STATISTICAL ANALYSIS

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based on the Danish national birth cohort. Am J Epidemiol 2009; 169: 313–22.

6. Gray R., Mukherjee R. A. S., Rutter M. Alcohol consumption during pregnancy and its effects on neurodevelopment: what is known and what remains uncertain. Addiction 2009; 104: 1270–3.

7 Kesmodel U., Kesmodel P. S., Larsen A., Secher N. J. Use of alcohol and illicit drugs among pregnant Danish women, 1998. Scand J Public Health 2003; 31: 5–11.

8. Olsen J., Frische G., Kirchheiner H., Poulsen A. O. [Alcohol- drinking habits among pregnant women in Odense 1985– 1986]. Ugeskr Laeger 1987; 149: 1420–2.

9. Tolstrup J. S., Nordestgaard B. G., Rasmussen S., Tybjaerg- Hansen A., Gronbaek M. Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes. Pharma- cogenomics J 2008; 8: 220–7.

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THE NEED FOR MORE QUASI- EXPERIMENTAL STUDIES OF ALCOHOL CONSUMPTION DURING PREGNANCY

The review by Gray, Mukherjee & Rutter [1] presents succinctly and accurately what we do and do not (unfortunately) know concerning the effects of alcohol consumption during pregnancy (ACDP). The review highlights two key problems related to extant human studies of ACDP: (i) the difficulties in understanding the implications of variability in the quantity, pattern and timing of alcohol exposure and (ii) the potential of corre- lated risks to confound the associations between ACDP and offspring neurodevelopmental traits. I will focus on the latter concern, although research obviously relies heavily on clearly defined and accurate measurement. One of the major recommendations the authors make is that researchers should use natural experiments, or quasi-experimental approaches, which help to delineate between the possible causal influence of ACDP and the effects of covarying risks. The purpose of this commen- tary is to emphasize this need further and provide additional examples of quasi-experimental designs to encourage additional research in this area. Interestingly, many of these approaches have been used to study the effects of an associated risk, that of maternal smoking during pregnancy (SDP) [2].

As Gray and colleagues [1] point out, the comparison of differentially exposed siblings is a research approach that can help to rule out confounding genetic and envi- ronmental risks [3,4]. Converging evidence from sibling comparison studies suggests that SDP is associated inde- pendently with pregnancy-related outcomes (e.g. birth weight and placenta ruptures) [5–8], consistent with a causal inference. However, recent sibling-comparison studies indicate that the association between SDP and later neurodevelopmental traits, such as intellectual abilities/academic achievement [7–10] and childhood

conduct problems [6,7], are due to family background factors, not the teratogenic effects of SDP. As such, the findings suggest that the underlying causal mechanisms related to SDP depend upon the specific trait being studied. Very few sibling comparison studies, however, have explored ACDP [11].

The Children of Twins (CoT) design, an extension of the cousin comparison design that accounts for environ- mental factors that influence all family members in an extended family, and genetic factors passed down from the twin parent [12–14], can also be used to study pre- natal risks. A CoT study found an independent associa- tion between SDP and offspring birth weight [13], providing converging evidence with sibling-comparison studies. There are two extant CoT studies of ACDP; they do not, however, provide consistent results concerning the association between ACDP and offspring attention deficit hyperactivity disorder [15,16].

Researchers are also incorporating numerous quasi- experimental approaches into studies to test simulta- neously alternative causal processes and account for limitations/assumptions inherent in each. For example, a comparison of differentially exposed full siblings, half- siblings, full cousins (offspring of full siblings) and half- cousins (offspring of half-siblings) suggests that genetic factors passed down from mothers and fathers account for the statistical association between SDP and offspring academic functioning [10]. I am unaware of any such studies of ACDP.

Many different quasi-experimental (or natural ex- periments) can be used to study ACDP (reviews in [2,17]). In designing future studies of ACDP, researchers should consider including multiple offspring per family, numerous mothers (and their offspring) in extended families, and twin families. Future studies should also consider including adopted individuals [18], partner drug use during pregnancy and biomarkers to use Mendelian randomization, as recommended by Gray et al. [1]. These designs will provide invaluable insight into the role of ACDP, but such research requires special resources (e.g. access to twin registries) and the passage of considerable time to follow a sample longitu- dinally. In the meantime, are there data sets available to researchers with multiple siblings, cousins or offspring of twins, which include assessments of ACDP and offspring adjustment? Such secondary data analysis projects frequently require the use of less than ideal assessments of alcohol use (e.g. [11]), but the field needs many studies, using multiple samples and designs (each with their own strengths and weaknesses) to draw stronger inferences regarding the putative effects of ACDP [17].

Certainly, more animal research and family studies of ACDP need to be completed. Given the potential role of

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confounding variables, however, the design and imple- mentation of new natural experiments and the use of existing quasi-experimental studies will be crucial for our understanding of ACDP.

Acknowledgements

Special thanks to Valerie Knopik and Amber Singh for their help preparing the text. The author is supported by grants from NICHD (HD056354 and HD053550) and Indiana University (Faculty Research Support Program).

Keywords Alcohol, children of twins, natural experiments, pregnancy, quasi-experiments, sibling comparisons.

