This disclosure relates generally to methods and systems for unobtrusive digital health assessment of high risk subjects, wherein bio-markers pertaining to a disease are identified automatically using physical activity and physiology monitoring on a continuous basis. Identification of bio-markers in the medical domain is conventionally dependent on insights derived from medical tests which are obtrusive in nature. Systems and methods of the present disclosure integrate physical characteristics, lifestyle habits and prevailing medical conditions with monitored physical activities and physiological measurements to assess health of high risk subjects. Systems and methods of the present disclosure also enable automatic generation of control class and treatment class that may be effectively used for health assessment.