peak creatine kinase
indicators of severity.
• Note: although test of interactions with age and sex were carried
out they are not explicitly reported: findings for two indicators are
reported separately by sex.
Applied Epidemiologic Analysis
Fall 2002
Applied Epidemiologic Analysis
Fall 2002
Selection and inclusion of confounders in the analysis
• Note that Table 1 shows a significant increase in
risk/comorbidity (except smoking) and a nearly significant
(p = .081 for trend across 4 year periods) but text says
AOver time, no change in the age distribution and degree of
comorbidity was observed.@
• What is the role of risk factors as potential confounders?
Of treatment?
Applied Epidemiologic Analysis
Fall 2002
TABLE 2. Distributions of ST-segment elevation and severity
indicators, Olmsted County, Minnesota, 1983–1994
Applied Epidemiologic Analysis
Fall 2002
TABLE 3. Change in severity indicators among 1,295 hospitalized
myocardial infarction patients, Olmsted County,
Minnesota, 1983–1994
Applied Epidemiologic Analysis
Fall 2002
Conclusion: MI study
• Severity of cases of incident MI to these hospitals
declined over this 12 year period in spite of
greater survival prior to arrival.
• Question: why did they use only incident MI?
Applied Epidemiologic Analysis
Fall 2002
Second Study : Physical inactivity is associated
with lower forced expiratory volume
Reference:
Jakes RW, Day NE, Patel B, Khaw K-T, Oakes S,
Luben R, Welch A, Bingham S, Wareham NJ.
American Journal of Epidemiology, 156, No 2, p
1389-147, 2002
Applied Epidemiologic Analysis
Fall 2002
The problem: Forced expiratory volume (FEV)
•Although low forced expiratory volume has been
shown to be a risk for cardiovascular disease,
stroke, lung cancer, and all-cause mortality, its
relationship to physical activity has not been
extensively studied.
• Is there a relationship that is independent of other
correlates such as weight?
Applied Epidemiologic Analysis
Fall 2002
Population studied, study design, and
sample size : FEV study
• UK general practice prospective cohort of 25,000
persons ages 45-74 who had an initial health
assessment and a second assessment 3.7 years
later on average.
• Exclusions: history or current respiratory disease
Applied Epidemiologic Analysis
Fall 2002
Measurement issues: FEV study
Created values of tests taken on admission:
• Complex self-report of activity levels at home, work, and
recreationally
• Standard FEV per 1 second test
• Height, weight, plasma vitamin C, smoking
• Stratifier: By sex in initial analyses, sex included as a
covariate in final analyses
Applied Epidemiologic Analysis
Fall 2002
The effect being estimated:
Independent association between FEV and activity level
Basic analysis to answer study questions:
Multiple linear regression analyses:
Dependent variables:
• FEV, average FEV, and % change in FEV
Basic independent variables (Aexposure@):
• Level of activity or average level of activity,
• Daily hours of TV viewing
Applied Epidemiologic Analysis
Fall 2002
Selection and inclusion of confounders in the analysis
• Height , Vitamin C, smoking status
• Sex, age (also examined obesity)
Applied Epidemiologic Analysis
Fall 2002
Jakes, et al.
TABLE 1. Baseline
characteristics
5,467 men and 6,816women
Men
mean (SD†)
Women
mean (SD)
Age (years)
59.6 (8.9)
58.4 (8.9)
Weight (kg)
80.1 (10.8)
67.0 (11.0)
Height (cm)
174.2 (6.6)
161.2 (6.1)
Vitamin C (mmol/liter)
49.3 (18.4)
60.7 (19.1)
FEV1† (liter) (baseline)
3.01 (0.7)
2.21 (0.5)
FEV1 (liter)
(second health check)
2.93 (0.7)
2.17 (0.5)
% change in FEV1
(per year)‡
–0.74 (4.2)
–0.60 (4.1)
%
%
Never
37
61
Former
53
30
Current
10
9
Smoking
Applied Epidemiologic Analysis
Fall 2002
Television viewing in hours per day (proportion)
FIGURE 1. Adjusted mean forced expiratory volume in 1 second
(FEV1) (liters) by categories of television viewing (hours per day)
Adjusted for age (continuous), height (continuous), plasma vitamin C
(continuous),
Applied
Epidemiologic sex,
Analysisand smoking status (never, former, and current).
