药物基因组学临床决策支持系统综述
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摘要
近几年来精准医学成为生物医学的一个热门领域,世界各国都致力于率先在这一领域取得突破性的进展。药物基因组学(PGx),通过基因组学和其他"组学"知识来个性化药物选择和药物使用以避免药物不良反应和最大化药物疗效,是精准医学的重要组成部分,也是目前最有希望在临床上实现日常应用的精准医学领域之一。其中药物基因组学临床决策支持(PGx-CDS)系统,是实现PGx临床应用和知识转化必不可少的工具。目前很多临床医疗机构已经开展PGx服务并部署PGx-CDS系统,同时更多的临床医疗和研究机构正在筹备开展这类服务。对目前已出现并被报道的主要PGx-CDS系统和研究进行文献综述,共涉及11个PGx-CDS系统。通过对这些系统的临床应用场景、系统设计、知识表达、干预方式和应用评估等方面的综合回顾,总结目前PGx-CDS系统的研究进展和发展现状,然后对PGx-CDS系统目前面临的主要挑战和未来发展方向进行讨论,为在国内落地PGx服务和PGx-CDS系统提供借鉴。
In recent years, precision medicine has become an intensively researched issue in the field of biomedicine. Many countries in the world have been endeavoring to make breakthroughs in this field. Pharmacogenomics(PGx) which use of genomics and other "omics" knowledge to individualize drug selection and drug use to avoid adverse drug reactions and to maximize drug efficacy is an important part of precision medicine, as well as one of the most promising parts in the field of precision medicine to realize the clinical routine use of PGx and promote the progress of precision medicine. The pharmacogenomics clinical decision support(PGx-CDS) system is an essential tool for the clinical implementation and knowledge translation of pharmacogenomics. In many clinical institutions, pharmacogenomics services have been successfully implemented along with the deployment of the PGx-CDS system, and many clinical and research institutions are also preparing to conduct these services. In this paper, the main PGx-CDS systems that have been presented and reported in literatures are reviewed, 11 PGx-CDS systems are involved in total. Through a comprehensive review of the clinical application background, system design, knowledge representation, intervention mode and system evaluation aspects of these PGx-CDS systems, the research progress and development status of the current PGx-CDS systems are summarized, and the main challenges and the future development directions of the PGx-CDS system are discussed.
In recent years, precision medicine has become an intensively researched issue in the field of biomedicine. Many countries in the world have been endeavoring to make breakthroughs in this field. Pharmacogenomics(PGx) which use of genomics and other "omics" knowledge to individualize drug selection and drug use to avoid adverse drug reactions and to maximize drug efficacy is an important part of precision medicine, as well as one of the most promising parts in the field of precision medicine to realize the clinical routine use of PGx and promote the progress of precision medicine. The pharmacogenomics clinical decision support(PGx-CDS) system is an essential tool for the clinical implementation and knowledge translation of pharmacogenomics. In many clinical institutions, pharmacogenomics services have been successfully implemented along with the deployment of the PGx-CDS system, and many clinical and research institutions are also preparing to conduct these services. In this paper, the main PGx-CDS systems that have been presented and reported in literatures are reviewed, 11 PGx-CDS systems are involved in total. Through a comprehensive review of the clinical application background, system design, knowledge representation, intervention mode and system evaluation aspects of these PGx-CDS systems, the research progress and development status of the current PGx-CDS systems are summarized, and the main challenges and the future development directions of the PGx-CDS system are discussed.
引文
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[7] Ji Y,Skierka JM,Blommel JH,et al. Preemptive pharmacogenomic testing for precision medicine: A comprehensive analysis of five actionable pharmacogenomic genes using next-generation DNA sequencing and a customized CYP2D6 genotyping cascade [J]. The Journal of Molecular Diagnostics, 2016, 18(3): 438-445.
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[9] Ehmann FCL, Prasad K, Paulmichl M, et al. Pharmacogenomic information in drug labels: European Medicines Agency perspective [J]. Pharmacogenomics J, 2015, 15(3): 201-210.
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[11] Johnson JA. Pharmacogenetics in clinical practice: How far have we come and where are we going? [J]. Pharmacogenomics, 2013, 14(7): 835-843.
[12] Scott SA. Clinical pharmacogenomics: opportunities and challenges at point of care [J]. Clinical Pharmacology and Therapeutics, 2013, 93(1): 33-35.
