Genetic and Molecular Epidemiology (Modern epidemiology Chap. 28)

Chapter 28 Genetic and Molecular Epidemiology Muin J. Khoury, Robert
Millikan, and Marta Gwinn Chuntaro (@Shuntarooo3) 1 Modern Epidemiology

Genome? Gene? Omic 2 ਫౡ-ੁ໺७ࢠʢஶʣɾαΩϚΠίʢ࡞ըʣʢ2018ʣʰϚϯΨͰΘ͔Δ ήϊϜҩֶʱ༽౔ࣾɹ Λࢀߟʹ࡞੒ ճ Λ 䎠
࣏འ ڵ ↴ɾ ੨ɺ ᮊɾ ე 㥕 ࡉ๔ ֩ છ৭ମ %/" Ҩ఻ࢠ" Ҩ ఻ ࢠ # %/" N3/" λϯύΫ࣭ ήϊϜʢHFOPNFʣ ͋Δੜ෺͕΋ͭછ৭ମதʹ͋Δ ͢΂ͯͷ%/"഑ྻ৘ใͷ͜ͱ ʢશҨ఻৘ใʣ Ҩ఻ࢠʢHFOFʣ %/"ͷҰ෦Ͱɼʮ͜ͷ഑ྻʹ͠ ͕ͨͬͯλϯύΫ࣭Λ࡞Εʯͱ໋ ྩ͍ͯ͠Δ෦෼ͷ͜ͱ (FOPNJDT 1SPUFPNJDT w 5SBOTDSJQUPNJDT w .FUBCPOPNJDT w /VUSJHFOPNJDT w 1IBSNBDPHFOPNJDT w 5PYJDPHFOPNJDT 0NJD ͞·͟·ͳ໢ཏతੜମ෼ࢠΛ ·ͱΊͨ஌ࣝɾू߹ͷ͜ͱ

Genetic and Molecular Epidemiology 3 &YQPTVSFT 4VTDFQUJCJMJUZ 0VUDPNFT #JPMPHJDNBSLFST w
ײછ঱Ӹֶɿ߅ମՁ w ৺݂؅࣬ױӸֶɿ݂தࢷ࣭ w ؀ڥӸֶɿಟૉͷ݂தೱ౓ .PMFDVMBSFQJEFNJPMPHZʢ෼ࢠӸֶʣ (FOFUJDFQJEFNJPMPHZʢҨ఻Ӹֶʣ (FOFUJD GBDUPST 0VUDPNFT Wellcome Trust Case Control Consortium. (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447(7145), 661. (FOF %JTFBTF %JTFBTF (FOF (FOF º (FOF &OWJSPONFOU º %JTFBTF

Overview 4 (FOF %JTFBTF %JTFBTF (FOF (FOF º (FOF &OWJSPONFOU
º %JTFBTF "OBMZUJDBOENFUIPEPMPHJDBMJTTVFT &YBNQMF w େ௎͕Μ w Ԍ঱ੑେ௎Ԍ %POPUDPWFSUSBEJUJPOBMHFOFUJDBOBMZTFT w Ոܥ෼ੳ w ࿈࠯ղੳ w Ϛοϐϯά

MULTIDISCIPLINARY APPROACHES TO THE EVALUATION OF BIOMARKERS (p. 566) 5
"OBMZUJDWBMJEJUZʢ෼ੳతଥ౰ੑʣ ͲͷΑ͏ͳόΠΦϚʔΧʔͰ͋ͬͯ΋ଥ౰ੑͷධՁ͸ඞཁ $MJOJDBMWBMJEJUZʢྟচతଥ౰ੑʣ $MJOJDBMVUJMJUZʢྟচత༗༻ੑʣ

ANALYTIC VALIDITY (p. 566) 6 "OBMZUJDWBMJEJUZ ʢ෼ੳతଥ౰ੑʣ "DDVSBDZ ʢਖ਼֬ੑʣ
Biomarker Test Present Absent + A B - C D = A A + C = D B + D "OBMZUJDTFOTJUJWJUZ ʢײ౓ʣ "OBMZUJDTQFDJpDJUZ ʢಛҟ౓ʣ ෼ੳతଥ౰ੑ͸ɼαϯϓϧͷछྨɼॲཧɼอଘ͓ΑͼΞοηΠͷଥ౰ੑʹґଘ͢Δ

