How to provide uncertain information

• NGS makes genetic counseling complicated.
• The followings are some notes on statistical aspects of interpretation of NGS for genetic counseling.
• Three validities
  • (1) Conevntional genetic validity
  • (2) New NGS-related validities
    • (2-1) Analytic validity
    • (2-2) Clinical validity
• (1) Conventional genetic validity
  • You should be able to calculate heritage pattern and probability based on pedigree with probability of 1/2 to descend genetic variants to offsprings.
  • You should consider genetic models (dominant/recessive). If you consider intermediate models, that is estimated in a probability distribution.
  • You should consider penetrance and phenocopy that take probability densities.
• (2) New NGS-related validities
  • (2-1) Analytic validity
    • NGS evaluates locus with variable depths per bases, which makes sensitivity and specificity variable per bases.
    • NGS data can be analyzed with different tools with various options, which makes sensitivity and specificity vary.
  • (2-2) Clinical validity
    • When variants you find have been already reported as ones related with your target phenotype, but the reports might be false. You have to think that the variants explain your patients' phenotype with probability and the probability in a shape of distribution.
    • When variants you find have not been reported, then you have to estimate how likely they are responsible based on functionality prediction tools that only give you likeliness that they are responsible and the likeliness is in density form.