Topic and design considerations in epidemiologic research

Shi Wu Wen

University of Ottawa/Ottawa Hospital Research Institute

July 3, 2015

Some diseases lack animal models: preeclampsia, autism, psychological issues such as preference (prostate cancer)

Animal models cannot be repeated in human studies because of the ethical issues

Design/implementation issues

Inter-species difference huge and beyond imagination: transfusion research of fresh versus old blood

Importance of epidemiologic research

Effects of antibiotics were demonstrated without formal evaluation: hundreds and thousands deaths formed the basis of background comparison, so a consecutive recovery of 5 TB or pneumonia cases is sufficient

Even non-infectious diseases can have such a dramatic effect as well

Historically effects are relatively easy to be detected

James Lind

Born 1716Died 1794

Scottish physician

British Naval Surgeon•Surgeon’s Mate in 1739•HMS Salisbury in 1747

James Lind allocated 12 sailors to 6 interventions:

• 2 received oranges and lemons

• 2 received cider

• 2 received vinegar

• 2 received elixir vitriol

• 2 received spices and garlic

• 2 received sea water

Results

•Within six days, the 2 sailors given oranges

and lemons became well

•The 10 others did not do well

•The 2 that became well looked after the sick

•Took 40 years (1795) before findings adopted

and implemented by Royal Navy – 2/3rd of an

ounce of lemon juice mixed in “grog” daily

Therapeutical effects become smaller and smaller

Gaps exist and therefore opportunities

Increased exposure to previously not existing risks (e.g., chemicals, radiations, obesity, “super-hygiene” environment such as asthma and polio theory)

Side effects

Quality of life

Challenges and opportunities in modern epidemiologic research

Categories of epidemiologic studies – by study design

Epidemiologic studies

Observational Studies Experimental Studies

Descriptive Studies Analytic Studies

Case report

Case Series

Cross sectional studies

Case control

Cohort

RCTs

Cross-sectional

Purposes of clinical studies

Treatment effects (main or intended effects): RCTs (confounding by indication)

Evaluation of diagnostic tools: RCTs or observational studies

Etiologic risk factors: observational studies (ethical issues)

Patient’s need/satisfaction: observational studies (surveys)

Confounding by indication for intended treatment effects by observational studies

Occurrence of thrombosis in relation to warfarin use, as indicated by histories of warfarin use among cases and reference subjects

Warfarin use No useCases 17 5References 213 1571

Rate ratio estimate:Crude: 25Controlling age: 27Controlling history: 4.5Controlling history, age, and sex: 3.9

Miettinen, Statistics in Medicine 1983

Storage Time:Is fresh better?

Berezina LT et al. Influence of Storage on Red Blood Cell Rheological Properties. Journal of Surgical Research 102: 6-12, 2002

RBCs Day 5 RBCs Day 14

– Numerous (but not all) animal studies point to deleterious effects of older red cells

The ARIPI Trial:Age of Red Cells In Premature Infants

ARIPI Trial

Design: Randomized, double blind ‑ Setting: 377 infants from 6 Canadian NICUs Population: neonates (<1250 grams) who

require at least one red cell transfusion 1° Outcome: campsite of major

morbidity/mortality up to 90 days– high risk of transfusion (50-80%)– very high risk of serious morbidities

(50-80%)

Primary Outcome

(0.82, 1.21)1.00Composite (any of above)

(0.61, 1.54)0.97 Death

(0.72, 1.28)0.96Bronchopulmonary dysplasia

(0.50, 1.45)0.85Retinopathy of prematurity (Stage ≥ 3)

(0.80, 3.39)1.65Intraventricular hemorrhage (Papile grade ≥ 3)

(0.48, 2.12)1.00Necrotizing enterocolitis (Bell stage ≥ 2)

Risk Ratio (95% CI) 

52.7%9952.9%100

16.03016.431

31.96033.363

11.72213.826

9.6185.811

8.0157.915

%N%N

Fresh (n=188)

Standard (n=189)

Fergusson et al, JAMA, 2012

Study example – comparing alternative treatments

Percent distribution of characteristics among patients delivered by vacuum, forcepts, and naturally

Vacuum (n=31015) Forceps (n=18727) Natural (n=255649)Age< 20 years 4.8 4.5 4.7>= 35 years 7.5 9.5 8.7Dystocia 30.4 34.5 6.6Fetal distress 30.2 36.7 8.6Gestational diabetes 2.9 2.9 2.9PIH 4.0 4.3 2.7Labor induction 16.1 19.4 13.1

Wen et al AJE 2001

Study example – comparing alternative treatments

Occurrence (per 1000 births) of major adverse maternal and infant outcomes among patients delivered by vacuum, forcepts, and naturally

Vacuum (n=31015) Forceps (n=18727) Natural (n=255649)

Severe perineal laceration 173.9 308.0 46.2IVH 0.1 0.1 0.1Facial-nervus injury 1.2 5.1 0.4Cephalhematoma 128.2 68.2 13.8Neonatal death 0.3 0.3 0.2

Wen et al AJE 2001

Study example – evaluating a diagnostic tool

The product: Al-sense blue pad The purpose: if Al-sense blue device can reliably rule in

or rule out amniotic fluid leak as a cause of vaginal wetness in pregnancy, and therefore thus, can be adopted by hospitals as Standard of Care for as an amniotic fluid leak detection tool, and can be used in a home usage setting amniotic fluid leak detection

The design: prospective study The patients: pregnant women ages 18 and above

attending the triage/delivery room

Study example – evaluating a diagnostic tool

The comparison: with unidentified wetness (undetermined whether this is amniotic fluid leakage or urinary incontinence) versus no unidentified wetness

The evaluation: color change (the indicator changes color to blue-green and fades back to yellow in case of urine and changes to stable blue-green in case of amniotic fluid)

The analysis?