[13] Lam YW. Scientific challenges and implementation barriers to translation of pharmacogenomics in clinical practice [J]. ISRN Pharmacol, 2013, 2013(1): 641089.
[14] 弓孟春. 精准医学对医学信息学提出的挑战与任务 [J]. 医学信息学杂志, 2016, 37(1): 2-7.
[15] 弓孟春,王慧君,卢宇蓝,等. 药物基因组学临床部署的顶层设计 [J]. 中国循证儿科杂志, 2016, 11(3): 161-167.
[16] Kawamoto K,Lobach DF,Willard HF,et al. A national clinical decision support infrastructure to enable the widespread and consistent practice of genomic and personalized medicine [J]. BMC Medical Informatics and Decision Making, 2009, 2009(9): 17.
[17] Hicks JK,Dunnenberger HM,Gumpper KF,et al. Integrating pharmacogenomics into electronic health records with clinical decision support [J]. American Journal of Health-System Pharmacy, 2016, 73(23): 1967-1976.
[18] Manzi SF,Fusaro VA,Chadwick L,et al. Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration - Experience from a pediatric tertiary care facility [J]. Journal of the American Medical Informatics Association, 2017, 24(1): 74-80.
[19] Fusaro VA,Brownstein C,Wolf W,et al. Development of a scalable pharmacogenomic clinical decision support service[C]//AMIA Jt Summits Transl Sci Proc, San Francisco: AMIA, 2013: 60-60.
[20] Overby CL,Tarczy-Hornoch P,Hoath JI,et al. Feasibility of incorporating genomic knowledge into electronic medical records for pharmacogenomic clinical decision support [J]. BMC Bioinformatics, 2010, 11(Suppl 9): 9.
[21] Overby CL,Devine EB,Abernethy N,et al. Making pharmacogenomic-based prescribing alerts more effective: A scenario-based pilot study with physicians [J]. Journal of Biomedical Informatics, 2015, 55: 249-259.
[22] Overby CL,Tarczy-Hornoch P,Kalet IJ,et al. Developing a prototype system for integrating pharmacogenomics findings into clinical practice [J]. J Pers Med, 2012, 2(4): 241-256.
[23] Devine EB,Lee CJ,Overby CL,et al. Usability evaluation of pharmacogenomics clinical decision support aids and clinical knowledge resources in a computerized provider order entry system: a mixed methods approach [J]. Int J Med Inform, 2014, 83(7): 473-483.
[24] Nishimura AA,Shirts BH,Dorschner MO,et al. Development of clinical decision support alerts for pharmacogenomic incidental findings from exome sequencing [J]. Genetics in Medicine, 2015, 17(11): 939-942.
[25] Nishimura AA,Shirts BH,Salama J,et al. Physician perspectives of CYP2C19 and clopidogrel drug-gene interaction active clinical decision support alerts [J]. Int J Med Inform, 2016, 86(86): 117-125.
[26] Caraballo PJ,Hodge LS,Bielinski SJ,et al. Multidisciplinary model to implement pharmacogenomics at the point of care [J]. Genetics in Medicine, 2017, 19(4): 421-429.
[27] Pulley JM,Denny JC,Peterson JF,et al. Operational implementation of prospective genotyping for personalized medicine: The design of the Vanderbilt PREDICT project [J]. Clinical Pharmacology and Therapeutics, 2012, 92(1): 87-95.
[28] Peterson JF,Bowton E,Field JR,et al. Electronic health record design and implementation for pharmacogenomics: A local perspective [J]. Genetics in Medicine, 2013, 15(10): 833-841.
[29] Hicks JK,Stowe D,Willner MA,et al. Implementation of clinical pharmacogenomics within a large health system: From electronic health record decision support to consultation services [J]. Pharmacotherapy, 2016, 36(8): 940-948.
[30] Owusu-Obeng A,Weitzel KW,Hatton RC,et al. Emerging roles for pharmacists in clinical implementation of pharmacogenomics [J]. Pharmacotherapy, 2014, 34(10): 1102-1112.
[31] Bell GC,Crews KR,Wilkinson MR,et al. Development and use of active clinical decision support for preemptive pharmacogenomics [J]. Journal of the American Medical Informatics Association, 2014, 21(21): e93-e99.