CLINICAL VALIDITY (p. 566) 7 ෼ੳతଥ౰ੑΛ্ཱ֬ͨ͠Ͱɼ ࣍͸ྟচతଥ౰ੑΛྟচ͓ΑͼӸֶݚڀͰධՁ͢Δඞཁ͕͋Δ Clinical Outcome Biomarker
Present Absent + A B - C D = A A + C = D B + D $MJOJDBMTFOTJUJWJUZ ʢײ౓ʣ $MJOJDBMTQFDJpDJUZ ʢಛҟ౓ʣ = A A + B = D C + D 1PTJUJWFQSFEJDUJWFWBMVF ʢཅੑదத཰ʣ /FHBUJWFQSFEJDUJWFWBMVF ʢӄੑదத཰ʣ ࣬ױ͋Γͷݸମʹରͯ͠ ʢਖ਼͘͠ʣཅੑͱ਍அ͢Δ֬཰ ࣬ױͳ͠ͷݸମʹରͯ͠ ʢਖ਼͘͠ʣӄੑͱ਍அ͢Δ֬཰ ཅੑͱ਍அ͞Εͨݸମʹ͓͍ͯ ਅʹ࣬ױ͕ଘࡏ͢Δ֬཰ ӄੑͱ਍அ͞Εͨݸମʹ͓͍ͯ ਅʹ࣬ױ͕ଘࡏ͠ͳ͍֬཰

CLINICAL UTILITY (p. 567) 8 ྟচత༗༻ੑͱ͸ɼݕࠪʹΑΓΞ΢τΧϜ͕ྑ͘ͳΔ֬཰Λࣔ͢ #VSLFFUBM Outcome Intervention Sick
Not 1 A B 2 C D όΠΦϚʔΧʔ͕ཅੑͷݸମͷྟচత༗༻ੑධՁ ͜ͷද͸ɼόΠΦϚʔΧʔཅੑͷݸମʹରͯ͠ɼ ϥϯμϜʹ࣏ྍΛׂΓ౰ͯɼ࣏ྍͷޮՌΛධՁ͍ͯ͠Δ 3$5ˠ όΠΦϚʔΧʔͷྟচత༗༻ੑͷධՁʹͳ͍ͬͯΔʁ ?

ETHICAL, LEGAL, AND SOCIAL ISSUES (p. 567) 9 όΠΦϚʔΧʔʢಛʹҨ఻৘ใʣΛ࢖༻͢Δݚڀ͸ɼͨ͘͞Μͷ FUIJDBMʢྙཧతʣ
MFHBMʢ๏తʣ TPDJBMʢࣾձతʣͷJTTVFʢ՝୊ʣ E L S I w ΠϯϑΥʔϜυɾίϯηϯτ w ඃݧऀͷืू w ݚڀ݁Ռʹؔ͢Δ৘ใͷ։ࣔ w ݸਓ΍ूஂʹର͢ΔࠩผͷՄೳੑ

CONVENTIONAL EPIDEMIOLOGIC STUDIES (p. 568) 10 w $BTFDPOUSPMTUVEJFT w $PIPSUTUVEJFT
w $SPTTTFDUJPOBMTUVEJFT

AlleleɾGenotype 11 છ৭ମ A - T T - A G
- C C - G T - A ߏ଄Λ֦େ Ԙج഑ྻ %/" ˢ૬ิ࠯഑ྻ A A A A A A A a ෕༝དྷ ฼༝དྷ w ԘجͷόϦΤʔγϣϯΛΞϦϧʢBMMFMFʣ ͱ͍͏ w ΞϦϧͷ૊Έ߹Θͤ ʮ""PS"BPSBBʯΛδΣϊλΠϓ ʢHFOPUZQFʣͱ͍͏

SNV (Single Nucleotide Variant) 12 *% MPDVT MPDVT MPDVT MPDVT
MPDVT "" "" "" "" "" "" "" "( "" "" "" "" (( "" "" ௕͞ͷԘجΛ࠲ҐʢMPDVTʣͱ͢Δ େ൒͸ಉҰ w ͱ͖Ͳ͖ҟͳΔΞϦϧΛؚΉมҟʢόϦΞϯτɼWBSJBOUʣ͕͋Δ w ԘجͷόϦΞϯτ͸4/7ʢ4JOHMF/VDMFPUJEF7BSJBOUʣ

