Is there a phenotypic difference between probands in case‐control versus family‐based association studies?

Recently, Malhotra et al. [2002] investigated whether probands from case-control (CCPs) and family-based association studies (FBPs) of schizophrenia differed in phenotypic features. We thank the authors for their attempt to address our recent finding on this issue in a large sample of patients with bipolar affective disorder [Schulze et al., 2001]. Bruun and Ewald [1999] were the first to suggest that CCPs and FBPs might differ on genetically influenced phenotypic characteristics. Subsequently, we compared 122 CCPs and 54 FBPs with bipolar disorder and observed that CCPs presented with a significantly higher age at onset as well as with a significantly elevated frequency of suicidal behavior [Schulze et al., 2001]. Malhotra et al. [2002] argue that our findingmight be due merely to the fact that we did not match our two groups for factors like age at interview or gender. However, they do not mention that we performed a logistic regression analysis to control for age at interview, duration of disease, and gender. This analysis corroborated our observation that the frequency of suicidal behavior differed between CCPs and FBPs. Furthermore, Malhotra et al. [2002] suggest that undetected ethnic differences between CCPs and FBPs in our study sample might have led to the differences we observed. We might not have been precise enough on the homogeneity of our sample: All patients in our study were of German descent and had been systematically recruited in a well-defined catchment area (university hospital and mental state hospital serving the city of Bonn and its immediate vicinity). The study by Bruun and Ewald [1999] and our study [Schulze et al., 2001] focus on bipolar affective disorder. Malhotra et al. [2002] are the first to investigate this issue for patients enrolled in studies on schizophrenia. They analyzed whether CCPs and FBPs differed on age at onset of psychotic symptoms and cognitive functioning. They did not find significant differences for age at onset of psychotic features or any of the 7 measures on cognitive functioning included in their test battery. However, a close look at the study of Malhotra et al. [2002] raises serious questions about their conclusion that there are no phenotypic differences between CCPs and FBPs in this sample. First, in contrast to the study by Bruun and Ewald [1999] and our study [Schulze et al., 2001], Malhotra et al. [2002] apparently do not have a diagnostically homogenous sample. The authors report that they ‘‘have studied a group of 37 CCPs and 37 FBPs with a primary diagnosis of schizophrenia or other axis I psychotic disorder. ’’ Thus it remains unclear how many patients actually fulfilled DSM-IV criteria for schizophrenia. The authors claim that they ‘‘rigorously matched the subjects. ’’ Were these subjects matched for their diseasephenotype? This is akey issue ina study on phenotypic differences. Second, the study sample byMalhotra et al. [2002] (37 CCPs and 37 FBPs) is very small by any standards and considerably smaller than the sample we studied (122 CCPs and 54 FBPs). The authors claim that they had sufficient power to detect differences on their cognitive measures, if present. Power estimates for a matched pair design require assumptions about the expected difference in themeansaswell as the standarddeviation of the difference scores. Malhotra et al. [2002] state that they based their power estimate of 84% on the assumption of ‘‘a moderate effect size (i.e., a difference between groups of one half a standard deviation for each measure). ’’ For sample sizes equal to or larger than 34 comparison pairs, the power at an alpha level of 0.05 is indeed larger than 80%. Yet, for four out of the seven cognitivemeasures they tested, the authors had data on fewer than 34 pairs, resulting in a power as low as 67%. Furthermore, since age at onset is not a normally distributed variable, applying a t-test, which assumes a normal distribution will further limit the chance to detect an effect. These statistical issues are important, since they directly affect the ability of this study to reject the null hypothesis correctly. For instance, given the small sample size, the result on the CVLT (P1⁄40.079) might become significant if a fewmore individuals were included. For the variable ‘‘age at onset of psychotic *Correspondence to: Thomas G. Schulze, M.D., National Institute of Mental Health, Mood and Anxiety Disorders Program, Bldg. 36 Rm. 4C12, 36 Convent Drive, Bethesda, Maryland 20892. E-mail: schulzet@intra.nimh. nih.gov