Program outline

1
Program outline

• Welcome (Pr Geneviève Chêne)
• Meta-analysis principles (Pr Louis Rachid Salmi)
• SYROCOT protocol (Dr Ruth Gilbert Rodolphe
  Thiébaut)
• rationale
• Cochrane protocol version 2
• Study process
• selection of the studies
• contact to the investigators
• materials requested
• Current status of the study
• Plan of statistical analyses

2
SYstematic Review Of the effect of timing and
type of prenatal treatment on COngenital
Toxoplasmosis

• SYROCOT

www.isped.u-bordeaux2.fr/ISPED/RECHERCHE/SYROCOT/F
R-ISPED-SYROCOT.htm
3
Cochrane protocol version 2published in Issue 1,
2003

• Systematic Review on Congenital Toxoplasmosis

4
Rationale

• Question What is the effect of prenatal
  treatment
• On transmission from the mother to the child
• On clinical signs in the child
• Answer ?
• No randomised clinical trial
• Results from observational studies
• Discrepancies
• Methodological issues

5
Rationale

• What are the main methodological issues?
• Bias
• Systematic error
• Several kind of bias
• Heterogeneity
• Uncertainty

6
Rationale
S/C -
Serology
Transmission -
S/C
Clinical signs -
S or PS
Transmission
S and PS
Clinical signs
S and PS
Selection biasSerologyif suspicion
Indication biasPS if transmission
Confusion bias gestation at SC
Measurement and attrition bias(followed if
treated)
7
Rationale

• Selection bias
• Some women are referred for a serological
  diagnosis because of a suspicion of signs in
  fetus
• Diagnosis of S/C and transmission at the same
  time
• No time lag to be treated
• Increased risk of transmission in untreated
  patients

8
Rationale

• Confusion bias

Treatment
Transmission
Gestational age at seroconversion
9
Rationale

• Indication bias
• Women are treated because of a high risk of
  infection in fetus
• To be untreated seems to be protector
• Attrition bias
• Children with poorest prognostic are more likely
• followed (increase probability of finding signs)
• treated
• To be untreated seems to be protector because
  signs are not diagnosed in this group

10
Rationale

• What are the main methodological issues?
• Bias
• Heterogeneity
• Due to type of screening, lab assays, treatment,
  local epidemiology
• Consequences
• A noise with few data
• An information with enough data
• Is there any factor that modifies the prenatal
  treatment effect ?
• Uncertainty

11
Rationale

• What are the main methodological issues?
• Bias
• Heterogeneity
• Uncertainty
• In evaluation of gestation at seroconversion
• Increase variability if taken into account

12
Rationale

• Arguments for a systematic review
• discrepancies in published results
• explore heterogeneity
• Arguments for an IPD analysis
• methods for taking into account the strong effect
  of gestational age at maternal seroconversion
  were often not consistent
• differences in handling of potential biases
• lack of variability of treatment measure and / or
  limited applicability

13
Objectives

• The study aims to explore the effect of the
  timing and type of prenatal treatment on
• a) mother to child transmission of T.gondii
• b) clinical manifestations in children with
  congenital toxoplasmosis
• With a special interest on the factors associated
  with a variation of this effect (heterogeneity)

14
Structure

• The systematic is composed by two studies
• Mother to child transmission study
• Clinical manifestations study
• Three level of information are distinguished
• Study
• Centre
• Patient

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Inclusion criteria for studies

• Transmission study
• Cohort studies identifying seroconverting women
  by prenatal screening
• Required data collected
• Dates of last negative / first positive test
• Prenatal treatment starting date
• Date of birth
• Congenital infection status based on serologic
  status at 12 months postnatal age

16
Inclusion criteria for studies

• Clinical signs
• Cohort studies of children with congenital
  toxoplasmosis identified by prenatal or neonatal
  screening for maternal toxo
• Required data collected
• Prenatal treatment starting date
• Date of birth
• Congenital infection status based on serologic
  status at 12 months postnatal age
• Results of at least one ophtalmoscopy or
  intracranial imaging examination

17
Inclusion criteria for participants(primary
analyses)

• Transmission study
• delivery after 1979
• whatever the outcome of pregnancy
• infected women without a negative test during
  pregnancy excluded
• mother-child pairs suspected to have been
  referred for testing due to problems excluded

18
Inclusion criteria for participants(primary
analyses)

• Signs study
• live born children with confirmed congenital
  toxoplasmosis
• mother-child pairs suspected to have been
  referred for testing due to problems excluded