SNPɾMAF 13 δΣϊλΠϓ "" "B BB 5PUBM /
͋Δूஂʢ໊ʣͷ͋Δ4/7Λߟ͑Δ ΞϦϧ " B 5PUBM / ස౓ º º ϚΠφʔΞϦϧස౓ ʢ."'NJOPSBMMFMF GSFRVFODZʣ ස౓ͷগͳ͍ΞϦϧ 4/1ʢҰԘجଟܕʣ."'㱢΍ͷ4/7ͷ͜ͱ

CASE-CONTROL STUDIES (1) (p. 568) 14 Ҩ఻ࢠϚʔΧʔ͸ײडੑҼࢠͱͯ҆͠ఆ͍ͯ͠ΔͨΊɼ DBTFDPOUSPMTUVEJFTʹద͍ͯ͠Δ 3FDBMMCJBT͸গͳ͍
4VTDFQUJCJMJUZʢײडੑʣͱ͸ʁ Ҩ఻ੑ࣬ױ ୯ҰҨ఻ࢠ࣬ױ ଟҨ఻ੑ࣬ױʢ͋Γ;Εͨ࣬ױɼෳࡶ࣬ױɼDPNNPOEJTFBTFʣ ͭͷ࠲ҐʹΑܾͬͯఆతʹӨڹ͞ΕΔ খ͍͞د༩౓Λ΋ͬͨଟ͘ͷҨ఻తཁҼʹΑͬͯදݱܕ͕ܾఆ͞ΕΔ ײडੑҼࢠʢTVTDFQUJCJMJUZGBDUPSʣ w $POUSPM܈ʹରͯ͠$BTF܈ͰόϦΞϯτͷස౓͕༗ҙʹߴ͍͕ɼ Ұൠͷ݈ৗਓ΋͠͹͠͹ͦͷόϦΞϯτΛ༗͢Δ w $BTF܈Ͱ͋ͬͯ΋όϦΞϯτ͕ͳ͍ݸମ΋͋ΓಘΔ

CASE-CONTROL STUDIES (2) (p. 568) 15 ͭͷόϦΞϯτͱ࣬ױͱͷؔ࿈͚ͩͰ͸ͳ͘ɼ ଞͷόϦΞϯτ΍ཁҼͱڞʹ࣬ױͱͷؔ࿈Λ୳ࡧͰ͖Δ w
(FOFHFOFJOUFSBDUJPO w (FOFFOWJSPONFOUJOUFSBDUJPO ·ΕͳΤϯυϙΠϯτʢ3BSFEJTFBTFʣʹద͍ͯ͠Δ

CASE-CONTROL STUDIES (3) (p. 568) 16 0VUDPNF : $PWBSJBUF &
4/1 ( 4/1 ( ʜ 4/1K ( w ήϊϜϫΠυؔ࿈ղੳʢ(8"4HFOPNFXJEFBTTPDJBUJPOTUVEZʣ w σβΠϯ͸έʔεɾίϯτϩʔϧݚڀ w ֤4/1ͱΞ΢τΧϜʢ஋ܗ࣭ʣͱͷؔ࿈Λݕ౼͢ΔϞσϧ w 4/1ͷ਺͚ͩݕఆΛ܁Γฦ͢ 4/1਺͸਺ेສʙ਺ઍສ

COHORT STUDIES (p. 568) 17 ͋Γ;Εͨ࣬ױͱؔ࿈͢ΔҨ఻ࢠΛൃݟ͢ΔͨΊʹ໾ཱͭ w ॎஅతͳඇৗʹେن໛ͳूஂ w όΠΦόϯΫͷཱ֬
Study Sample size Population Study Objectives Decode Genetics > 100,000 Iceland • ͋Γ;Εͨ࣬ױͷݪҼͱͳΔҨ఻ࢠͷಉఆ • ৽ༀͷ։ൃ౳ UK Biobank 500,000 Population sample of persons aged 45-69 y • Ҩ఻ࢠɼ؀ڥɼੜ׆ελΠϧͷ໾ׂ • Medical recordͱϦϯΫ CartaGene (Quebec) > 60,000 Population sample of persons aged 25-74 y • Ҩ఻ࢠɼ؀ڥɼੜ׆ελΠϧɼ Medical recordͱϦϯΫ Estonia Genome Project > 1,000,000 Estonian population • ͋Γ;Εͨ࣬ױͷݪҼͱͳΔҨ఻ࢠͷಉఆ • Medical recordͱϦϯΫ GenomeEUTwin ʙ800,000 twin pairs Twin cohorts from 7 European countries + Australia • Ҩ఻ࢠɼ؀ڥɼੜ׆ελΠϧͷ໾ׂ ॊೈʹෳࡶͳϝΧχζϜɾԾઆ ʹରԠͰ͖Δ

