Proposal for Issue-driven Research and Development III Promoting Life Course Health-care -Importance of Preemptive Medicine in pregnancy to childhood-/CRDS-FY2014-SP-03
Executive Summary

Japan is experiencing rapid progress in the aging of the population ahead of the rest of the world, and the total population is considered to significantly decrease in the future especially for the young working age group. Additionally, medical and nursing care costs are considered to further increase in the future due to the advancement of medical techniques and increased demand for medical and health care. It is predicted that these issues will result in slowdown in the economic growth potential due to reduced domestic demands, reduction in the domestic production capability due to a decreasing working population, and failure of the medical and nursing care system, posing an extremely severe and difficult future for Japan. There are various factors intricately involved with the said issues. However, it should be possible to change the future of Japan by continuously promoting appropriate mid-to-long term remedial measures from early stages. CRDS has considered possible solutions by means of science and technology from the perspective of human health, in order to identify effective measures to counter these difficult issues.
First, CRDS specified three social expectations related to human health, namely, 1) realization of healthy longevity from the viewpoint of the nation, 2) ensured continuation of social security systems (e.g., optimization of medical and nursing care costs) from the viewpoint of the government, and 3) activation of medical and healthcare industry from the viewpoint of the industry. CRDS concluded that science and technology that satisfy these expectations and have the maximum impact on each social expectation are strongly required. In order to identify the specific direction of science and technology, CRDS conducted numerous literature reviews, overseas on-site investigations, opinion exchanges with experts, discussions at workshops, and so on. CRDS then conducted consideration on R&D strategy that needs to be promoted by overlooking the medical service provision and medical techniques for each health phase, the main health status and disease for each age group, the main relevant science and technology measures in
Japan, and so on.
Diseases that may cause significant reduction in QOL of people and cause a large social burden in the future have become a major concern in both developed and developing countries through the world. Examples of such diseases are cardio-metabolic diseases, chronic obstructive pulmonary disease (COPD), mental disorders, dementia, and cancers. Appropriate measures against such diseases are in strong demand.
It has been known that these diseases break out as a result of gradual accumulation of disease risk factors through long-term interactions between genetic predisposition and environmental factors. It is considered that diseases that develop through such process are difficult to cure completely after onset and it is more efficient to intervene at early stages. For that reason, in FY2010, CRDS proposed the importance of a new healthcare and medical concept called preemptive medicine. Preemptive medicine is a medical method that identifies high risk groups through low-cost and highly accurate onset prediction techniques. Its aim is to protect the health of the nation through application of low-cost and effective preventive intervention techniques and to significantly reduce medical costs etc. by drastically reducing the number of progressors. It also aims at acquisition of foreign currencies through overseas expansion of preemptive medicine developed by Japan. Therefore, preemptive medicine satisfies all three social expectations stated above simultaneously. In late years scientific findings related to preemptive medicine have rapidly accumulated, and CRDS conducted consideration on R&D strategies taking into account their latest trend and on the measures for social implementation.
The onset period of chronic diseases subject to preemptive medicine varies depending on the disease (e.g., diabetes, Alzheimer dementia, cancer). Therefore, accumulation of disease risk factors may also exhibit various time dependencies related to the disease. In order to realize highly efficient and effective preemptive medicine, establishment of highly accurate disease risk assessment techniques as well as risk-specific preventive intervention techniques is strongly required through comprehensive identification of disease risk factors (i.e. what kinds of risk factors exist at what time and period of human life and at what strength) and time-serial analysis of the factors.
Regarding the time and period that preemptive medicine needs to focus on, important findings have become available recently. There are various reports (e.g., birth cohort studies conducted for decades in Europe and so on) indicating strong associations between environmental factors during the fetal period and infancy and obesity, cardio-metabolic diseases (e.g., diabetes, cardiovascular diseases), developmental disorders, mental disorders, and so on. All these diseases are considered to become an increasingly serious issue in Japan and the rest of the world in the future, and this is a highly important finding.
The above finding has a major significance in envisaging the ideal future healthcare and medical services. For instance, obesity and cardio-metabolic diseases are considered to develop over a long period of time, and conventional treatment methods have provided care mainly for healthy-looking middle-aged and elderly people. The above finding, however, indicates the importance of care from a far earlier time of life, even as far back as to the fetal period and infancy. Therefore, in order to efficiently and effectively promote preemptive medicine and assuredly satisfy social expectations, it is important to promote preemptive medicine throughout a lifetime.
Representative risk factors identified by cohort studies in Europe include undernutrition of pregnant women and low birth weight. Japanese women are relatively lean compared to those in other developed countries and the rate of low birth weight infants is high supported by the medical concept existing in Japan, have a small baby and raise to grow big. These facts indicate Japanese children are born with high disease risks, and it can be said that strategic action against these facts is an urgent task. Additionally, genetic predisposition of Japanese people is different that of western people, and environmental factors, medical services, social environment, etc. in Japan are different from those in western countries. For that reason, findings obtained in Europe may not be directly applicable to Japanese people, and establishment of scientific evidence targeting Japanese people is urgently required.
Childhood that comes after infancy is also a period where major physical development takes place, and it is considered that many disease risk factors accumulate during childhood due to the external environment. Childhood also allows for application of a wider variety of preventive intervention techniques (e.g., health education), and childhood is considered to be an important period to focus on in addition to the fetal period and infancy.
Currently, measures involved with preemptive medicine are gradually put into practice in Japan. While the number of measures that apply to the period from the fetal period to childhood is small, establishment of epidemiology bases required to conduct such studies is in progress. An environment that significantly accelerates research in the relevant fields in the future is gradually forming. Therefore, the present proposal addresses preemptive medicine promotion strategies focusing on the period from the fetal period to childhood.
CRDS conducted considerations on specific R&D strategies based on the factors above. CRDS came to a conclusion that it is important to carry out measures that 1) identify associations between the environmental factors during the period from the fetal period to childhood and onset of diseases at a later time, 2) elucidate the background mechanisms, 3) establish preemptive medicine techniques based on the basic findings, and 4) promote social implementation taking into account the ethical, legal and social implications (ELSI) and costs.

