초록 ▼

- 정량적 변수의 자동 추출 기술 개발, 다양한 전문가 의견을 반영한 객관적 체질진단 알고리즘 개발, 웹 기반 서비스 시스템 개발을 통하여 사상체질진단툴 SCAT을 개발하였음.
- 이후 SCAT을 활용하여 2만9천여건의 체질임상정보를 축척하고, 지속적인 피드백을 통하여 체질진단툴의 자동분석, 진단 모델, 웹 서비스의 편의성 및 안정성 개선하였으며, 체질분석 결과뿐만 아니라 다양한 세부 표현형 정보 및 건강정보제공을 통하여 한의사 진단에 도움을 주는 의사결정기능을 강화함으로써, SCAT의 완성도를 크게 높였음.
- 이를 기

- 정량적 변수의 자동 추출 기술 개발, 다양한 전문가 의견을 반영한 객관적 체질진단 알고리즘 개발, 웹 기반 서비스 시스템 개발을 통하여 사상체질진단툴 SCAT을 개발하였음.
- 이후 SCAT을 활용하여 2만9천여건의 체질임상정보를 축척하고, 지속적인 피드백을 통하여 체질진단툴의 자동분석, 진단 모델, 웹 서비스의 편의성 및 안정성 개선하였으며, 체질분석 결과뿐만 아니라 다양한 세부 표현형 정보 및 건강정보제공을 통하여 한의사 진단에 도움을 주는 의사결정기능을 강화함으로써, SCAT의 완성도를 크게 높였음.
- 이를 기반으로 보다 높은 신뢰도와 다양한 체질 정보를 가지고 임상 및 체질 관련 유전학적, 생리학적, 질환 관련 연구에 활용할 수 있게 됨.
- 심혈관대사질환 발병 위험의 10년간 변화량 분석을 통해 연관 유전인자를 체질별로 발굴하고, 혈청 및 세포 내 기능을 규명함.
- 체질 및 체질 판별에 유효한 세부 형질과 연관된 16개의 유전인자를 발굴하고,체질별 연령 상관성을 규명함.
- 체질별 한방조성물 피부 주름개선 효과 시험 평가를 통해 눈가 주름개선 효과를 태음인, 소음인, 소양인 모두에서 입증함.

( 출처 : 요약서 3p )

Abstract ▼

Ⅳ. Results
1. Basic analysis of constitutional clinical information and experimental modeling (Step 1)
- Analysis of decision tree and preprocessing of constitutional clinical data
- Development of constitutional discriminant algorithm using face, body shape, blood, voice,SNP, questionnaire

Ⅳ. Results
1. Basic analysis of constitutional clinical information and experimental modeling (Step 1)
- Analysis of decision tree and preprocessing of constitutional clinical data
- Development of constitutional discriminant algorithm using face, body shape, blood, voice,SNP, questionnaire information
- High diagnostic concordance, but high overfitting possibility due to the variable selection from the tremendous number of candidate ones for whole data set.

2. Development of SCAT (Step 2, 3)
A. Development of SCAT ver. 1 (Step 2)
- Development of objective constitutional diagnosis model using the information acquired with non-invasive methods
- Automation of diagnostic analysis by developing automatic facial and vocal feature extraction algorithm
- Removement of age effects and improvement of overfitting problem
- Development of web-based SCAT system for practical use

B. Use of SCAT and improvement of the performance (Step 2, 3)
- Distribution of SCAT and its use of 29,226 cases in 26 institutions
- Improvement of face analysis performance by expanding the number of faical feature, improving automatic feature extraction algorithm, and developing color-chart detector.
- Improvement of voice analysis performance by improving repeatability of analysis results, data collection quality, and ease of recording.
- Improvement of sensitivity and diagnostic concordance by improving variable selection method, scoring method, and learning method.
- Development of a diagnostic model for Tae-yang type
- Development of Caucasian constitutional diagnostic model by collecting and analysing the Caucasian constitutional data
- Development of a representative face model which shows face appearance differences between each constitution intuitively and realistically.
- Development of a new web service system improving ease of use and stability.

C. Development of SCAT ver. 2 (Step 3)
- Finding and quantifying the phenotype from face, voice, body shape information.
- Development of phenotype analysis model which classifies the phenotype variable in five grades and shows its grade.
- Improved diagnostic performance of 5% when a cutoff value is applied to the developed diagnostic model.
- Implementation of web service system providing phenotype analysis result.
- Development of prediction model of obesity, type 2 diabetes, high blood pressure, low blood pressure, and hypertriglyceridemia using face, voice, body shape information.
- Implementation of web service system providing health risk information

3. Building a virtuous cycle of SCAT and KCMB(Korea Constituional Multicenter Bank) (Step 3)
- Rule-making and installation of the steering committee for the integrated management of SCAT-KCMB
- Development of error checking program and improvement of error filtering method for the maintenance of data quality of SCAT and KCMB
- Building a web page summarizing SCAT and KCMB information for the data compatibility and integrated management of SCAT-KCMB

4. Identification of genetic factors associated with constitution itself and constitution-related trait: family study (Stept 1 to 3)
A. Presenting heritability of constitution (Step 1)
- Heritability of constitution in 101 pedigrees was So-Eum 47.6%, So-Yang 40.5%, and Tae-Eum 55.2%.