[32] Hicks JK,Crews KR,Hoffman JM,et al. A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record [J]. Clinical Pharmacology and Therapeutics, 2012, 92(5): 563-566.
[33] Gammal RS,Crews KR,Haidar CE,et al. Pharmacogenetics for safe codeine use in sickle cell disease [J]. Pediatrics, 2016, 138(1): e20153479.
[34] Gottesman O,Scott SA,Ellis SB,et al. The CLIPMERGE PGx Program: Clinical implementation of personalized medicine through electronic health records and genomics-pharmacogenomics [J]. Clinical Pharmacology and Therapeutics, 2013, 94(2): 214-217.
[35] Goldspiel BR,Flegel WA,Dipatrizio G,et al. Integrating pharmacogenetic information and clinical decision support into the electronic health record [J]. Journal of the American Medical Informatics Association, 2014, 21(3): 522-528.
[36] Minarro-Gimenez JA,Blagec K,Boyce RD,et al. An ontology-based, mobile-optimized system for pharmacogenomic decision support at the point-of-care [J]. PLoS ONE, 2014, 9(5): e93769.
[37] Samwald M,Minarro Gimenez JA,Boyce RD,et al. Pharmacogenomic knowledge representation, reasoning and genome-based clinical decision support based on OWL 2 DL ontologies [J]. BMC Medical Informatics and Decision Making, 2015, 2015(15): 12.
[38] Blagec K,Romagnoli KM,Boyce RD,et al. Examining perceptions of the usefulness and usability of a mobile-based system for pharmacogenomics clinical decision support: a mixed methods study [J]. Peer J, 2016, 2016(e1671): 1671-1694.
[39] Danahey K,Borden BA,Furner B,et al. Simplifying the use of pharmacogenomics in clinical practice: Building the genomic prescribing system [J]. Journal of Biomedical Informatics, 2017, 75(75): 110-121.
[40] O′donnell PH,Bush A,Spitz J,et al. The 1200 patients project: creating a new medical model system for clinical implementation of pharmacogenomics [J]. Clinical Pharmacology and Therapeutics, 2012, 92(4): 446-449.
[41] Hussain S,Kenigsberg BB,Danahey K,et al. Disease-drug database for pharmacogenomic-based prescribing [J]. Clinical Pharmacology and Therapeutics, 2016, 100(2): 179-190.
[42] O′donnell PH,Wadhwa N,Danahey K,et al. Pharmacogenomics-based point-of-care clinical decision support significantly alters drug prescribing [J]. Clinical Pharmacology and Therapeutics, 2017, 102(5): 859-869.
[43] Laerum H,Bremer S,Bergan S,et al. A taste of individualized medicine: physicians′ reactions to automated genetic interpretations [J]. Journal of the American Medical Informatics Association, 2014, 21(21): e143-e146.
[44] Haga SB. Challenges of development and implementation of point of care pharmacogenetic testing [J]. Expert Rev Mol Diagn, 2016, 16(9): 949-960.
[45] Moyer AM,Caraballo PJ. The challenges of implementing pharmacogenomic testing in the clinic [J]. Expert Review of Pharmacoeconomics & Outcomes Research, 2017, 17(6): 567-577.
[46] Schildcrout JS,Shi Y,Danciu I,et al. A prognostic model based on readily available clinical data enriched a pre-emptive pharmacogenetic testing program [J]. Journal of Clinical Epidemiology, 2016, 72(72): 107-115.
[47] What Are Rs Numbers (Rsid) [EB/OL]. https://customercare.23andme.com/hc/en-us/articles/212196908-What-are-rs-numbers-rsid, 2018-07-04/2018-07-04.
[48] Den Dunnen JT,Dalgleish R,Maglott DR,et al. HGVS recommendations for the description of sequence variants: 2016 update [J]. Hum Mutat, 2016, 37(6): 564-569.
[49] Ingelman-Sundberg SCSaM. The human cytochrome P450 (CYP) allele nomenclature website: A peer-reviewed database of CYP variants and their associated effects [J]. Human Genomics, 2010, 4(4): 278-281.
[50] William B, Wong JJC, Rahber T et al. Cost effectiveness of pharmacogenomics: A critical and systematic review [J]. Pharmacoeconomics, 2010, 28(11): 1001-1013.
