PYTHIA aims at developing a monolithic optical biosensor-array microchip based on standard silicon technology for label free determinations. These biochips are envisioned to “prophesize” predisposition and detect the very early onset of human diseases, paving the way for advances in personalized medicine. Monolithic integration of the optical components, including silicon avalanche light emitting diodes optically coupled to Mach-Zehnder Interferometer waveguides, will bypass manufacturability issues and will enable the simultaneous detection of analytes. Biomolecular binding on the functionalized Mach-Zehnder branch will create an optical path difference resulting into changes in the output intensity and spectral characteristics, recorded via either an also monolithically integrated photodetector or an external spectrometer. Integration of microfluidic channels at wafer scale and encapsulation in a low-cost disposable cartridge will allow easy delivery of specimens and will ensure facile contact with external low-noise electronic components. The system is completed by user-friendly software for easy, real-time multi-analyte detection tailored to diverse diagnostic applications. The great and diverse potential and analytical breakthroughs of the proposed multi-analyte biochip allow for a wide range of clinical applications and will be demonstrated in: a) Prostate cancer, a frequently occurring disease severely burdening health care systems. Very early diagnosis, crucial for cure, will be targeted through high-resolution determination of total and free PSA b) MEN2, a not very common medical condition, linked to an inherited faulty gene (RET), demonstrating the feasibility of custom-designed biochips for efficient predisposition screening of population-specific genetic profiles c) Retinitis Pigmentosa (inherited diseases group causing retinal degeneration and vision loss) demonstrating substantial downgrading of the diagnostics costs of genetically complex diseases.