# Presentation: 623679

## Chlorpyrifos Exposure and Neurobehavioral Outcomes in Infants and Pre-School Children:  

- Pamela Mink, Ph.D., M.P.H.
- Assistant Professor of Epidemiology
- Rollins School of Public Health
- Emory University
- September 16, 2008

**Epidemiologic Interpretation and Comments Regarding **
**Rauh et al. 2006**

## Context

- US EPA is seeking comments on the following issue:
- 	“*Interpretation of recent epidemiological studies associating in utero and/or post-natal chlorpyrifos exposure with health outcomes*” (Federal Register 2008)
- Neurobehavioral outcomes in infants and pre-school children
- Interpretation of Rauh et al. 2006
- Charge 4 to SAP, Issue Paper Sections 2.3.1.2 and 3.4, Appendix D, and Supplemental Documents submitted by Dr. Rauh

## Overview

- 	RE:  Rauh et al. 2006 *(Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children)*
- Neurobehavioral Testing
- Bayley Scales of Infant Development II (BSID-II)
- Child Behavior Check List (CBCL)
- Potential Confounding
- Interpretation Issues
- Additional/Alternative Analyses

## BSID-II:  Overview

- 	The BSID-II assess mental (cognitive) and motor development in infants and toddlers.  It is a well-accepted measure for assessing infant development; however it does not provide diagnostic information.  The BSID-II is designed to sample a wide array of emergent developmental abilities and to inventory the attainment of developmental milestones.

## BSID-II:  Administration (1)

- Guidelines
- Examiners typically have training at the master’s or doctoral level and supervised experience, in accordance with guidelines from the APA
- Administrators should ensure that infants are well-fed and well-rested prior to testing
- Factors related to the testing environment can play a role in performance
- Consideration of these factors during analysis and interpretation of results

## BSID-II:  Administration (2)

- Rauh et al. 2006
- “Each child was tested under controlled conditions in the study office by a trained bilingual research assistant, checked for reliability” (p. e1848)
- Information on training/expertise of examiners not provided; details and clarification would be helpful
- Detailed information on testing environment not provided
- Only one location
- Eskenazi et al. 2007
- BSID scales were administered by “...psychometricians blind to exposure.  Psychometricians were trained using standardized protocols and were supervised for quality assurance by a clinical neuropsychologist” (p. 793)
- Statistical analyses were adjusted for certain aspects of the testing environment (e.g., examiner, location)

## Testing Administration Summary

- Implications:
- Misclassification of outcome (i.e., BSID-II scores)
- Potential for misclassification of test scores to be related to exposure (and/or, to factors related to exposure)
- Information bias
- Confounding by factors related to the testing environment also a concern
- Does Rauh et al. (2006) provide “more robust information” than other two studies? (Charge to Panel)

## Potential Confounding

- Confounder:  a factor that distorts the effect of the risk factor (exposure) under study
- Critical issue in observational studies
- For studies of neurobehavioral testing outcomes (e.g., BSID-II, CBCL), it is important to consider/evaluate the constellation of established predictors of performance
- Concern:  uncontrolled or residual confounding

## Potential Confounding Factors -1

|   | Rauh et al. 2006 | Eskenazi et al. 2007 |
| --- | --- | --- |
| Factor | Evaluated/Included in BSID-II MV Analysis? | Evaluated/Included in BSID-II MV Analysis? |
| Examiner | N | Y |
| Exact age at evaluation | N | Y |
| HOME score | Y | Y |
| Maternal Intelligence*
 | Y* | Y |
| Maternal Education  | Y | Y/N |
| Household Income | Y?/N | Y |

## Potential Confounding Factors -2

|   | Rauh et al. 2006 | Eskenazi et al. 2007 |
| --- | --- | --- |
| Factor | Evaluated/Included in BSID-II MV Analysis? | Evaluated/Included in BSID-II MV Analysis? |
| Breast feeding duration | N | Y |
| Birth weight | Y/N* | N |
| Gestational age at birth | Y | N |
| Parity | N | Y |
| Prenatal environmental tobacco exposure | Y | Y/N |
| Maternal Depression*  | N | Y (CBCL model only) |

## Confounding Summary

- Selecting, measuring, and appropriate adjustment for potential confounding factors have important implications in epidemiologic studies
- Concerns about uncontrolled or residual confounding in both studies
- The method of measuring potential confounders (e.g., maternal intelligence) may also be important

## Interpretation Issues

- Modeling Exposure (chlorpyrifos) - 1
- Authors initially categorized chlorpyrifos levels into 4 groups:
- Undetectable levels (n=80)
- Tertile 1 (n=65)
- Tertile 2 (n=39)
- Tertile 3 (n=44)
- Preliminary analyses indicated significant differences in scores on the PDI in the highest group (tertile 3) vs. each of the lower 3 groups
- In contrast, the only significant mean difference in MDI scores was between tertile 3 and tertile 1

## Interpretation Issues

- Modeling Exposure (chlorpyrifos) - 2
- Authors then created 2-level categorical variable with the highest group (tertile 3; >6.17 pg/g) being compared to the three other groups combined
- Was this appropriate?
- “The most highly exposed group and the undetectable group had lower mean MDI and PDI scores than did the middle levels.” (Rauh et al. 2006)
- “Ideal categories would be such that any important differences in risk will exist between them but not within them” (Rothman and Greenland 1998)
- By creating a 2-level variable, Rauh et al. (2006) created categories that potentially had important differences in risk within a category

## Interpretation Issues

- Modeling Outcomes (BSID-II MDI and PDI)
- BSID-II Scoring for Mental and Motor Scales (mean =100, sd = 15):
- 115 and above		Accelerated performance
- 85 – 114		Within normal limits
- 70 – 84			Mildly delayed performance
- _<_ 69*			Significantly delayed performance
- Rauh et al. (2006)
- Multivariate linear regression (continuous outcomes)
- Dichotomized scores as < 85 vs. _>_ 85
- Proportion of infants who are mildly vs. significantly delayed is not provided in the published paper; thus the reader cannot assess severity

- *Normed scores not available for scores _<_ 50.

## Additional/Alternative Analyses

- Further evaluation of potential confounding and other biases
- Additional analyses of existing data
- Sensitivity and uncertainty analyses
- Re-evaluate categorization of chlorpyrifos exposure
- Re-evaluate categorization of testing scores

## Conclusions (1)

- It would be premature to attribute observed differences neurobehavioral testing scores observed by Rauh and colleagues (2006) to chlorpyrifos exposure:
- These data should be interpreted cautiously
- Additional information about study procedures would be helpful
- Further analyses of these data are warranted
- Existing data
- Additional follow-up

## Conclusions (2)

- Limitations in Rauh et al. (2006) may have influenced the study results, and therefore hinder their interpretation:
- Testing administration protocols
- Interpretation of testing results (see written comments)
- Inappropriate categorization of exposure and outcome variables
- Incomplete control of confounding
- Potential information bias
- Potential selection bias (see written comments)

## Conclusions (3)

- Further analyses of these data (Rauh et al. 2006) would be informative, e.g.,:
- Analyses using more and/or different categories for the independent and dependent variables
- Analyses using an “unexposed” reference group
- Analyses evaluating continuous exposure and outcome variables
- Sensitivity and uncertainty analyses to evaluate potential role of bias (systematic error) on study results
- confounding, information bias [including misclassification], selection bias