 Specific R&D Tasks and Promotion Measures
The themes that need to be promoted in the future are roughly classified into the three categories listed below. The important items common to all three themes include: specification of core institutions and organizations that supervise the whole project from a mid-to-long term viewpoint; acquisition of human resources and development of the next generation; and appropriate activities in the perspective of ELSI.
 Establishment, operation and utilization of epidemiology bases
Integration (formation of consortium) of existing birth cohort, relevant biobank and so on shall be promoted in order to establish an environment that facilitates access to the data by researchers. Regarding important data items which are unable to be obtained by existing epidemiology bases, establishment of new epidemiology bases shall be planned based on thorough discussions (including measures to ensure mid-to-long term funding) and are to be commenced at the optimal time. The value of epidemiology information bases drastically increases through as-available introduction of latest findings and techniques from life sciences, measurement and analysis techniques, big data studies, and so on.
 Promotion of basic and fundamental life science studies
Epigenetic studies using model animals and human samples (placentas, umbilical cord blood, blood of pregnant women, and other biological samples), nutritional science studies, disease studies, and behavior science studies shall be promoted. Associations between the environmental factors during the period from the fetal period to childhood and related diseases and epigenetic transitions shall be elucidated. The importance of dietary habit (nutrition) is considered to be high among environmental factors, and nutrients with larger impacts shall be identified in detail. Additionally, biomarker discovery and a search for intervention methods for the period from the fetal period to childhood shall be conducted by making the best use of findings mainly obtained in disease studies for adults. Associations between various activities (e.g., sleep) and disease onset shall be clarified through promotion of behavior science studies on human fetuses and infants. Measurement techniques are essential for promotion of these scientific studies, and fetal measurement and analysis technique studies (as well as infant and child measurement and analysis technique studies) shall be promoted where a major breakthrough is expectant.
 Promotion of R&D towards social implementation and impact assessment involved with implementation
A package (disease risk assessment and intervention model) necessary for social implementation of preemptive medicine shall be established for each disease by collecting, managing and analyzing in detail the big data obtained through promotion of epidemiological studies and life science studies. Impact on the health, economy and society shall be quantitatively assessed in order to achieve maximum impact for the minimum implementation costs (measurement and analysis items).

In studies using prospective birth cohorts, the timing of obtaining achievements may vary depending on the onset age of the disease. For instance, studies on developmental disorders are expected to produce major outcomes in a few years, while studies on lifestyle-related diseases may require approximately 30-50 years or more to obtain meaningful outcomes and thus mid-to-long term activities are essential. Meanwhile, integrated analysis of various existing cohort and data groups obtained through governmental measures as well as studies using model animals and human samples are expected to produce a certain level of outcome in a relatively short period of time. It is important to continue producing various outcomes in a short-, medium- and long-term basis through strategic promotion of these studies and to continue promoting social implementation of preemptive medicine at the same time.