B. Analysis on facial characteristics related with constitution (Step 1)
- Among totally 14 indices of face in 38 digrees (n = 232), forehead length, eye length, the width of the lower jaw, and nose height were differentially manifested according to constitution

C. Analysis on mitochondria characteristics (of thermogenesis) related with constitution(Step 1)
- Mitochondrial measurements (heritability: 77% - 78%) from 487 family subjects was linked with genetic loci in chromosome 11 (LOD > 3), whereas there was no linkage with constitution.

D. Identification of genetic factors associated with constitution itself and the sub-phenotypes by family study (Steps 1 and 3)
- In project step 1, genetic loci linked with Tae-Eum type were identified as results of genome-wide linkage analysis (GWLA) in two large families (A and H pedigrees) and 382 unrelated subjects.
- In project step 3, as a result of GWLA on totally 40 SCAT constitution and the sub-phenotypes, a genetic locus linked with thoracic-to-hip ratio (THR) was showed and genes linked with that was identified by followed next generation sequencing.

5. Identification of genetic factors associated with constitution itself and constitution-related trait: unrelated population study (Stept 1 to 3)
A. Search of constitution-associated with genetic factors using GWAS (Steps 1 to 3)
- In project step 1, as results of association using GWAS and copy-number variation(CNV) in about 1,350 subjects, genetic factors strongly associated with total bilirubin among several factors were reported.
- In project step 2, principal genes interacted with constitution-related pathway, 5 in Tae-Eum, 10 in So-Eum, and 5 in So-Yang, were selected via constitutional pathway and network analyses.
- In project step 3, it was elucidated that obesity- and diabetes-risk variants of FTO was associated with So-Eum categorized by SCAT, via GWAS and replication analysis in about 5,000 subjects.

B. Search of constitution-associated genetic factors using candidate gene approach (Steps 1 to 2)
- Constitution-associated genetic factors were searched for differential sweating pattern among constitutional types, and candidate genetic loci were selected (Step 1).
- Each 3 of constitution- and physique-associated genetic factors was identified based on the concept of constitutional Sacho (Step 2).

C. Identification of genetic factors associated with sub-phenotypes of constitution (Step 3)
- GWAS and replication analysis were performed for 85 facial sub-phenotypes, 3 lipid ratios, 3 vocal traits, 1 trait of cold hands and feet, and 3 traits of Sasang personality questionnaire (SPQ).
- Totally 14 genetic factors associated with the sub-phenotypes were identified: 5 of face, 2 of THR, 4 of lipid ratios, 4 of voice, 1 of cold hands and feet, and 1 of SPQ.

D. Analysis of age-relatedness of genetic factors associated with sub-phenotypes of constitution (Step 3)
- It was analyzed in which age groups of tertiles association signals of SNPs associated with constitution categorized by SCAT were enriched.
- It was identified that constitutional and age-related genetic factors were presented 6 of face, 3 of THR, 10 of lipid ratios, 11 of voice, 2 of cold hands and feet, and 6 of SPQ in cohorts, whereas the associations of 3 genetic factors with lipid ratios were remained in constitution-confirmed population.

6. Identification of aging-related factors on the constitutional five viscera (Stept 2 to 3)
A. Identification of aging-related factors on the constitutional five viscera: tracing 3 years(Stept 2 to 3)
- Variation in aging-related factors on the constitutional five viscera was analyzed by tracing 4,832 subjects in cohorts during average 3 years and 4 months.
- Totally 22 factors for changes in the five viscera-related factors according to constitution were identified, by selecting 6, 5, 3, 2, and 6 factors related with the five viscera of liver, lungs, spleen, kidneys, and heart, respectively.

B. Secureness of functional dyspepsia factors according to constitutional types
- Differential prevalence of functional dyspepsia and assocition signals of serum biological markers (Cortisol, adrenalin, ROS, and MDA) according to constitutional types were presented from 517 subjects categorized by SCAT.

7. Elucidation of genetic factors associated with risks on cardiometabolic disease incidence according to constitution (Stept 1 to 3)
A. Elementary study on genetic factors associated with cardiometabolic disease (Step 1)
- Elementary study on constitutional association with cardiometabolic risk factors was performed, on the basis of previously reported SNP database on dyslipidemia-,hypertension-, and obesity-related traits.
- The association of FTO SNPs with BMI was reported firstly in Asia, and constitutioanl differential association signals of variants in MC4R and FTO on weight decrease were identified.