BRIAN M. D’ONOFRIO

Indiana University Bloomington, Department of Psychological and Brain Sciences,

1101 East 10th Street, Bloomington, IN 47405, USA. E-mail: bmdonofr@indiana.edu

References

1. Gray R., Mukherjee R. A. S., Rutter M. Alcohol consumption during pregnancy and its effects on neurodevelopment: what is known and what remains uncertain. Addiction 104: 1270–3.

2. Knopik V. S. Maternal smoking during pregnancy and child outcomes: real or spurious effect? Dev Neuropsychol 2009; 34: 1–36.

3. Rodgers J. L., Cleveland H., van den Oord E., Rowe D. Resolv- ing the debate over birth order, family size, and intelligence. Am Psychol 2000; 55: 599–612.

4. Lahey B. B., D’Onofrio B. M., Waldman I. D. Using epidemio- logic methods to test hypotheses regarding causal influences on child and adolescent mental disorders. J Child Psychol Psychiatry 2009; 50: 53–62.

5. Cnattingius S. The epidemiology of smoking during preg- nancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res 2004; 6: S125–40.

6. D’Onofrio B. M., Van Hulle C. A., Waldman I. D., Rodgers J. L., Harden K. P., Rathouz P. J. et al. Smoking during preg- nancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol 2008; 20: 139–64.

7. Gilman S. E., Gardener H., Buka S. L. Maternal smoking during pregnancy and children’s cognitive and physical development: A causal risk factor? Am J Epidemiol 2008; 168: 522–31.

8. Lundberg F., Cnattingius S., D’Onofrio B., Altman D., Lambe M., Hultman C. et al. Maternal smoking during pregnancy and intellectual performance in young adult Swedish male offspring. Paediatr Perinat Epidemiol 2009; in press.

9. Lambe M., Hultman C., Torrang A., MacCabe J., Cnattingius S. Maternal smoking during pregnancy and school perfor- mance at age 15. Epidemiology 2006; 17: 524–30.

10. D’Onofrio B. M., Singh A. L., Iliadou A., Lambe M., Hultman C., Neiderhiser J. M. et al. A quasi-experimental study of maternal smoking during pregnancy and offspring aca- demic achievement. Child Dev 2009; in press.

11. D’Onofrio B. M., Van Hulle C. A., Waldman I. D., Rodgers J. L., Rathouz P. J., Lahey B. B. Causal inferences regarding prenatal alcohol exposure and childhood externalizing problems. Arch Gen Psychiatry 2007; 64: 1296–304.

12. Silberg J. L., Eaves L. J. Analyzing the contribution of genes and parent–child interaction to childhood behavioral and emotional problems: a model for the children of twins. Psychol Med 2004; 34: 347–56.

13. D’Onofrio B. M., Turkheimer E., Eaves L. J., Corey L. A., Berg K., Solaas M. H. et al. The role of the Children of Twins design in elucidating causal relations between parent char- acteristics and child outcomes. J Child Psychol Psychiatry 2003; 44: 1130–44.

14. Heath A. C., Kendler K. S., Eaves L. J., Markell D. The resolution of cultural and biological inheritance: informa- tiveness of different relationships. Behav Genet 1985; 15: 439–65.

15. Knopik V. S., Heath A. C., Jacob T., Slutske W. S., Bucholz K. K., Madden P. A. F. et al. Maternal alcoholism and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design. Psychol Med 2006; 2006: 1461–71.

16. Knopik V. S., Jacob T., Haber J. R., Swenson L. P., Howell D. N. Paternal alcoholism and offspring ADHD problems: the chil- dren of twins design. Twin Res Hum Genet 2009; 12: 53–62.

17. Rutter M., Pickles A., Murray R., Eaves L. J. Testing hypoth- eses on specific environmental causal effects on behavior. Psychol Bull 2001; 127: 291–324.

18. Neiderhiser J. M., Leve L. D., Ge X., Scaramella L. V., Conger R. D., Reid J. B. et al. The impact of prenatal drug exposure on toddler behavior: distinguishing genetic effects from exposure using an adoption design. Behav Genet 2007; 37: 780.

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NEURODEVELOPMENT AND PRENATAL ALCOHOL CONSUMPTION

We are grateful for this opportunity to respond to the commentaries on our paper [1]. While there is general agreement on making more use of natural experiments to draw causal inference there is also a concern that two of the main problems, misclassification of exposure and confounding, may continue to pose problems and should be addressed. We agree fully with this assessment. More- over, it was, in part, to deal with these problems that we suggested the natural experiment approach.

While the issue of accurate measurement and classi- fication of alcohol consumption during pregnancy is important, we do not agree with O’Leary & Bower’s sug- gestion that we need to improve this before going on to develop new research designs [2]. Rather, we would see these aims as complementary. Furthermore, given the social undesirability of drinking during pregnancy in many countries and the difficulties in accurate appraisal and recall of quantity, frequency and timing of drinking behaviour by self-report, we doubt that this problem could be eliminated, although the use of more consistent methods for classifying maternal alcohol consumption throughout pregnancy may improve matters.

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