and mortality. A primary message is the need to assess precursors to disease at points more distant temporally than has been examined in most previous research. Equally important is the need to study the biological, behavioral, psychological, and social precursors to disease simultaneously. Wider time horizons are required to understand early antecedents to later risk factors as well as the long-term etiological processes involved in multiple disease outcomes. Predisease pathways thus include a broad array of factors that affect the individual from conception (or before) through development and adulthood into later life. Illustrative influences include prenatal and early risk factors, along with a diverse array of psychological factors (e.g., control and efficacy, temperament, optimism, cognitive states, emotion regulation), behavioral factors (e.g., diet, exercise, smoking, alcohol consumption, drug abuse, sexual activity), and familial and environmental influences (e.g., social ties and support, family stress, work conditions, community supports).

Building on the guiding theme of integrative research, there is need to assess physiological risk across multiple systems simultaneously. Repeated or continuous exposure to challenge or chronic underexposure and social isolation disrupts basic biological regulatory processes central to the maintenance of homeostasis and health. When exposed to challenge at vulnerable times (e.g., during early stages of pre-and postnatal development) or repeatedly during later periods of life, multiple physiological responses may operate outside of normal ranges. Over time, this exacts wear and tear—i.e., cumulative physiological risk—on humans and animals. Operationalization of culmulative risk across systems and across time is an important aspect of characterizing predisease pathways. Illustrating needed research in this direction are emerging studies of allostatic load, a preliminary formulation of cumulative physiological risk. Also critical is the need to track the unfolding interactions between genetic factors and environmental influences over time.

A basic research initiative throughout the NIH institutes should be focused on predisease pathways, including the following topics:

  • identification of early markers of predisease states;

  • examination of their genetic and environmental origins through animal and human studies;

  • identification of behavioral risk factors in the exacerbation or amelioration of predisease pathways;

  • prioritization of experimental and longitudinal research to chart these trajectories across the life span; studies should consider biological, behavioral, psychological, and social precursors to disease simultaneously;

  • focus on the mechanisms by which genetic influences, early life experiences, and behavioral and psychosocial risk factors across the life span

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