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Referee comments: Referee 1 (Pierre Hainaut)

Posted by PLOS_ONE_Group on 04 Apr 2008 at 16:37 GMT

Referee 1's review (Pierre Hainaut):

This manuscript provides an interesting approach to stratify BE patients into risk of progression categories based on the combination of clinical, pathological and molecular parameters. The model proposed is flexible and may further evolve by addition/refinement of parameters. Of particular interest is the notion that DNA mehylation (in the form of a methylation index based on 3 genes) is one of the most reliable and informative component of this predictive model. This observation supports the hypothesis that progression of BE towards neoplasia involves the acquisition of a "methylator" phenotype (which may also contribute to explain the high prevalence of CpG mutations often found in genes such as TP53 in EADC).
The main limitation of the study is its small size; however, as such, the study may be relatively easy to repeat by other groups who may already have accumulated datasets of similar size.

Remarks:
1: In the introduction, more details should be given on (1) the prevalence of BE in the general population; (2) the suspected molecular mechanisms of BE progression including the roles of DNA methylation;
2: In the Methods section, how the MI is constructed should be better explained (this information is central for the paper; it is not good enough to refer to previous papers and suppl material)
3: In the Results and Discussion sections, more attention should be given to possible variation in MI assessment; this parameter is indeed likely to be more heterogenous than any of the other parameters used and criteria need to be given).
4: The interest of the final calculation on how many endoscopies would be saved is of limited interest. It would be much more interesting to assess how implementation of this risk prediction model may contribute to a better and quicker identification of patients with progressibe BE diseases.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.

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