POPULATION RESEARCH SEMINAR SERIES
Sponsored by the Statistics and Survey Methods Core of the U54 Partnership
Integration of Survey and Biospecimen
Data Collection in Longitudinal Studies
Bringing Epidemiology and Biology
Together into Cohesive Studies
Jill A. Macoska, Ph.D.
Director, CPCT
Biology and Epidemiology: Cause and Effect
Biology:
▸ The science of life or living matter in all its forms
and phenomena = CAUSE (End Here)
Epidemiology:
▸ The branch of medicine dealing with the incidence
and prevalence of disease in large populations =
EFFECT (Start Here)
Epidemiology demonstrates observational
connections, Biology establishes causal
connections.
Types of Epidemiological Studies
Cross-sectional:
Study is conducted at a single time point.
Comprises observation of one or more variables at
single period of time.
Longitudinal:
Study is conducted at multiple, consecutive time
points.
Comprises repeated observations of the same
variables over long periods of time.
Types of Epidemiological Studies: Examples
Cross-sectional:
▸ Study percentage of obese individuals in a given
population.
▸ Randomly sample 1,000 individuals, measure
weight and height, calculate % of obese
individuals.
▸ Results: Individuals in Ohio are more obese
than those in Massachusetts.
Obesity Rates in U.S. Populations: By State
OH: 11-14%
MA: <10%
Types of Epidemiological Studies: Examples
Longitudinal:
Study obesity trends in a given population.
Recruit 1,000 individuals, measure weight and
height at one-year intervals over 10 years,
calculate obesity rates over time.
Results: Obesity rates doubled in both Ohio and
Massachusetts in 25 year period between 19852010.
Obesity Rates in U.S. Populations: By State
OH: 11-14%
MA: <10%
OH: 25-29%
MA: 20-24%
Example: Longitudinal Study of BPH and Lower
Urinary Tract Symptoms (LUTS)
Bladder
Normal Prostate
Normal
Urine Flow
Bladder
Enlarged Prostate
Obstructed
Urine Flow
(Experienced
as LUTS)
The Olmsted County Study of Urinary
Symptoms and Health Status Among Men
▸ Initiated in 1990 to determine the natural history of Benign
Prostatic Hyperplasia (BPH) in the community.
▸ Association of BPH with age suggested that a longitudinal
study design would be most optimal.
▸ A sampling frame was developed using the resources of
the Rochester (Minnesota) Epidemiology Project: Identified
male residents of Olmsted County 40 to 79 years old on
January 1,1990.
▸ 3,658 men were identified.
The Olmsted County Study of Urinary
Symptoms and Health Status Among Men
Of these
men, 2,115 (55%)
1990 3,658 1992
1994
completed the study protocol:
• Personal interview to elicit a
family history of urological
disease and current medications;
• Completion of a self administered
questionnaire: lower urinary tract
symptoms, basic demographic
information and psychological
well-being,
• Measurement of urinary flow
rates with a portable
uroflowmeter.
The Olmsted County Study of Urinary
Symptoms and Health Status Among Men
• 25% of total cohort each round were
invited to participate in a clinical
urologic examination (clinic cohort):
• Uroflow measurements,
• Transrectal and transabdominal
ultrasound,
• Venipuncture and blood
collection
• Brief focused physical exam
• Serum PSA measurement.
• 80-90% of those invited completed the
exam.
Inclusion of Blood Collection in Protocol Permitted
Biological Studies Based on Epidimiological Data
Several Studies Associate Inflammation
With LUTS
Rodrigues-Nieves et al., Nat Rev Urol. 10:546-50 (2013)
Olmsted Epid/Bio Study: Serum C-reactive
Protein
• C-reactive protein was measured in blood samples from 1996
cohort (Round 4).
• Urologic symptoms compared in men between 1996 (Round
4) and 2004 (Round 8).
• Men with CRP levels of >3.0 mg/L were more likely to have
rapid increases in irritative LUTS and rapid decreases in peak
flow rates compared to men with lower CRP levels.
