In the era of precision medicine, biomarker plays a vital role in drug clinical trials. It helps select the patients more likely to respond to the therapy and increases the possibility of success of the trial. Model selection is critical in the development of the algorithm. Traditional model selection metrics ignore two clinical utilities of the biomarker in drug clinical trials, one is its ability to distinguish positive and negative patients in terms of treatment effect and another is the total cost of the biomarker-based drug clinical trial. We proposed a new model selection metric that estimates the above two clinical utilities of biomarker detection algorithms without the need for a real drug clinical trial. In the simulation, we will compare the proposed metric with the widely used ROC-based metric in selecting the optimal cutoff value for the model and discuss which one to choose under various circumstances.

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is characterized by frequent mutation in PTEN gene. PHTS patients have numerous neurological defects including macrocephaly and autism spectrum disorder. While clinical features of PHTS are likely the result of PTEN haploinsufficiency, the role of PTEN gene dosage in driving transcriptomic changes in specific neural cell types is not known. Methods: We performed transcriptomic and proteomic analysis on neural tissues and primary cultures from Pten heterozygous and homozygous knockout mice. Results: We found that somatosensory cortex (SSC) of Pten heterozygous mice are enriched with immune response and oligodendrocyte development Gene Ontology (GO) terms. Parallel proteomic analysis reveals differentially expressed proteins (DEPs) related to dendritic spine development, keratinization and hamartoma signatures. The lack of concordance between transcriptomic and proteomic data prompted us to profile the transcriptomes of specific neural cell types. Overall, Pten homozygous knockout cells have much greater differential expressed genes (DEGs) than Pten heterozygous knockout cells. Pten heterozygous knockout primary astrocytes (AST) are enriched in Extracellular Matrix GO terms while primary cortical neurons (PCN) are enriched with immediate-early genes. In Pten homozygous knockout AST, cilium-related activity is enriched while PCN exhibited downregulation of forebrain neuron generation and differentiation which may lead to disruption of excitatory/inhibitory balance in brain. By integrating DEPs with a pre-filtered DEGs, we identified traits of intelligence and cognitive function, and schizophrenia being enriched, and DEP from AST is significantly associated with intelligence and depression.Limitations: First, bulk tissues were used for transcriptomic and proteomics analysis. Cell type specific expression changes may not be revealed. Second, primary neural cell cultures were used for transcriptomic analysis, which may not reflect the normal physiological conditions.Conclusions: We have uncovered transcriptomic alterations and molecular pathways that may explain neurological disorders associated with PHTS.

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