[51] Plothner M,Ribbentrop D,Hartman JP,et al. Cost-effectiveness of pharmacogenomic and pharmacogenetic test-guided personalized therapies: A systematic review of the approved active substances for personalized medicine in Germany [J]. Adv Ther, 2016, 33(9): 1461-1480.
[52] Caudle KE,Dunnenberger HM,Freimuth RR,et al. Standardizing terms for clinical pharmacogenetic test results: Consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC) [J]. Genetics in Medicine, 2017, 19(2): 215-223.
[53] 翟娅婧,贺海蓉,吕军. 药物基因组学的发展与临床应用现状 [J]. 河南大学学报(医学版), 2017, 36(2): 145-148.
[54] 国家卫生计生委医政医管局. 关于印发《药物代谢酶和药物作用靶点基因检测技术指南(试行)》和《肿瘤个体化治疗检测技术指南(试行)》的通知 [EB/OL]. http://www.nhfpc.gov.cn/yzygj/s3593/201507/fca7d0216fed429cac797cdafa2ba466.shtml, 2015-07-31/2018-07-04.
[2] Collins FS,Varmus H. A new initiative on precision medicine [J]. N Engl J Med, 2015, 372(9): 793-795.
[3] 赵晓宇,刁天喜,高云华,等. 美国“精准医学计划”解读与思考 [J]. 军事医学, 2015, 39(4): 241-244.
[4] 何明燕,夏景林,王向东. 精准医学研究进展 [J]. 世界临床药物, 2015, 36(6): 418-422.
[5] Klein ME,Parvez MM,Shin JG. Clinical implementation of pharmacogenomics for personalized precision medicine: Barriers and solutions [J]. Journal of Pharmaceutical Sciences, 2017, 106(9): 2368-2379.
[6] Hoffman JM,Haidar CE,Wilkinson MR,et al. PG4KDS: A model for the clinical implementation of pre-emptive pharmacogenetics [J]. American Journal of Medical Genetics Part C, 2014, 166C(1): 45-55.
[7] Ji Y,Skierka JM,Blommel JH,et al. Preemptive pharmacogenomic testing for precision medicine: A comprehensive analysis of five actionable pharmacogenomic genes using next-generation DNA sequencing and a customized CYP2D6 genotyping cascade [J]. The Journal of Molecular Diagnostics, 2016, 18(3): 438-445.
[8] Relling MV,Evans WE. Pharmacogenomics in the clinic [J]. Nature, 2015, 526(7573): 343-350.
[9] Ehmann FCL, Prasad K, Paulmichl M, et al. Pharmacogenomic information in drug labels: European Medicines Agency perspective [J]. Pharmacogenomics J, 2015, 15(3): 201-210.
[10] Korngiebel DM,Thummel KE,Burke W. Implementing precision medicine: The ethical challenges [J]. Trends Pharmacol Sci, 2017, 38(1): 8-14.
[11] Johnson JA. Pharmacogenetics in clinical practice: How far have we come and where are we going? [J]. Pharmacogenomics, 2013, 14(7): 835-843.
[12] Scott SA. Clinical pharmacogenomics: opportunities and challenges at point of care [J]. Clinical Pharmacology and Therapeutics, 2013, 93(1): 33-35.
[13] Lam YW. Scientific challenges and implementation barriers to translation of pharmacogenomics in clinical practice [J]. ISRN Pharmacol, 2013, 2013(1): 641089.
[14] 弓孟春. 精准医学对医学信息学提出的挑战与任务 [J]. 医学信息学杂志, 2016, 37(1): 2-7.
[15] 弓孟春,王慧君,卢宇蓝,等. 药物基因组学临床部署的顶层设计 [J]. 中国循证儿科杂志, 2016, 11(3): 161-167.
[16] Kawamoto K,Lobach DF,Willard HF,et al. A national clinical decision support infrastructure to enable the widespread and consistent practice of genomic and personalized medicine [J]. BMC Medical Informatics and Decision Making, 2009, 2009(9): 17.
[17] Hicks JK,Dunnenberger HM,Gumpper KF,et al. Integrating pharmacogenomics into electronic health records with clinical decision support [J]. American Journal of Health-System Pharmacy, 2016, 73(23): 1967-1976.
