유전체 자료분석을 위한 생존분석방법에 관한 고찰

이승연(Seungyeoun Lee) 한국데이터정보과학회 2018 한국데이터정보과학회지 Vol.29 No.6

관심의 대상이 되는 사건이 발생할 때까지 걸리는 생존시간을 다루는 생존분석의 가장 큰 특성은 생존시간이 완전하게 관측되지 않고 중도 절단 된다는 점이다. 이러한 중도절단자료의 특성을 고려하여 추정, 검정 및 모형적합에 대하여 고전적인 생존분석 방법들이 많이 개발되어져 왔으나, 마이크로 어레이자료를 시작으로 대용량의 유전체 자료가 수집되면서 유전적 정보와 생존시간과의 연관성 연구가 진행되면서 표본의 수에 비하여 엄청나게 많은 수의 유전정보 변수들을 다루는 새로운 통계적인 방법들이 생존자료에 확장되었다. 결과적으로 기존의 임상자료로만 구축된 통계예측모형에 유전체 정보가 추가적으로 고려됨으로써 생존함수에 대한 예측력이 향상되었고, 개인의 유전정보에 따라 더 적합한 치료방법이나 치료약을 개발해야 한다는 개인맞춤의학의 필요성이 부각되기 시작되었다. 다양한 첨단 생물학 기술을 통하여 서로 다른 형태의 대용량의 유전체 자료를 통합하는 방법론에 대한 연구들이 이루어지면서 기계학습 방법이 생존분석에 접목되어 많은 연구방법들이 개발되고 있다. 본 연구에서는 기존의 임상자료를 기반으로 분석하는 전통적인 생존분석 방법들을 소개하고, 고차원의 유전체 자료를 분석하기 위한 생존분석 방법들과 통합적인 유전체 자료분석을 위하여 생존분석에 접목된 기계학습방법들에 대하여 간략하게 살펴보고자 한다. Survival analysis focuses on the statistical inference for the time to event of interest, which cannot be often completely observed due to censoring. Considering the characteristics of these censored data, traditional survival analysis methods have been developed for estimation, testing, and model development to predict survival time for patients based on clinical data. However, large-scale data from high-throughput genomic technologies, especially microarrays, have been collected, which poses the challenging statistical issues in combining those with the survival time. Many statistical methods have been developed by additionally considering the high-dimensional genomic information in the statistical prediction model constructed only by the existing clinical data. Recently, there have been many studies on the methodology of integrating different types of genomic data through various advanced biologic techniques, which results in making an early prediction for the disease and developing personalized medicine. As well, there has been considerable interest in applying machine learning techniques to analyse these complex and huge amount of genomic data associated with the censored data. In this paper, we review the basic concepts in survival analysis, traditional statistical methods based on clinical data, more appropriate statistical methods dealing with genomic data, and machine learning methods extended to the survival analysis.

양극성장애 환자와 대조군에서 뇌파 코히런스의 성별 차이

유현주,이유상,안은숙,정동화,김성균,정재승,곽용태,이승연,You, Hyunju,Lee, Yu Sang,An, Eunsoog,Jeong, Donghwa,Kim, Seongkyun,Jeong, Jaeseung,Kwak, Yongtae,Lee, Seungyeoun 대한생물정신의학회 2015 생물정신의학 Vol.22 No.4

Objectives Sex hormones exposure during the prenatal period has an effect on cerebral lateralization. Male brains are thought to be more lateralized than female brains. Bipolar disorder was known to show abnormalities in cerebral laterality whose characteristics could be estimated by electroencephalography (EEG) coherences. We studied sex-related differences of EEG coherences between healthy controls and patients with bipolar disorder to examine the sex effects in the genesis of bipolar disorder. Methods Participants were 25 patients with bipolar disorder (11 male, 14 female) and 46 healthy controls (23 male, 23 female). EEG was recorded in the eyes closed resting state. To examine dominant EEG coherence associated with sex differences in both groups within five frequency bands (delta, theta, alpha, beta, and gamma) across several brain regions, statistical analyses were performed using analysis of covariance. Results Though statistically meaningful results were not found, some remarkable findings were noted. Healthy control females showed more increased interhemispheric coherences than control males in gamma frequency band. There were no differences in the intrahemispheric coherences between the healthy control males and females. In patients with bipolar disorder, female dominant pattern in interhemispheric coherences was attenuated compared with healthy control. Conclusions Sex differences of EEG coherences, which could be a marker for cerebral laterality, were attenuated in patients with bipolar disorder compared with healthy controls. These results imply that abnormal sex hormone exposure during early development might play some role in the pathogenesis of bipolar disorder.

