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closeReferee Comments: Referee 1
Posted by PLOS_ONE_Group on 03 May 2007 at 14:00 GMT
Reviewer #1's Review
“Using a cohort of 90 families with 90 Hodgkin's lymphoma (HL) index cases, the authors investigated the role of the KIR gene cluster on HL. By applying a step by step process, the authors were able to reconstruct haplotypes and carry out specific family-based analyses. Based on their findings the authors conclude that KIR3DS1 and/or 2DS1 (they are in LD with one another) were associated with protection. Further, the protective effect of these KIRs tended to be stronger in HL patients with detectable EBV in blood or tumour cells. However, the authors were unable to reproduce their results in a case/control study. This is the first study to provide evidence for the role of KIR in HL.
This study examines the role of the KIR genes in HL using a family-based approach. Based on their findings the authors conclude that KIR3DS1/2DS1 are significantly associated with protection, and this protection seems to be stronger in patients with detectable EBV in blood or tumour cells. However, the authors were unable to reproduce their results in a case/control study. In general, the analyses are appropriate and the study was carefully carried out.”
N.B. These are the general comments made by the reviewer when reviewing this paper. Specific points addressed during revision of the paper are not shown.
RE: Referee Comments: Referee 1
cbesson replied to PLOS_ONE_Group on 07 May 2007 at 15:04 GMT
In order to understand the lack of reproducibility between the family study and the case/control study, we first searched for differences between the two study populations. There did not appear to be a difference of ethnicity between the two studies since cases and controls of non Caucasian origin were excluded from the analysis. However, the case/control population has been recruited in the Northern, Western and Southern parts of France whereas the familial cases were included in the Paris area. We do not think that this limited geographical difference could explain the lack of replication we noticed here.
There is also a difference in age distribution between the two populations. The cases recruited in the familial population are between 15 and 35 years old while the cases of the case/control study are between 18 and 71 years old. When the analysis in the case/control sample was limited to the 32 HL patients aged between 18 and 35, no significant association with KIR alleles was observed. However, in this situation, the sample is small and we certainly have a lack of power. Another difference between the two samples is that EBV viral loads were not available in the case/control sample, while this information appears to influence the strength of association in the familial sample.
Finally, in the case/control sample, the control population has been recruited in hospital mainly and we cannot exclude an unknown selection bias of controls. This potential bias is fully overcome by the familial design since the control alleles are the non transmitted parental alleles. This is a major strength of family-based association studies over the case/control association studies, and why we think that the results we observed in the familial sample are the more reliable.