[18] Manzi SF,Fusaro VA,Chadwick L,et al. Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration - Experience from a pediatric tertiary care facility [J]. Journal of the American Medical Informatics Association, 2017, 24(1): 74-80.
[19] Fusaro VA,Brownstein C,Wolf W,et al. Development of a scalable pharmacogenomic clinical decision support service[C]//AMIA Jt Summits Transl Sci Proc, San Francisco: AMIA, 2013: 60-60.
[20] Overby CL,Tarczy-Hornoch P,Hoath JI,et al. Feasibility of incorporating genomic knowledge into electronic medical records for pharmacogenomic clinical decision support [J]. BMC Bioinformatics, 2010, 11(Suppl 9): 9.
[21] Overby CL,Devine EB,Abernethy N,et al. Making pharmacogenomic-based prescribing alerts more effective: A scenario-based pilot study with physicians [J]. Journal of Biomedical Informatics, 2015, 55: 249-259.
[22] Overby CL,Tarczy-Hornoch P,Kalet IJ,et al. Developing a prototype system for integrating pharmacogenomics findings into clinical practice [J]. J Pers Med, 2012, 2(4): 241-256.
[23] Devine EB,Lee CJ,Overby CL,et al. Usability evaluation of pharmacogenomics clinical decision support aids and clinical knowledge resources in a computerized provider order entry system: a mixed methods approach [J]. Int J Med Inform, 2014, 83(7): 473-483.
[24] Nishimura AA,Shirts BH,Dorschner MO,et al. Development of clinical decision support alerts for pharmacogenomic incidental findings from exome sequencing [J]. Genetics in Medicine, 2015, 17(11): 939-942.
[25] Nishimura AA,Shirts BH,Salama J,et al. Physician perspectives of CYP2C19 and clopidogrel drug-gene interaction active clinical decision support alerts [J]. Int J Med Inform, 2016, 86(86): 117-125.
[26] Caraballo PJ,Hodge LS,Bielinski SJ,et al. Multidisciplinary model to implement pharmacogenomics at the point of care [J]. Genetics in Medicine, 2017, 19(4): 421-429.
[27] Pulley JM,Denny JC,Peterson JF,et al. Operational implementation of prospective genotyping for personalized medicine: The design of the Vanderbilt PREDICT project [J]. Clinical Pharmacology and Therapeutics, 2012, 92(1): 87-95.
[28] Peterson JF,Bowton E,Field JR,et al. Electronic health record design and implementation for pharmacogenomics: A local perspective [J]. Genetics in Medicine, 2013, 15(10): 833-841.
[29] Hicks JK,Stowe D,Willner MA,et al. Implementation of clinical pharmacogenomics within a large health system: From electronic health record decision support to consultation services [J]. Pharmacotherapy, 2016, 36(8): 940-948.
[30] Owusu-Obeng A,Weitzel KW,Hatton RC,et al. Emerging roles for pharmacists in clinical implementation of pharmacogenomics [J]. Pharmacotherapy, 2014, 34(10): 1102-1112.
[31] Bell GC,Crews KR,Wilkinson MR,et al. Development and use of active clinical decision support for preemptive pharmacogenomics [J]. Journal of the American Medical Informatics Association, 2014, 21(21): e93-e99.
[32] Hicks JK,Crews KR,Hoffman JM,et al. A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record [J]. Clinical Pharmacology and Therapeutics, 2012, 92(5): 563-566.
[33] Gammal RS,Crews KR,Haidar CE,et al. Pharmacogenetics for safe codeine use in sickle cell disease [J]. Pediatrics, 2016, 138(1): e20153479.
[34] Gottesman O,Scott SA,Ellis SB,et al. The CLIPMERGE PGx Program: Clinical implementation of personalized medicine through electronic health records and genomics-pharmacogenomics [J]. Clinical Pharmacology and Therapeutics, 2013, 94(2): 214-217.
[35] Goldspiel BR,Flegel WA,Dipatrizio G,et al. Integrating pharmacogenetic information and clinical decision support into the electronic health record [J]. Journal of the American Medical Informatics Association, 2014, 21(3): 522-528.
[36] Minarro-Gimenez JA,Blagec K,Boyce RD,et al. An ontology-based, mobile-optimized system for pharmacogenomic decision support at the point-of-care [J]. PLoS ONE, 2014, 9(5): e93769.