B. Identification of genetic factors associated with disease prevalence: cross-sectional study in cohorts and constitution-confirmed populations (Step 2)
- For previously reported GWAS SNPs on cardiometabolic risk, totally 10 SNPs were identified by selecting constitution-specified genetic factors and performing replication in Ansung and Ansan populations.
- The combined genetic effects of SNP sets for predicting abdominal tratis and metabolic syndrome were presented.

C. Identification of genetic factors associated with disease incidence: longitudinal cohorts analyses and function studies (Step 3)
- For 89 GWAS SNPs on cardiometabolic risk, after analyzing constitutional age-relatedness (based on tertile) in 3,117 constitution-confirmed subjects, distribution of the association signals of 14 genetic factors in age groups were comprehended.
- Via 10-year longitudinal approaches in cohorts, genetic factors associated disease incidence risks were identified among 370 cardiometabolic GWAS SNPs (containing hematological traits): 36 in Tae-Eum, 58 in So-Eum, and 73 in So-Yang
- Functional relationships of the genetic factors on disease incidence were identified: 4 genetic factors were associated with cardiovascular serum markers and 3 hematological-related genetic factors were releted with allelic differentila expression(lymphoid cell lines).

D. Presenting effects of cardiometabolic risk-associated genetic factors in Tae-Yang type(Step 3)
- After analyzing effects of cardiometabolic risk-associated genetic factors in 80 Tae-Yang subjects, it was elucidated that unique clinical characteristics of Tae-Yang type was corresponded with genetic effects.

8. Establishment of research basis for constitution-based medical remedy (Stept 1 to 3)
A. Construction of herbal medicinal stuff DB and fundamentals in development of iPS constitutional cell line (Step 1)
- Web-based DB (Herbal Medicine on the Constitution) by collecting medicinal stuff information was constructed according to constitution, fundamental for developing iPS constitutional cell line was constructed.

B. Construction of constitutional cell-based measurement system for drug responses (Step 2)
- In order to measure drung responses using constitution-related cell line, an analyzing system comprised of three stages was constructed: (1) drug treatment on cell line and analysis of cDNA microarray, (2) analysis of pathway associated with constitutional differences according to drug treatment conditions, and (3) searches on functional gene of associated pathway and core proteins.

C. Clinical trials for improving effect on skin wrinkle by constitutional herbal composition(Step 3)
- After implementing clinical trials for improving the eye wrinkles in Tae-Eum, So-Eum, and So-Yang subjects categorized by SCAT, the effectiveness on wrinkle improvement were validated in visual assessment (in So-Yang and Tae-Eum) and replica wrinkle parameter assessment (in all three constitutional types).

( 출처 : SUMMARY 13p )

