Studying Rotavirus Vaccines and Intussusception in Mini-Sentinel W. - - PowerPoint PPT Presentation

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Studying Rotavirus Vaccines and Intussusception in Mini-Sentinel W. - - PowerPoint PPT Presentation

Nov 13, 2022 208 likes •407 views

Studying Rotavirus Vaccines and Intussusception in Mini-Sentinel W. Katherine Yih, PhD, MPH Harvard Pilgrim Health Care Institute and Harvard Medical School January 31, 2013 info@mini-sentinel.org 1 Rotavirus vaccines Live, attenuated,

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info@mini-sentinel.org 1

Studying Rotavirus Vaccines and Intussusception in Mini-Sentinel

  • W. Katherine Yih, PhD, MPH

Harvard Pilgrim Health Care Institute and Harvard Medical School January 31, 2013

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info@mini-sentinel.org 2

Rotavirus vaccines

 Live, attenuated, oral vaccines for

infants, multiple doses

 Rotashield licensed in August 1998  In 1999, Rotashield voluntarily withdrawn due to

increased risk of intussusception

  • Excess risk: 1-2 cases/10,000 vaccine recipients
  • Risk highest 3-7 days after Dose 1

 RotaTeq (2006) and Rotarix (2008) licensed after

clinical trials with >60,000 infants

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info@mini-sentinel.org 3

Post-licensure studies, RotaTeq & Rotarix Dose 1, 1-7 d after vaccination

1st author, date Site, system 1st doses

  • No. of

cases RR (95% CI) RotaTeq Buttery 2011 Australia 115,657 3 5.3 (1.1, 15) Haber (abstract) 2011 U.S., VAERS n.a. 66 1.5 (0.96, 2.3) Shui 2012 U.S., VSD 309,844 1 1.2 (0.03, 6.8) Rotarix Buttery 2011 Australia 163,709 3 3.5 (0.7, 10) Patel 2011 Mexico n.a. 24 5.3 (3.0, 9.3) 5.8 (2.6, 13) Velázquez 2012 Mexico n.a. 56 6.5 (95.5% CI 4.2, 10)

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info@mini-sentinel.org 4

Post-licensure studies, RotaTeq & Rotarix Dose 1, 1-7 d after vaccination

1st author, date Site, system 1st doses

  • No. of

cases RR (95% CI) RotaTeq Buttery 2011 Australia 115,657 3 5.3 (1.1, 15) Haber (abstract) 2011 U.S., VAERS n.a. 66 1.5 (0.96, 2.3) Shui 2012 U.S., VSD 309,844 1 1.2 (0.03, 6.8) Rotarix Buttery 2011 Australia 163,709 3 3.5 (0.7, 10) Patel 2011 Mexico n.a. 24 5.3 (3.0, 9.3) 5.8 (2.6, 13) Velázquez 2012 Mexico n.a. 56 6.5 (95.5% CI 4.2, 10)

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info@mini-sentinel.org 5

Rotavirus vaccine doses in Mini-Sentinel study (for period for which charts reviewed, through

6/2011 maximum) 1st doses All doses RotaTeq 507,874 1,277,556 Rotarix 53,638 103,098

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info@mini-sentinel.org 6

Intussusception case-finding algorithm

First-ever of any of these in ED or inpatient setting:

– ICD-9 560.0 (intussusception) – ICD-9 543.9 (unspec. diseases of appendix, including intussusception) – CPT 74283 (therapeutic enema, contrast or air, for reduction of intussusception or other intraluminal

  • bstruction)
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info@mini-sentinel.org 7

Chart review

 Purposes:

  • To confirm intussusception diagnoses
  • To confirm rotavirus vaccination (specific vaccine, dose,

age) of intussusception cases

 Standardized chart abstraction and adjudication

forms

 Pediatrician adjudicators reviewed chart material to

determine if cases found by algorithm truly intussusception

 Adjudicators blinded to vaccination status

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info@mini-sentinel.org 8

Chart review metrics

Algorithm-identified potential cases = 343 Those for whom chart obtained = 267 (78%) Those confirmed as intussusception = 124 (46%) Cases are from whole infant population and include unexposed

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info@mini-sentinel.org 9

Designs and analysis approaches

 Vaccinated infants only (self-controlled risk interval)

  • Uses just vaccinated cases with intussusception in either

pre-specified risk interval or comparison interval

  • Analysis by logistic regression

 All infants (cohort)