19
Types of outcome measure

• For transmission congenital infection
• Persistence of IgG beyond 12 months of age or in
  fetal losses or postnatal death, a positive
  culture or PCR result other criteria (PCR,)
• Absence of congenital infection undetectable
  specific IgG gt 2 mo of age
• For signs clinical manifestations
• Retinochoroiditis
• Intracranial lesions

20
Search strategy

• Electronic search undertaken using
• MEDLINE (1980-2002)
• EMBASE (1980-2002)
• PASCAL (1987-2002)
• No language restriction
• Contact with experts and investigators

21
Methods of the review

• Abstracts scanned by two reviewers (RT RG)
• Eligible studies retrieved in hard copy
• If agree or at least one reviewer need
• Eligible studies assessed by two reviewers
  against the inclusion criteria using a standard
  checklist

22
Methods of the review

• Quality of observational studies
• Prospective or retrospective
• Available information
• Dates of first positive test, treatment starting
  date, prenatal diagnosis
• Congenital infection status based on IgG beyond
  11 months
• Results for ophtalmoscopy or intracranial imaging
  examination

23
Study process

• Systematic Review on Congenital Toxoplasmosis

24
Study process

• Studies selection (see doc 1)
• Contact to investigator (see doc 2)
• Ask for eligibility, feasibility
• Ask for other potential eligible studies
• Sign agreement (see doc 3)
• Send datasets
• Data extraction (see doc 4)

25
Current status of the study

• Systematic Review on Congenital Toxoplasmosis

26
Current status (1)
27
Current status (2)
28
Current status

• Embase research
• N12 new papers
• N2 new studies
• N1 new cohort
• Pascal research
• Agreements
• 4/13 studies other than EMSCOT
• 8/13 centres from EMSCOT

29
Plan of statistical analyses

• Systematic Review on Congenital Toxoplasmosis

30
Principles

• Two analyses transmission and signs
• Main analyses dealing with issues as simply as
  possible
• Other analyses
• Secondary analyses
• Sensitivity analyses

31
Outcome

• For transmission congenital infection
• Persistence of IgG beyond 12 months of age or in
  fetal losses or postnatal death, a positive
  culture or PCR result
• Absence of congenital infection undetectable
  specific IgG gt 2 months of age
• Other definitions
• IgM, IgA before 6 months
• PCR or culture of amniotic fluid or fetal
  products
• Clinician opinion

32
Outcome

• For signs clinical manifestations
• Signs in the first year of age
• Ocular and intracranial lesions are investigated
  separately
• Retinochoroiditis by ophtalmoscopy on at least
  one examination
• Intracranial lesions
• calcifications, hydrocephalus, ventricular
  dilatation
• analyses grouped by type of examination

33
Type of intervention

• Type of first prenatal treatment
• (Spiramycine, pyrimethamine-sulphonamide, none)
• Prenatal treatment delay
• the interval between seroconversion and start of
  treatment (or delivery for untreated women)
• as a continuous variable if the effect is linear

34
Covariates

• Patient level
• gestation at seronconversion
• postnatal treatment
• maternal age, year of birth, parity, length of
  gestation
• Centre level
• geographic situation
• test schedule
• (postnatal treatment)
• Study level
• Prospective / retrospective
• Quality score based on completeness

35
Main analysis

• Hierarchical model accounting for levels
  (patient, centre, study)
• Adjustment for potential confounders(gestation
  at seroconversion)
• Interaction of covariates with treatment effect
  to study heterogeneity

36
Secondary analyses

• Effect of treatment throughout pregnancy
• Spir, Spir changed to PS, PS only, none
• Excluding women who underwent a prenatal
  diagnosis for transmission analysis
• Sub-group analysis on women who seroconverted
  during late pregnancy for transmission analysis
• Analysis including additional covariates
• type of delivery
• birth weight
• breastfeeding

37
Sensitivity analyses

• Handling of uncertainty of gestation at
  seroconversion
• Assess accuracy of outcome definition
• Effect of congenital infection definition
• Signs detected beyond 1 year
• Assessment of bias
• Publication bias (funnel plot)
• Selection bias (referred cases initially
  excluded)
• and any suggestions by investigators

38
Report of the results

• Based on MOOSE (Meta-analysis Of Observational
  Studies in Epidemiology)Donna Stroup et al. JAMA
  2000, 283 2008-12
• With a particular emphasis on
• heterogeneity assessment
• sensitivity testing