[37] Samwald M,Minarro Gimenez JA,Boyce RD,et al. Pharmacogenomic knowledge representation, reasoning and genome-based clinical decision support based on OWL 2 DL ontologies [J]. BMC Medical Informatics and Decision Making, 2015, 2015(15): 12.
[38] Blagec K,Romagnoli KM,Boyce RD,et al. Examining perceptions of the usefulness and usability of a mobile-based system for pharmacogenomics clinical decision support: a mixed methods study [J]. Peer J, 2016, 2016(e1671): 1671-1694.
[39] Danahey K,Borden BA,Furner B,et al. Simplifying the use of pharmacogenomics in clinical practice: Building the genomic prescribing system [J]. Journal of Biomedical Informatics, 2017, 75(75): 110-121.
[40] O′donnell PH,Bush A,Spitz J,et al. The 1200 patients project: creating a new medical model system for clinical implementation of pharmacogenomics [J]. Clinical Pharmacology and Therapeutics, 2012, 92(4): 446-449.
[41] Hussain S,Kenigsberg BB,Danahey K,et al. Disease-drug database for pharmacogenomic-based prescribing [J]. Clinical Pharmacology and Therapeutics, 2016, 100(2): 179-190.
[42] O′donnell PH,Wadhwa N,Danahey K,et al. Pharmacogenomics-based point-of-care clinical decision support significantly alters drug prescribing [J]. Clinical Pharmacology and Therapeutics, 2017, 102(5): 859-869.
[43] Laerum H,Bremer S,Bergan S,et al. A taste of individualized medicine: physicians′ reactions to automated genetic interpretations [J]. Journal of the American Medical Informatics Association, 2014, 21(21): e143-e146.
[44] Haga SB. Challenges of development and implementation of point of care pharmacogenetic testing [J]. Expert Rev Mol Diagn, 2016, 16(9): 949-960.
[45] Moyer AM,Caraballo PJ. The challenges of implementing pharmacogenomic testing in the clinic [J]. Expert Review of Pharmacoeconomics & Outcomes Research, 2017, 17(6): 567-577.
[46] Schildcrout JS,Shi Y,Danciu I,et al. A prognostic model based on readily available clinical data enriched a pre-emptive pharmacogenetic testing program [J]. Journal of Clinical Epidemiology, 2016, 72(72): 107-115.
[47] What Are Rs Numbers (Rsid) [EB/OL]. https://customercare.23andme.com/hc/en-us/articles/212196908-What-are-rs-numbers-rsid, 2018-07-04/2018-07-04.
[48] Den Dunnen JT,Dalgleish R,Maglott DR,et al. HGVS recommendations for the description of sequence variants: 2016 update [J]. Hum Mutat, 2016, 37(6): 564-569.
[49] Ingelman-Sundberg SCSaM. The human cytochrome P450 (CYP) allele nomenclature website: A peer-reviewed database of CYP variants and their associated effects [J]. Human Genomics, 2010, 4(4): 278-281.
[50] William B, Wong JJC, Rahber T et al. Cost effectiveness of pharmacogenomics: A critical and systematic review [J]. Pharmacoeconomics, 2010, 28(11): 1001-1013.
[51] Plothner M,Ribbentrop D,Hartman JP,et al. Cost-effectiveness of pharmacogenomic and pharmacogenetic test-guided personalized therapies: A systematic review of the approved active substances for personalized medicine in Germany [J]. Adv Ther, 2016, 33(9): 1461-1480.
[52] Caudle KE,Dunnenberger HM,Freimuth RR,et al. Standardizing terms for clinical pharmacogenetic test results: Consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC) [J]. Genetics in Medicine, 2017, 19(2): 215-223.
[53] 翟娅婧,贺海蓉,吕军. 药物基因组学的发展与临床应用现状 [J]. 河南大学学报(医学版), 2017, 36(2): 145-148.
[54] 国家卫生计生委医政医管局. 关于印发《药物代谢酶和药物作用靶点基因检测技术指南(试行)》和《肿瘤个体化治疗检测技术指南(试行)》的通知 [EB/OL]. http://www.nhfpc.gov.cn/yzygj/s3593/201507/fca7d0216fed429cac797cdafa2ba466.shtml, 2015-07-31/2018-07-04.