CROSS-SECTIONAL STUDIES (p. 569) 18 ௐࠪ࣌఺ʹ͓͚Δ࣬ױͷ༗ප཰΍ͦͷ࣬ױʹؔ࿈͢ΔҨ఻ࢠΛ୳ࡧͰ͖Δ

METHODOLOGIC ISSUES CONFOUNDING (p. 570) 19 ڵຯͷ͋ΔόϦΞϯτ ࣬ױ 3BDFFUIOJDJUZ ʢਓछຽ଒ੑʣ
ަབྷҼࢠ ަབྷҼࢠͷௐ੔ํ๏ -PHJTUJDSFHSFTTJPONPEFM :ˡ4/1 ڞมྔɹ㱺ɹ4/1ʹ͍ͭͯͷݕఆ :ˡ4/1 ڞมྔɹ㱺ɹ4/1ʹ͍ͭͯͷݕఆɹŋŋŋҎԼಉ༷ (FOPUZQFDPEJOH $PWBSJBUFT XIFSF Gi 2 {0, 1, 2} Ei logit[Pr(Yi = 1)] = logit[⇡i( 0, e, g)] = 0 + eEi + gGi ⇡i = Pr(Yi = 1)

GENOTYPE AND EXPOSURE MISCLASSIFICATION (1) (p. 570) 20 /POEJ⒎FSFOUJBMNJTDMBTTJpDBUJPOʢඇࠩҟޡ෼ྨʣ͸ όΠΦϚʔΧʔʢ஋ʣͱΞ΢τΧϜͱͷؔ࿈Λرऍ͢Δ
ଞͷม਺ͱແؔ܎ͳޡ෼ྨʢؔ܎͢Δͷ͸ࠩҟޡ෼ྨʣ$IBQ /VMMํ޲΁ಇ͘ ਖ਼֬ͳ෼ྨ ඇࠩҟ෼ྨΛͨ͠৔߹ (-)ͷ20%→(+) (-)ͷ20%→(+) (+)ͷ20%→(-) Biomarker Biomarker Biomarker Clinical outcome + - + - + - Present 250 450 360 360 410 290 Absent 100 900 720 280 740 260 Odds Ratio 5.0 2.4 2.0 Kenneth J. Rothman, ༁ʢຊా߶, ྛ༤Ұ, & ࠤ౻ت࿨ʣ. ϩεϚϯͷӸֶ ୈ2൛, 2013.ͷද7-6Λࢀߟʹ࡞੒

GENOTYPE AND EXPOSURE MISCLASSIFICATION (2) (p. 570) 21 w ࿈࠯ෆฏߧঢ়ଶ͕ڧ͍όϦΞϯτ͸ɼ࣬ױͱͷؔ࿈͕ڧ͘ͳΔ
w ੈ୅͕ܦͭʹͭΕɼ࿈࠯ෆฏߧঢ়ଶ͕ऑ͘ͳΓɼ࣬ױͱͷؔ࿈͸رऍ͞ΕΔ ୈੈ୅ Oੈ୅ ࣬ױͱؔ࿈ͷ͋ΔόϦΞϯτʢ"ʣ όϦΞϯτʢ"ʣͱڑ཭͕ۙ͘ɼOੈ୅ܦͬͯ΋࿈࠯ฏߧঢ়ଶʹͳ͍ w Ҩ఻ࢠ͸ɼݮ਺෼྾ͷࡍʹ૊Έ׵͑Λى͜͢ w ಉ͡છ৭ମͰɼڑ཭͕͍ۙҨ఻ࢠ࠲͸όϦΞϯτʢ"ʣͱ ηοτʹͳͬͯ఻ΘΔ w ͭͷҟͳΔόϦΞϯτͱͷؔ࿈ͷఔ౓Λ ࿈࠯ෆฏߧʢ-JOLBHFEFTFRVJMJCSJVNʣͱ͍͏ ʢ૬ؔΈ͍ͨͳ΋ͷʣ w ؔ࿈͕ڧ͍ͱ͖ɼ࿈࠯ෆฏߧ͸ڧ͍ ඇࠩҟޡ෼ྨʹΑΔ