Fall 2002
Stair climbing in flights per day (proportion)
FIGURE 2. Adjusted mean forced expiratory volume in 1 second
(FEV1) (liters) by categories of stair climbing (flights per day)
Adjusted for age (continuous), height (continuous), plasma vitamin C
(continuous),
Applied Epidemiologic
Analysissex, and smoking status (never, former, and current).
Fall 2002
Conclusions: FEV study
Higher FEV is related to level of physical activity
and low duration of TV watching independently of
other predictors and thus potentially causally.
Applied Epidemiologic Analysis
Fall 2002
Third Study :
Dietary soy isoflavones and bone
mineral density
Results from the Study of Women=s
Health Across the Nation
Reference:
Greendale GA, FitzGerald G, Huang M-H,
Sternfeld B, Gold E, Seeman T, Sherman S,
Sowers MF. American Journal of Epidemiology,
155, No. 8, p746-754. 2002
Applied Epidemiologic Analysis
Fall 2002
The problem: Bone density study
•Japanese and Chinese women are at about 2 the
risk of hip fracture as Caucasian women.
•May this be due to a high-soy diet?
Applied Epidemiologic Analysis
Fall 2002
Population studied, study design, and
sample size : Bone density study
• Multi-site longitudinal study of Chinese-American and
Japanese-American women ages 42-52 recruited from
clinical sites, pre-menopausal without a history of uterus or
ovary removal or hormone therapy. N = 200 and 227
respectively. Caucasian and African American women had
too low consumption of relevant nutrients to be included in
analysis.
• Excluded: eating disorder, hypercalcemia, and those who
took certain relevant medications.
Applied Epidemiologic Analysis
Fall 2002
Measurement issues: Bone density study
• Estimation of isoflavone phytoestrogen from food
frequency questionnaires. Quality control exclusions
were identified (basically too much or too little intake)
• Note that data were missing from some sites on certain
bone density measures: Measurement of bone density
subjected to standard data quality criteria and reviewed
for specific flagging criteria.
• Missing data are noted for entire sample but not
separated for the sample actually comprising the major
analysis.
• Because consumption of most nutrients is positively
related to total energy intake, it is necessary to adjust
for total energy. Therefore, our relational analyses used
energy-adjusted genistein as the primary exposure
variable.@ (p.748)
Applied Epidemiologic Analysis
Fall 2002
• Stratifiers: Ethnicity, menstrual status
Selection and inclusion of confounders in the analysis
No clear justification: selected on basis of statistical
significance
Applied Epidemiologic Analysis
Fall 2002
The effect being estimated:
The relationship between isoflavone phytoestrogen
consumption and indicators of bone density
Basic analysis to answer study questions:
A. Created separate residuals from the prediction of genistein
as indicated by codes of food frequency reports from
estimated total energy intake for Japanese- and ChineseAmerican women to predict indicators of BMD.
B. Analysis including age, smoking, activity level, dietary
calcium, alcohol use, protein, height, weight, menopause
status, duration in the US. Interaction of genistein with
menopause status was tested in each model. Menopausal
strata were pre-menopausal or early peri-menopausal.
Applied Epidemiologic Analysis
Fall 2002
TABLE 2. Means and frequencies of selected characteristics of
Japanese and Chinese women study participants,* Study of
Women’s Health Across the Nation, United States, 1996–1997
Applied Epidemiologic Analysis
Fall 2002
Greendale, et al.
TABLE 3. Tertile distributions of dietary genistein intake among
Japanese and Chinese women,* Study of Women’s Health Across the
Nation, United States, 1996–1997
Greendale, et al.