목차 Contents

• 표지 ... 1제 출 문 ... 2보고서 요약서 ... 3요 약 문 ... 4SUMMARY ... 11CONTENTS ... 19목차 ... 27제 1 장 연구개발과제의 개요 ... 34 제 1 절 연구개발의 필요성 ... 34 1. 연구개발의 목적 ... 34 2. 연구개발의 과학기술, 사회경제적 젓요성 ... 34 제 2 절 연구개발의 범위 ... 36 1. 체질 임상 정보 기초 분석 및 실험적 모델링 (1단계) ... 36 2. 체질진단툴(SCAT) 개발 (2, 3단계) ... 36 3. 체질진단툴(SCAT)과 체질정보은행(KCMB)의 선순환 구조 구축 (3단계) ... 37 4. 체질 및 관련 형질 연관 유전인자 발굴: 가계 연구(1, 3단계) ... 37 5. 체질 및 관련 형질 연관 유전인자 발굴: 비가계 연구(1~3단계) ... 37 6. 체질 오장 노화 인자 발굴(2~3단계) ... 38 7. 체질별 심혈관대사질환 발병 연관 유전인자 규명(1~3단계) ... 38 8. 체질 약물 연구 기반 구축(1~3단계) ... 38제 2 장 국내외 기술개발 현황 ... 40 제 1 절 국내 기술개발 현황 ... 40 1. 체질정보 통합 분석 ... 40 2. 진단기기 개발현황 ... 40 3. 유전체 및 연령 상관성 연구 ... 40 제 2 절 국외 기술개발 현황 ... 41 1. 사상체질 진단 연구 ... 41 2. 체질과 질병과의 연관성 ... 41 3. 유전체 연구 및 missing heritability의 문제 ... 42 제 3 절 연구결과가 국내외 기술개발현황에서 차지하는 위치 ... 43 1. 사상체질 진단분야 ... 43 2. 체질 유전체 연구 분야 확립 ... 43 3. 체질 한방조성물의 기술적 가치 제고 ... 43제 3 장 연구개발수행 내용 및 결과 ... 44 제 1 절 체질 임상 정보 기초 분석 및 실험적 모델링 (1단계) ... 44 1. 체질 임상 정보 분석 ... 44 2. 임상자료 및 계측자료를 통합한 체질 판별 알고리즘 개발 ... 51 제 2 절 체질진단툴(SCAT) 개발 및 활용 (2, 3 단계) ... 63 1. 체질진단툴(SCAT) ver. 1 개발 (2단계) ... 63 2. 체질진단툴(SCAT) 활용 및 성능 개선 (2, 3단계) ... 91 3. 체질진단툴(SCAT) ver. 2 개발 (3단계) ... 136 제 3 절 체질진단툴(SCAT)과 체질정보은행(KCMB)의 선순환 구조 구축 (3단계) ... 158 1. SCAT-KCMB 통합 관리를 위한 규정 제정 및 운영위원회 설치 ... 158 2. SCAT과 KCMB 데이터 품질 유지 및 향상을 위한 점검 시스템 구축 및 성능 개선 ... 160 3. SCAT과 KCMB 데이터 호환 및 통합관리 방안 마련 ... 162 제 4 절 체질 및 세부 형질 연관 유전인자 발굴: 가계 연구(1단계) ... 164 1. 체질 유전율 제시(1단계) ... 164 2. 체질 관련 안면 특성 분석(1단계) ... 166 3. 체질 관련 미토콘드리아(열 발생 관련) 특성 분석(1단계) ... 171 4. 가계도 분석을 통한 체질 및 세부형질과 연관된 유전 부위 발굴(1, 3단계) ... 176 제 5 절 체질 및 세부 형질 연관 유전인자 발굴: 비가계 연구 ... 185 1. 전장유전체 분석법을 활용한 체질 연관 유전인자 탐색(1∼3단계) ... 185 2. 후보 유전자 분석법을 활용한 체질 연관 유전인자 탐색(1∼2단계) ... 197 3. 체질 생체지수(세부 형질) 연관 유전인자 발굴(3단계) ... 202 4. 체질 세부 형질(생체지수) 연관 유전인자의 체질 및 연령 상관성 분석(3단계) ... 208 제 6 절 체질 오장 노화 인자 발굴 ... 217 1. 지역 코호트 대상 오장 연관 노화 인자 발굴: 3년간의 노화 추적 연구(2∼3단계) ... 217 2. 체질별 기능성 소화불량증 인자 확보 ... 228 제 7 절 체질별 심혈관대사질환 발병 연관 유전인자 규명 ... 229 1. 심혈관대사질환 연관 유전인자 대상 기반 연구(1단계) ... 229 2. 심혈관대사질환 연관 유전인자 발굴: 코호트 및 체질확진자 단면 연구(2단계) ... 232 3. 심혈관대사질환 발병 유전인자 규명: 체질확진자 연령대별 분석, 코호트 종적 분석 및 기능 연구(3단계) ... 237 4. 태양인 대상 심혈관대사질환 연관 유전인자 영향력 제시(3단계) ... 250 제 8 절 체질 약물 연구 기반 구축 ... 251 1. 체질 약재 방제 정보 DB 구축 및 iPS 체질 세포주 개발 기반 구축(1단계) ... 251 2. 체질 세포주 약물 반응 측정 체계 구축(2단계) ... 254 3. 체질별 한방조성물 피부 주름 개선효과 임상시험 검증(3단계) ... 256제 4 장 목표달성도 및 관련분야에의 기여도 ... 263 제 1 절 목표달성도 ... 263 1. 연구개발의 최종목표 ... 263 제 2 절 관련 분야의 기술발전에의 기여도 ... 263 1. 체질진단툴(SCAT) ... 263 2. 체질 형질 및 질병 유전인자 ... 264제 5 장 연구개발결과의 활용계획 ... 265 제 1 절 추가연구의 필요성 ... 265 1. 상품화 가능한 체질질병 분석기기의 개발 ... 265 2. 체질 형질 관련 유전인자의 확장 규명 ... 265 3. 체질 특화된 한방 화장품 라인 개발 ... 266 제 2 절 활용계획 ... 266 1. 체질진단툴(SCAT)의 활용계획 ... 266 2. 체질 형질 관련 유전인자의 활용 ... 267 3. 체질 특화된 한방 화장품 라인 개발에의 활용 ... 267제 6 장 연구개발과정에서 수집한 해외과학기술정보 ... 268 제 1 절 표현형 측정 및 분석 ... 268 제 2 절 맞춤의학을 위한 질병, 생리, 약물 ... 268제 7 장 연구시설ㆍ장비 현황 ... 271제 8 장 참고문헌 ... 271끝페이지 ... 275