  • Uses exposed and unexposed person-time of whole infant

population

  • Analysis by Poisson regression
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info@mini-sentinel.org 10

Intussusception incidence by age

10 20 30 40 50 60 70 0-6 DAYS 14-20 DAYS 28-34 DAYS 42-48 DAYS 56-62 DAYS 70-76 DAYS 84-90 DAYS 98-104 DAYS 112-118 DAYS 126-132 DAYS 140-146 DAYS 154-160 DAYS 168-174 DAYS 182-188 DAYS 196-202 DAYS 210-216 DAYS 224-230 DAYS 238-244 DAYS 252-258 DAYS 266-272 DAYS 280-286 DAYS 294-300 DAYS 308-314 DAYS 322-328 DAYS 336-342 DAYS 350-356 DAYS Rate per 100,000 infants

from Tate et al. Pediatrics 2008;121:e1125-e1132

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info@mini-sentinel.org 11

Intussusception incidence by age

10 20 30 40 50 60 70 0-6 DAYS 14-20 DAYS 28-34 DAYS 42-48 DAYS 56-62 DAYS 70-76 DAYS 84-90 DAYS 98-104 DAYS 112-118 DAYS 126-132 DAYS 140-146 DAYS 154-160 DAYS 168-174 DAYS 182-188 DAYS 196-202 DAYS 210-216 DAYS 224-230 DAYS 238-244 DAYS 252-258 DAYS 266-272 DAYS 280-286 DAYS 294-300 DAYS 308-314 DAYS 322-328 DAYS 336-342 DAYS 350-356 DAYS Rate per 100,000 infants

Dose 1 Dose 2 Dose 3 (for RotaTeq) from Tate et al. Pediatrics 2008;121:e1125-e1132

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info@mini-sentinel.org 12

Self-controlled risk interval design

 Each subject serves as own control; adjusts for

individuals’ characteristics that don’t change ____↓Ι___Ι_______Ι__________Ι_______ 0 1 7 22 42 days after vaccination

 Adjust for age-specific risk of intussusception using

logistic regression with offset term

vaccinated primary risk window comparison window

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info@mini-sentinel.org 13

Cohort design

 Uses exposed and unexposed person-time in 1st year

  • f life from whole population

Pt 1 __↓ Pt 2 ______________ Pt 3 _____RV_____________↓ Pt 4 __RV_______________________ Pt 5 __________________RV_↓

 Adjust for age-specific risk of intussusception using

Poisson regression with polynomial risk function

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info@mini-sentinel.org 14

Complementarity of designs

Design Pros Cons Self-controlled Controls well for

fixed risk factors,

e.g. race/ethnicity

Requires accurate age-specific incidence for age adjustment

Cohort

Higher statistical power; extrinsic background rates not needed Could be affected by residual confounding

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info@mini-sentinel.org 15 www.mini-sentinel.org/work_products/Statistical_Methods/Mini-Sentinel_Methods_Framework- for-Assessment-of-Signal-Refinement-Positive-Results.pdf

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Concern To address concern

  • 1. Data validity

Examine descriptive statistics in detail

  • 2. Systematic bias
  • a. Misclassification
  • i. Of exposure

Review charts to confirm RV exposure (type, dose number) Use 2 risk windows, 1-7 d and 1-21 d

  • ii. Of outcome

Review charts to confirm intussusception

  • b. Selection bias

Use exposed and unexposed person-time from same people (with self-controls and with the cohort)

  • c. Confounding

Use SCRI analysis to adjust for fixed risk factors Use multivariate adjustment in regression modeling Age: Adjust for age in all analyses, using either age- specific incidence from literature or in M-S data

List of concerns adapted from Mini-Sentinel Framework for Assessment of Positive Results (1st of 2 slides)

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info@mini-sentinel.org 17

Concern To address concern

  • 3. Magnitude of

influence of systematic error on risk estimates Quantitative bias analysis Examples: Re-do analyses including possible cases (neither confirmed nor ruled out) Re-do analyses taking into consideration cases whose charts were not obtained

Adapted from Mini-Sentinel Framework for Assessment of Positive Results (2nd of 2 slides) Additional secondary analysis: examine pattern in timing of onset after vaccination, using age-adjusted temporal scan statistics

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 Final results available by fall 2013