Developmental studies, statistics

H. Abbey and E. Howard, Statistical procedure in developmental studies on... 

Process validation can be done in different ways, viz. prospectively, by carrying out a planned program of experiments, before routine production is started concurrently, during routine production retrospectively, by statistical analysis of historical data and during scale-up studies (developmental validation). 

The test statistics from a Mann-Whitney are linearly related to those of Wilcoxon. The two tests will always yield the same result. The Mann-Whitney is presented here for historical completeness, as it has been much favored in reproductive and developmental toxicology studies. However, it should be noted that the author does not include it in the decision tree for method selection (Figure 22.2). 

Developmental Effects. Developmental effects associated with exposure of humans to endrin have not been reported. Prenatal exposure of animals to concentrations of endrin sufficient to cause maternal toxicity has resulted in a statistically significant increase in the incidence of fused ribs, cleft palate, exencephaly, microencephaloceles, and open eyes in hamsters and mice. Effects were not necessarily reproducible between studies. Adverse developmental effects generally have not been observed in rats (Kavlock et al. 1981) except for temporary increase in locomotor activity of pups (Gray et al. 1981) and delayed ossification at doses which resulted in maternal toxicity (Goldenthal 1978a). Developmental effects were found primarily in one species. It is unknown if these effects would occur in humans. 

The prenatal developmental toxicity study design includes sacrifice of the rodent or rabbit dam one day prior to expected delivery, in order to ensure that malformed fetuses are not lost to maternal cannibalism. .. Nevertheless, even the prenatal developmental toxicity study does not allow the researcher to distinguish the source or cause of prenatal mortality. Intrauterine deaths may be the result of malformations that are incompatible with continuing viability... The contribution of malformed fetuses to overall effect on litter viability can be appropriately analysed by combining the litter incidence of conceptuses that are malformed, resorbed (early and late), and dead (full term but nonviable at caesarean section) and performing appropriate statistical analyses of group values (13). 

Jarvis P et al (2010) The cynomolgus monkey as a model for developmental toxicity studies variability of pregnancy losses, statistical power estimates and group size considerations. Birth Defects Res B Dev Reprod Toxicol 89 175-187... 

Historical control data is an essential component of the study directors toolbox for interpreting reproductive and developmental toxicity data. Scientific judgment and expertise should be used to determine if historical control data is needed for interpretation of study data, which historical control data is appropriate, and how it should be used to support interpretation of a finding. This tool can be a valuable addition to a comprehensive assessment of the study data, which includes determining whether a dose-response is present and whether any statistically significant findings occurred. Sound data interpretation requires that the litter, not the fetus or pup, be used as the experimental unit in developmental and reproductive toxicity studies. For continuous data (e.g., fetal weight). 

Although childhood cases are rare (McKenna et ah, 1994), schizophrenia has been identified in children since its earliest descriptions. Despite this, the nosological status of schizophrenia in children was controversial for many years, and the Diagnostic and Statistical Manual of Mental Disorders, 2nd ed. (DSM-II) category childhood schizophrenia included other psychotic disorders in children as well as autistic disorder, limiting the usefulness of early studies. The landmark studies by Kolvin (1971), however, clearly differentiated schizophrenia with onset in childhood from pervasive developmental disorders. 

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