• Suggests that serum C-reactive protein may be a biomarker
for risk of LUTS development and progression.
• Suggests that inflammatory processes may be associated
with LUTS development and progression (BIOLOGY)
St. Sauver et al., Am. J. Epidemiol. 169:1281–1290 (2009).
Olmsted Epid/Bio Study: PTGS2 Gene Variants
• Inflammation observed as pathobiology concurrent
with BPH
• COX2 activity promotes inflammation; also promotes
BPH? (hypothesis)
• PTGS2 gene encodes COX2
• Are PTGS2 variants associated with increased RNA
stability (and more COX2) also associated with BPH?
Olmsted Epid/Bio Study: PTGS2 Gene Variants
▸ DNA was purified from blood collected from 356 Round 8
men (2004) and assessed for PTGS2 SNPs (also
assessed for SNPs for 27 other inflammation-associated
genes; results from all these were negative)
▸ Of 10 PTGS2 SNPs investigated, 4 were significantly
associated with prostate volumes >30 mL and 1 of these
(rs4648261) was also associated with prostate volumes
>40 ml
▸ NSAID use (anti-inflammatory) minimized these
associations
Olmsted Epid/Bio Study: Serum Steroids
▸ Steroid hormones (testosterone) are the main growth
factor of the prostate.
▸ Are high levels of steroid hormones evident for men with
progressive BPH?
▸ Blood from Round 2 (1992) men was assayed for serum
steroid hormone levels and urologic measures from Round
2 (1992) and Round 9 (2006) compared.
▸ Results: higher baseline and increased rate of change in
sex steroid levels were associated with worsening LUTS:
Serum testosterone decreases with increasing age and
LUTS; serum estradiol increases with increasing age and
LUTS.
Biological implications under investigation.
St. Sauver et al., BJU International 108: 1610-1615 (2011).
Integrating Biospecimen Collection Into
Longitudinal Survey-based Studies
Biospecimen collection can be pursued for a subgroup of individuals recruited into longitudinal
studies.
▸Cuts down on costs of collection and
storage.
▸Provides sufficient power to ask relevant
biological questions.
▸Easiest accomplished for relatively noninvasive biospecimen collection: buccal
swabs, urine, saliva, blood.
“Letting The Data Speak" –
Testing Epidemiological Associations
Through Biological Studies
Epidemiology:
British Doctor’s Study – 1951-2001
1956: statistical proof that tobacco smoking increased
the risk of lung cancer (=EFFECT)
Biology:
• There are more than 45 known or suspected chemical
carcinogens in cigarette smoke (=CAUSE)
• Some of these impair DNA damage repair
mechanisms and cause gene mutations (e.g., p53
gene mutations)
Longitudinal Studies Design:
Beginning, Middle, End (and Length!)
Length of study depends on many variables:
▸Pathobiology of interest (short- vs longterm disease development and
progression)
▸Population of interest:
▸ Community (static vs fluid) (longer studies)
▸ Clinic (shorter studies)
▸Funding (!)
▸Study team (stable/short-term)
Early Detection of Recurrent Breast
Cancer Using Metabolite Profiling
•
•
•
•
•
Clinic Based Longitudinal Study (5 years)
56 breast cancer patients enrolled
All patients received surgery;
20 recurred, 36 No Evidence of Disease (NED);
All followed ~ 5 years with annual sequential blood draws
Asiago et al., Cancer Res. 70:8309-8318, 2010.
Early Detection of Recurrent Breast
Cancer Using Metabolite Profiling
Asiago et al., Cancer Res. 70:8309-8318, 2010.
Early Detection of Recurrent Breast
Cancer Using Metabolite Profiling
Cases (patients with recurrence)
Asiago et al., Cancer Res. 70:8309-8318, 2010.
Controls (no evidence of disease)
POPULATION RESEARCH SEMINAR SERIES
Sponsored by the Statistics and Survey Methods Core of the U54 Partnership
Questions? Comments?
Type them in or ask over your
webcam/microphone
Or send an email to
u54.ssmc@gmail.com