Study example – assessing a screening program

Gestationals diabetes and pre-pregnancy diabetes in Canada, 1984-1996

0

0.5

1

1.5

2

2.5

3

1 2 3 4 5 6 7

Study example – assessing a screening program

Gestational diabetes in Metro-Hamilton versus the rest of Ontario, 1984-1996

0

0.5

1

1.5

2

2.5

1 2 3 4 5 6 7

Study example – assessing a screening program

Fetal macrosomia in Metro-Hamilton versus the rest of Ontario, Canada, 1984-11996

10

10.511

11.512

12.513

13.514

14.5

1 2 3 4 5 6 7

Study example – etiologic risk factors

Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(15):878-81

Background: adenocarcinoma of the vagina is rare and normally occur in women > 50. Between 1966 and 1969, 7 girls 15-22 years of age with this condition were seen in Vincent Memorial Hospital in Boston and another in a neighboring hospital

Purpose of the study: to identify the etiologic risk factors of this rare disease

Study example – etiologic risk factors

Study design: case control (four matched controls for each patient: girls born within 5 days and on the same service), exposure data by structured interview of all mothers

No difference in maternal age (26.1 vs 29.3), smoking (7/8 vs 21/32), breast feeding (3/8 vs 3/32), intrauterine X-ray (1/8 vs 4/32) exposure was found

Significantly high rates of bleeding of the index pregnancy (3/8 vs 1/32), history of pregnancy loss (6/8 vs 5/32), and (especially) estrogen use in the index pregnancy (7/8 vs 0/32) in the cases than in the controls

Study example – etiologic risk factors

Landmark study Appropriate design: rare events Biological rationale Strength of the association Specificity of the association

Challenges for clinicians to conduct research

Time management See trees not forests Often have a lot of clinical questions but the questions

are often too big and complex and don’t know how to translate it into a simple research question

How to dissect a complex clinical question, tease out the most relevant issue, when thinking about a question think about a study design, and select/modify a question that is answerable is the key for success

Occurrence, clinical predictors, and outcomes in cesarean delivery for the second twin after vaginal delivery of the first twin

Objectives

To estimate the occurrence of cesarean delivery for the second twin after vaginal delivery of the first twin

To assess clinical predictors of cesarean delivery for the second twin after vaginal delivery of the first twin

To assess outcomes of cesarean delivery for the second twin after vaginal delivery of the first twin

Methods

Population-based retrospective cohort study, using the 1995-1997 linked mother/infant twin data of the United States

The adjusted risk ratios and population attributable risks of clinical predictors of emergent cesarean delivery in the second twin were estimated in the overall study sample and after stratifying the data by gestational age (preterm and term births)

Maternal and fetal characteristics for the second twins, United States, 1995-1997

Characteristics Number Percent

Delivery method

Vaginal birth 56003 90.55

Cesarean delivery 5842 9.45

Breech/other malpresentations

No 51841 83.82

Yes 10004 16.18

Operative vaginal delivery of first twin

No 53290 86.17

Yes 8555 13.83

Predictors of emergent cesarean section for the second twin after vaginal birth of the first twin, United States, 1995-1997, overall study samples

Predictors Number (%) Cesarean section

Adjusted odds ratios (95% CIs)

Population attributable Risks (95% CIs) expressed as percent

Breech/other malpresentations

No 3495 (6.74) Reference Reference

Yes 2347 (23.46) 4.10 (3.86, 4.360 33.2 (31.8, 34.6)

Cephalo-pelvic disproportion

No 5784 (9.35) Reference Reference

Yes 58 (44.96) 8.93 (6.16, 12.96) 1.6 (1.2, 1.9)

Comparison of neonatal mortality rates (asphyxia-related deaths) in second twin according to gestational age at birth and mode of delivery, United States, 1995-1997

Mode of delivery and gestational age birth Number (%)

Neonatal death

Adjusted odds

Ratios (95% CIs)

Preterm births:

Both twins cesarean delivery 18 (0.07) Reference

Both twins vaginal delivery 25 (0.13) 2.79 (1.48, 5.25)

First twin vaginal and second twin cesarean delivery

8 (0.33) 4.04 (1.72, 9.51)

Term births:

Both twins cesarean delivery 4 (0.01) Reference

Both twins vaginal delivery 6 (0.02) 1.76 (0.48, 6.42)

First twin vaginal and second twin cesarean delivery

8 (0.24) 13.22 (3.50, 49.89)

Example of topic choice: Association of infant sex and postpartum depression (PPD)

Example of topic choice: Infant sex, social support, and PPD

The reasons for the increased risk of PPD in Chinese women who gave birth to a female infant as compared with those who gave birth to a male infant are unclear.

We hypothesize that the lack of social support after childbirth for Chinese women who give birth to a female infant, secondary to the male-preference in Chinese society, is the underlying cause of increased risk of PPD in them.

Example of topic choice: Association between infant sex and PPD

Conclusion- TIPS

Topic

Intervention

Persistency

Success