Causal Inference因果推论.


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Causal Inference因果推论 Of Moderate 中级 Phenotypes 表型 and Biomarkers 生物标记 in Rheumatoid Joint inflammation 风湿性关节炎 [An Utilization of Machine Learning 机器学习 Strategies to Hereditary The study of disease transmission 遗传流行病学] Wentian Li 李问天 , Ph.D Feinstein Foundation for Restorative Examination Hereditary Affiliation
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Causal Inference因果推论 Of Intermediate 中级 Phenotypes 表型 and Biomarkers 生物标记 in Rheumatoid Arthritis 风湿性关节炎 [An Application of Machine Learning 机器学习 Techniques to Genetic Epidemiology 遗传流行病学] Wentian Li 李问天 , Ph.D Feinstein Institute for Medical Research Wentian Li, North Shore LIJ Health System

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Genetic Association 相关 is not identical to causal 因果的 relationship Wrinkle-Cancer danger affiliation does not mean one reasons 导è‡\' another Age is a frustrating element 混杂因ç\'  Wentian Li, North Shore LIJ Health System

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When do we have to know circumstances and end results? Once in a while talked about in hereditary investigation on the grounds that genotype is dependably the reason 原因, and phenotype is dependably the impact 效果 In the study of disease transmission 流行病学 component 因ç\' -infection 疾病 affiliation can fit in with three circumstances (1) element is a reason; (2) reverse causality; (3) a third puzzling element For two middle of the road phenotypes (biomarkers), causal bolt can point whichever way Wentian Li, North Shore LIJ Health System

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Causal Inference in Machine Learning Large content database (e.g. google) Observational information (no controlled trial, and no different ways to deal with focus causality) Two-point affiliation in reality can\'t be utilized to claim causality The key is a third variable , and additionally contingent 条件的 affiliation taking into account the third variable Wentian Li, North Shore LIJ Health System

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Wentian Li, North Shore LIJ Health System

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Wentian Li, North Shore LIJ Health System

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Data Mining and Knowledge Discovery (2000) v4, pp.163-192 Wentian Li, North Shore LIJ Health System

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An Example Wentian Li, North Shore LIJ Health System

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Cooper’s Local Causality Discovery (LCD) Rule Six suspicions: 1.database fulfillment. 2. discrete variables. 3. Bayesian system model (coordinated non-cyclic 非环式的 diagram: no circles ). 4…. 5. no choice inclination. 6. substantial factual testing. Three variables: x,y,z Hidden 潜在的 variable is permitted (however not in the dataset) Determine three connections: unqualified C(x,y), C(y,z) and restrictive C(x,z|y) Wentian Li, North Shore LIJ Health System

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Between two variables, there are just 6(4) causal connections (permitting puzzling variable) perplexing no relationship confounding+causing bringing on NO jumbling in addition to rev creating Reverse bringing about Wentian Li, North Shore LIJ Health System

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Number of causal connections among three variables 6x6x6= 216 conceivable outcomes 4x4x6= 96 if x is not brought on by either y or z (but rather can get a bolt from a concealed variable) [Cooper’97 paper] 2x2x6= 24 if x doesn’t even get a bolt from shrouded frustrating variables [Li and Wang, unpublished] Wentian Li, North Shore LIJ Health System

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Given a causal model… Unconditional 无条件 relationship between any two variables can be controlled by whether they are joined by a way Conditional 条件的 affiliation can be dictated by the purported “d-separation” guideline Wentian Li, North Shore LIJ Health System

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“CCC” causal surmising tenet (Cooper rendition) if C(x,y) + , C(y,z) + , yet C(x,z|y) - , then there are just three conceivable causal models: x => y => z x <= h => y => z h =>x => y =>z (Silverstein et al. adaptation) if C(x,y) + , C(y,z) + , C(x,z) + , yet C(x,z|y) - , C(x,y|y) + , C(y,z|x) + , then... Wentian Li, North Shore LIJ Health System

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In a three-manner related set If one of the variable (x) is not an impact (just a reason) AND If connection is lost in the middle of x and z restrictively, THEN y causes z x : quality y,z : two transitional phenotypes Wentian Li, North Shore LIJ Health System

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The utilization of a not-an impact variable has an astonishing parallel in the study of disease transmission Called “instrumental variable” Martjin Katan’s thought on cholesterol 胆固醇 tumor 癌症 affiliation: he proposed to utilize a genotype (apoliprotein 载脂蛋白 E) as the third variable (Lancer 1986, i:507-508) Katan did not utilize contingent relationship This thought is presently called “Mendelian randomization” Wentian Li, North Shore LIJ Health System

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Wentian Li, North Shore LIJ Health System

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Rheumatoid Arthritis (RA) An immune system 自我免疫的 sickness Chronic aggravation 炎症 of joints 关节 Three times more prone to happen in ladies than men Age of onset 40-60 Twin 双胞胎 concordance rates: 12-15% for MZ单合子, 单卵双生 , 5% for DZ 异卵双生 Genetic and natural (e.g. smoking) danger components Wentian Li, North Shore LIJ Health System

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MHC/HLA: the fundamental hereditary commitment of RA MHC ( Major Histocompatibility Complex主要组织相容性复合体) or HLA (Human leukocyte antigens 人类白血球抗原) : HLA-DRB1 quality on chromosome 6 (6p21.3) The RA related alleles are HLA-DRB1*0401, *0404, *0408 (Caucasian), not *0402, *0403, *0407 In Asian populace, diverse DRB1 alleles are connected with RA (e.g. *0405, *0901) A gathering of DRB1 danger alleles are called “shared epitope” ( SE ) 共同表位, or rheumatoid epitope, code position 70-74 amino acids in the third hypervariable district Wentian Li, North Shore LIJ Health System

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Two Auto-antibodies are unequivocally connected with RA: RF and hostile to CCP RF (rheumatoid component 类风湿因子 ): 80% of RA patients are RF positive against CCP (against cyclic citrullinated peptide counter acting agent 抗环瓜氨酸肽抗体, 抗CCP抗体 ): far superior indicator of RA in right on time stage HLA-DRB1, RF, against CCP are all connected with the RA illness, and they are connected with one another. CCC guideline can be connected! 张利方,阎有功,黄前川,等, “抗环瓜氨酸肽抗体在类风湿性关节炎诊断中的应用”, 免疫学杂志,2004,20:52-57 Wentian Li, North Shore LIJ Health System

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Q: Between RF and hostile to CCP, which one is the reason and which is the impact? Wentian Li, North Shore LIJ Health System

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1723 Caucasian RA patients against CCP positive hostile to CCP negative Wentian Li, North Shore LIJ Health System

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Association in the middle of RF and DRB1 genotype is lost contingent on against CCP Wentian Li, North Shore LIJ Health System

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By the CCC standard, hostile to CCP is the reason, RF is the impact Or, hostile to CCP is upstream and RF is downstream in a pathway Wentian Li, North Shore LIJ Health System

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Discussions/Issues There are confirmations that RA patients get to be hostile to CCP positive before getting to be RF positive The three-way connection may be lost in ordinary controls (here we have a “case-only” investigation) in the middle of hostile to CCP and RF, different elements are conceivable (so the reason impact may not be immediate) It is not clear where the smoking element comes in (could be a captivating examination with smoking information!) Wentian Li, North Shore LIJ Health System

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MR needs a not-an-impact variable (quality) Conditional affiliation is not utilized Only need a counter sample (e.g. Apo E2 tests have low cholesterol, yet NOT high growth hazard) LCD needs a vari

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