ATTACHMENT C
This attachment summarizes the substantive issues raised in the committee’s previous report (NASEM 2020) concerning the general systematic review methods and the evaluation of the human evidence. Because NTP decided to base its conclusions on the human evidence, it did not re-evaluate the animal evidence to address the committee’s previous concerns. Instead, it added a disclaimer to the revised monograph and left the original text unchanged. For that reason, the committee’s concerns regarding the animal evidence are not listed here.
Committee Issue on Methods and Communication | NTP Response |
---|---|
Role of OHAT Handbook unclear | NTP added foreword to monograph and text to protocol to clarify relationship. |
Details missing from protocol | NTP added text to protocol and monograph to clarify literature search strategy and to clarify assessment of animal data. |
Absence of exclusion–inclusion criteria from protocol | No information provided. |
Lack of justification for some decisions | NTP added information to the monograph on SWIFT-Active screener to justify approach. |
Inconsistencies between protocol and monograph | NTP clarified text in protocol and monograph concerning critical confounders to evaluate. |
Communication concerning how monograph can be used (or not) to inform water fluoridation concentrations | No information provided. |
Committee Issue on Evaluation of Human Evidence | NTP Response |
Potential for Biased Selection of Studies | NTP conducted supplemental searches of Chinese databases and identified additional studies. |
Lack of Independence of Studies | NTP revised the monograph to indicate the multiple publications on the same population. However, when conducting the meta-analysis, NTP included more than one publication for a single study population in at least one case. |
Inconsistent Application of Risk-of Bias Criteria | NTP added Appendix 4. |
Evaluation of Confounding Insufficient, Difficult to Understand, or Applied Inconsistently | NTP revised text to identify clearly key confounders that applied to all study populations. NTP added Appendix 4. |
Possibility of Exposure Misclassification | NTP added Appendix 4. |
Need for Further Consideration of Failure to Blind Examiners | NTP added Appendix 4. |
Flawed Measures of Neurodevelopmental and Cognitive Outcomes | NTP verified lower risk-of-bias studies that did not provide direct evidence of imprecision or lack of blinding. |
Lack of Rigorous Statistical Review | NTP examined studies identified by committee and included discussion in Appendix 4. |
Need to Juxtapose Results across Broadly Comparable Studies | NTP conducted subgroup analyses as part of meta-analysis to address heterogeneity in the data and further analyze consistency of data. |
Need to Consider Conducting Meta-Analysis | NTP updated meta-analyses and conducted new meta-analysis using individual-level exposure data. |
Lack of Support for Conclusion that Effects Occur at Higher Fluoride Doses | NTP conducted dose–response analysis as part of meta-analysis. |