조현병 환자에서 성별에 따른 검지 대 약지의 길이 비율과 뇌파 동시성의 관련성

최병하,이유상,한은선,김성균,정재승,이승연,김범준,Choi, Byungha,Lee, Yu Sang,Han, Eun-Seun,Kim, Seongkyun,Jeong, Jaeseung,Lee, Seungyeoun,Kim, Bum Joon 대한생물정신의학회 2014 생물정신의학 Vol.21 No.4

Objectives Prenatal testosterone is known to influence both cerebral laterality and 2nd to 4th digit ratio (2D : 4D). Epigenetic changes are thought to play some role in it. We studied sex-related differences between 2D : 4D and cerebral laterality in patients with schizophrenia and controls to examine the effects of prenatal testosterone in the development of schizophrenia. Methods Forty one men (18 schizophrenic patients and 23 controls) and 40 women (17 schizophrenic patients and 23 controls) were recruited from one psychiatric hospital in Korea. The 2D : 4D and electroencephalographic (EEG) coherence in 19 channels (66 pairs of interhemispheric coherence and 54 pairs of intrahemispheric coherence) were measured. The sex-related statistical analyses between 2D : 4D and EEG coherence in controls and patients with schizophrenia were performed using multiple regression. Results In male patients, the relationship between 2D : 4D and right intrahemispheric EEG coherence showed mainly positive correlation in delta and theta frequency bands, while it showed negative correlation in male controls. In female patients, the relationship between 2D : 4D and interhemispheric EEG coherence showed stronger positive correlation in alpha and beta frequency bands, while it showed weaker positive correlation in female controls. Conclusions Low prenatal testosterone may play certain roles in altered correlation between 2D : 4D and cerebral laterality in schizophrenia and the development of schizophrenia by epigenetic mechanism.

조현병 환자와 건강한 대조군에서 성별에 따른 뇌파 동시성의 차이

정혜민,이유상,김성수,김성균,정재승,오진석,이승연,김범준,장재승,Jung, Hye Min,Lee, Yu Sang,Kim, Seongsu,Kim, Seongkyun,Jeong, Jaeseung,Oh, Jin-Seok,Lee, Seungyeoun,Kim, Bum Joon,Chang, Jae Seung 대한생물정신의학회 2013 생물정신의학 Vol.20 No.4

Objectives Alteration of epigenetic effects of testosterone during early development was suggested as an ancillary mechanism for the genesis of schizophrenia. EEG coherence was thought to be a marker for cerebral laterality of which important determinant was testosterone during early development. We studied sex-related differences of EEG coherences between patients with schizophrenia and controls to examine the sex effects in the genesis of schizophrenia. Methods EEG was recorded in 35 patients with schizophrenia and 46 healthy controls in the eyes closed resting state. Pair-wise EEG coherences were calculated over delta, theta, alpha, beta and gamma frequency bands. To examine the differences of EEG coherence according to sex in each group, ANCOVA was performed using Statistical Analysis system (SAS, Ver 9.3) and R (Ver 2.15.2). Results Healthy control males showed more increased right intrahemispheric coherences than healthy control females in delta, theta, alpha and beta frequency bands. In patients with schizophrenia, this male dominant pattern in right intrahemispheric coherences was attenuated especially in alpha and beta bands. Healthy control females showed more increased interhemispheric coherences than healthy control males in delta, theta, beta and gamma frequency bands. In patients with schizophrenia, these female dominant patterns in interhemispheric coherences were attenuated especially in delta, theta, and beta bands, which were commonly observed in frontal to central areas. Conclusion Sex differences in resting EEG coherences were attenuated in schizophrenia patients. These results imply that sex-related aberrant cerebral lateralization might exist in patients with schizophrenia, which are partly due to sex hormones via epigenetic mechanisms.