Biomarkers exploratory approaches

Cloarec O, Dnmas M E, Craig A, et al. (2005). Statistical total correlation spectroscopy An exploratory approach for latent biomarker identification from metabolic H NMR data sets. Analyt. Chem. 77 1282-1289. 

Besides the examples listed above, there are numerous exploratory association studies that have identified many potential polymorphism biomarkers for treatment response in membrane transporter, drug-metabolizing enzyme, and drug target genes. The methodology and statistical analysis for the candidate gene approach are simple the results are easy to interpret. 

Cmax and safety biomarker baseline values were two informative predictors that could be used to explain the response (safety biomarker elevation) based on the first two nodes of the tree derived from the TBM approach. However, the usefulness of further divisions was limited. The TBM approach is useful as an initial exploratory procedure, but its usefulness is enhanced if the derived model is validated. 

Documentation on assumptions should address those assumptions implicit in the pharmacokinetic or pharmacodynamic model and the statistical methodology chosen to evaluate the data. It should also state the assumed sensitivity of the parameters required to define the model relative to the data space being evaluated as well as any preconceived notions regarding biomarkers or surrogate markers evaluated as responses or covariates in the analysis. Hypotheses should be defined based on what was held a priori as true before the study or analysis, what was developed from preliminary or exploratory data analysis, and what would constitute a difference or equivalence in an effect or outcome, hi some instances the criteria for difference as opposed to equivalence can be defined from a statistical viewpoint independent of the actual study design. This approach does not always confer regulatory acceptance, however. 

Careful understauding of the effects of each preanalytical variable on the biomarker data is complex and necessitates a staged approach conceptually similar to the fit-for-purpose analytical validation of a biomarker assay (see Chapter 41). In the early exploratory phase of biomarker investigation, standardization of procedures with a defined protocol for sample collection and handling will permit comparative interpretation and analysis of the data within study and/or between studies. Minimally, variables that should be experimentally evaluated to optimize sample collection for a specific biomarker will include matrix type, preservation... 

A generic operational strategy to qualify translational safety biomarkers using a two-stage approach of (Jenkins et al., 2011) initial exploratory studies to identify and characterize candidate biomarkers followed by (Eosho et al., 2012) confirmatory studies to build upon the evidence of the initial studies has been described (Matheis et al., 2011). We highlight key statistical considerations in these contexts. 

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