SYSTEMATIC REVIEW TO EVALUATE THE EVIDENCE FOR AN ASSOCIATION BETWEEN PERFLUOROOCTANOIC ACID (PFOA) OR PERFLUROOCTANE SULFONATE (PFOS) EXPOSURE AND IMMUNOTOXICITY April 9 2013 Office of Health Assessment and Translation Division of the National Toxicology Program National Institute of Environmental Health Sciences This draft document is being disseminated to obtain public comment. It does not represent and should not be construed to represent any NTP determination or policy. Draft (April 9, 2013) TABLE OF CONTENTS Step 1: Prepare the topic .................................................................................................................... 1 Background ........................................................................................................................................... 1 Rationale for topic ........................................................................................................................ 1 Use of protocol as a case study to assess OHAT’s Draft Approach for Systematic Review and Evidence Integration for Literature-Based Health Assessments ........................ 2 Objectives ............................................................................................................................................. 2 Specific aims: ................................................................................................................................ 3 Eligibility criteria for considering studies for this review ..................................................................... 3 Types of studies ............................................................................................................................ 3 Types of human studies and model systems ................................................................................ 3 Types of exposures ....................................................................................................................... 3 Types of outcomes ....................................................................................................................... 3 Types of publications .................................................................................................................... 5 Step 2: Search for and select studies for inclusion ............................................................................... 5 Electronic searches ............................................................................................................................... 5 Databases to be searched ............................................................................................................ 5 Ongoing Trials databases .............................................................................................................. 6 Searching other resources .................................................................................................................... 6 Hand searches .............................................................................................................................. 6 Grey literature and public request for information ..................................................................... 6 Screening studies for eligibility ............................................................................................................. 8 Planned interim analyses.............................................................................................................. 8 Step 3: Extract data from studies ...................................................................................................... 10 Data extraction and management ...................................................................................................... 10 Missing data................................................................................................................................ 10 Summarizing study design, experimental model, methodology, and results .................................... 10 Step 4: Assess quality of individual studies ....................................................................................... 15 Human and animal studies ................................................................................................................. 15 Each of the risk of bias questions is answered on a 4 point scale: ............................................. 16 Rules for non-reporting .............................................................................................................. 16 Consideration of timing and duration of exposure in relation to health outcome assessment ........................................................................................................................... 16 Consideration of source of funding and disclosed conflict of interest ....................................... 19 Determining Tiers of Study Quality ............................................................................................ 19 In vitro studies and other relevant data ............................................................................................. 23 In vitro studies ............................................................................................................................ 23 Other relevant data .................................................................................................................... 23 Data Display .................................................................................................................................... 23 Software used for data management, analysis, and display .............................................................. 24 Step 5: Rate confidence in body of evidence ..................................................................................... 30 Evaluation of PFOA or PFOS Exposure and Immunotoxicity ii Draft (April 9, 2013) Planned interim analyses............................................................................................................ 32 Initial confidence based on study design ............................................................................................ 35 Domains that can reduce confidence ................................................................................................. 35 Risk of bias across studies .......................................................................................................... 35 Unexplained inconsistency ......................................................................................................... 38 Directness and applicability ........................................................................................................ 41 Imprecision ................................................................................................................................. 44 Publication bias........................................................................................................................... 46 Domains that can increase confidence ............................................................................................... 47 Large magnitude of association or effect ................................................................................... 47 Dose-response ............................................................................................................................ 48 Plausible confounding or other residual biases that would increase our confidence in estimated effect ................................................................................................................... 50 Consistency across study types, experimental model systems, or populations ........................ 50 Other ........................................................................................................................................... 51 Combine confidence conclusions for all study types and multiple outcomes ................................... 51 Step 6: Translate Confidence Ratings into Level of Evidence for Health Effect .................................... 52 Step 7: Integrate evidence to develop hazard identification conclusions ............................................ 54 Assessment of biological plausibility provided by other relevant studies .......................................... 56 Data that inform the biological plausibility of observed outcomes from in vivo data ............... 56 Strength of in vitro studies in the absence of human or animal in vivo data ............................ 58 Peer-Review .................................................................................................................................... 58 Review Team ................................................................................................................................... 59 Author Declarations of interest ........................................................................................................ 59 Technical advisors ............................................................................................................................ 59 Sources of support ........................................................................................................................... 59 Internal sources .......................................................................................................................... 59 External sources ........................................................................................................................