Applied Epidemiologic Analysis
Fall 2002
TABLE 4. Adjusted* mean values of spine and femoral neck bone mineral densities, by
tertile of genistein intake, among Japanese premenopausal, Japanese perimenopausal,
and Chinese women, Study of Women’s Health Across the Nation, United States, 1996–
1997
Greendale, et al.
Applied Epidemiologic Analysis
Fall 2002
Conclusions: Bone density study
ABecause the estimated genistein consumption by Japanese
women was greater than that of Chinese women, it was
important to discern whether the apparent ethnic difference in
the effect of genistein on BMD was due to variation in the
dose.. or to an ethnic difference in physiologic response.
Results of the combined model including both Chinese and
Japanese women supported the latter conclusion.@
Possible mechanisms discussed, including both biological
differences and differences in the form in which isoflavones
appear in the culturally different foods due to more fermented
forms of soy in the Japanese diet.
Applied Epidemiologic Analysis
Fall 2002
Fourth Study : Associations of blood lead,
dimercaptosuccinic acid-chelatable lead,
and tibia lead with neurobehavioral test
scores in South Korean lead workers
Reference:
Schwartz BS, Lee B-K, Lee G-S, Stewart WF, Lee S-S,
Hwang K-Y, Ahn K-D, Kim Y-B, Bolla KI, Simon D,
Parsons PJ, Todd AC. American Journal of
Epidemiology 153, No 5, 453-464, 2001.
Applied Epidemiologic Analysis
Fall 2002
The problem: Lead study
What are the associations between alternative
measures of lead exposure and neurobehavioral
and peripheral nervous system function?
Applied Epidemiologic Analysis
Fall 2002
Population studied, study design, and
sample size : Lead study
803 South Korean lead-exposed and 135 control
workers studied cross-sectionally.
Applied Epidemiologic Analysis
Fall 2002
Measurement issues: Lead study
• Standardized all neurobehavioral measures
such that a higher test score always indicated
better performance.
• Stratifiers: (none used as such)
Applied Epidemiologic Analysis
Fall 2002
The effect being estimated:
The associations of lead exposure measures with
neurobehavioral test scores
Basic analysis to answer study questions:
Multiple linear regression analyses:
– Dependent variables: 19 measures of neurobehavioral
and peripheral nervous system function.
– Basic IV (Aexposure@):
• blood lead level
• tibia lead level
• job duration
Applied Epidemiologic Analysis
Fall 2002
Selection and inclusion of confounders in the analysis
Age, gender, and education
Applied Epidemiologic Analysis
Fall 2002
TABLE 5. Linear regression modeling† of relations of neurobehavioral and
peripheral nervous system measures with blood lead levels, Republic of Korea,
1997–1999
Applied Epidemiologic Analysis
Fall 2002
Footnotes to previous table
* p < 0.10; ** p < 0.05; *** p < 0.01.
† All models controlled for age, gender, and education. Models of the peripheral nervous system sensory
measures also included height; models of the
peripheral nervous system strength measures also included body mass index. All outcomes have been
standardized, so a negative ?coefficient indicates that
performance is worse with increasing tibia lead. The tabulated ?coefficients are for the tibia lead term
and are expressed in units of test score per g Pb/g bone
mineral.
‡ Included tibia lead alone.
§ Included tibia lead and blood lead.
¶ Included tibia lead and job duration.
# Included tibia lead, blood lead, and job duration.
†† SE, standard error; SD, standard deviation; MSD, mean square deviation; CES-D, Center for
Epidemiologic Studies Depression Scale.
‡‡ Vibration unit = 1/2 (amplitude ())2.
Applied Epidemiologic Analysis
Fall 2002
FIGURE 2. Associations of blood lead, tibia lead, job duration, and
age with scores (number of correct responses) on the Pursuit
Applied Epidemiologic Analysis
Aiming Test (correct responses) (PATR) among 803 lead-exposed
Fall 2002
workers in South Korea
Conclusions: Bone density study
• Blood levels of lead are much better indicators
than tibia lead.
• Test scores tended to improve with increasing job
durations, suggesting a Asurvivor bias.@
Applied Epidemiologic Analysis
Fall 2002