Knowledge Network and Information Commons are very good concept to achieve the individual-focused precision medicine objective. A few points I would like to mention:

1. Extend association study to multiscale modeling. One central goal in precision medicine is to find the correlation between genotypes and phenotypes based on individual patient's lab data information and clinical data information. GWAS association study is designed for such a purpose. However, we do not know the paths from genotypes (molecular markers) all way to the phenotypes at tissue or organ level based on the GWAS data. Also it is not clear a general association model can be made specific to the individual without incorporating the detailed information of this patient to the model. Multiscale modeling can integrate such a common knowledge and information from a group of patients and individual patient's molecular cellular, cellular and tissue level information seamlessly. The question is how we can collect such data sets.

2. How to make use of biomarkers and regulators in multiscale modeling? FIGURE 3-1 depicts "building a biomedical Knowledge Network for basic discovery and Medicine" in the Precision_meidicne.pdf. New classification of diseases are mainly based on newly discovered driver mutation genes. Such biomarkers could be a potential targets in drug design which can be incorporated to the multiscale modeling. Some biomarkers such as gene/set signature and regulatory elements. It is not easy to consider them in mathematical modeling.

3.How to incorporate patient-specific drug-induced network to the multiscale model? Drug-induced pathway network inference is very important for us to predict drug treatment response at intracellular and intercellular level. However inferring patient-specific pathways and side effects is challenging due to the limited phosphoproteomics , genomics and metabolic data under different conditions.

4. Challenges in Multiscale modeling of patient-specific environment We are focusing on one particular ligand-receptor pathway (hypothesis driven) in multiscale models from molecular level -- intracellular level - intercellular level -- tissue level - organ/body - population level. The models at intercellular level is very complex, e.g., model cancer stem cell niche and immune system. If we consider and model detailed pathway maps in intracellular level, the whole multiscale models could be very complex and unstable, but such detailed information is probably patient-specific information which we have to consider for good prediction purpose.