GENE-ENVIRONMENT INTERACTION (1) (p. 570) 22 (FOFUJDGBDUPS ( EJTFBTF &OWJSPONFOUBMGBDUPS
& PS&YQPTVSF "MMIVNBOEJTFBTF͸Ҩ఻ͱ؀ڥཁҼͱͷ૬ޓ࡞༻͕ݪҼͰ͋Δ º .BSHJOBMʹධՁ͢Δͱɼ૬ޓ࡞༻͕ϚεΫ͞ΕΔ (FOFUJDGBDUPS ( EJTFBTF EJTFBTF &OWJSPONFOUBMGBDUPS & PS&YQPTVSF Ҩ఻ཁҼʹΑΔϦεΫ ؀ڥཁҼʹΑΔϦεΫ

GENE-ENVIRONMENT INTERACTION(2) (p. 570) 23 Exposure Geno- type Cases Controls
Contrast Odds ratio Main information - - A00 B00 A OR00 = 1.0 (Reference) Common reference - + A01 B01 B B vs. A OR01 = A01B00 /(A00B01) Genotype alone vs. none + - A10 B10 C C vs. A OR10 = A10B00 /(A00B10) Environmental factor alone vs. none + + A11 B11 D D vs. A OR11 = A11B00 /(A00B11) Join genotype and environmental factor vs. none Multiplicative interaction D/(B * C) Deviation from multiplicative modelʢ৐๏Ϟσϧʣof interaction Additive interaction D - (B + C - 1) Deviation from additive modelʢՃ๏Ϟσϧʣof interaction (FOF&OWJSPONFOU*OUFSBDUJPO"OBMZTJTJOB$BTF$POUSPM4UVEZ Ҩ఻؀ڥަޓ࡞༻ͷղੳ͸͜ͷද͕͓͢͢Ί w ৘ใͷϩε͕ͳ͍ w ަޓ࡞༻ͷد༩͕෼͔Δ w ૉͷ৘ใ͕͋Δ͔Βɼ৴པ۠ؒ౳ͷܭࢉ΋Մೳ

EMERGING ANALYTIC COMPLEXITY(1) (p. 571) 24 ِཅੑͷ੍ޚʢଟॏੑͷ໰୊ʣ w (8"4Ͱ͸ଟ͘ͷ4/7ʹ͍ͭͯݕఆΛ͓͜ͳ͏ˠଟॏੑͷ໰୊ w
#POGFSSPOJิਖ਼Ͱ͸ɼ༗ҙਫ४͸º w ϕΠζతख๏΋։ൃ͞Ε͍ͯΔ খඪຊߴ࣍ݩσʔλ w QO໰୊ w ม਺ʹൺֱͯ͠αϯϓϧαΠζ͕খ͍͞ w ݟ্͔͚׬શʹ༧ଌͰ͖ΔϞσϧʢཁҼͷ૊Έ߹Θͤʣ͕๲େʹಘΒΕͯ͠ ·͏ w ࣍ݩͷढ͍ w ૊Έ߹ΘͤʢHFOFHFOF HFOFFOWJSPONFOUBMJOUFSBDUJPOʣ͕രൃతʹ૿ ͑Δ

EMERGING ANALYTIC COMPLEXITY(2) (p. 571) 25 /PWFMBOBMZUJDTUSBUFHJFT w ֊૚ܕճؼ෼ੳ w
ϕΠζਪఆ w $PNCJOBUPSJBMQBSUJUJPOJOHNFUIPE $1. w .VMUJGBDUPSEJNFOTJPOBMJUZSFEVDUJPO .%3 NFUIPE Flanders, W. D., & Khoury, M. J. (1996). Analysis of case-parental control studies: method for the study of associations between disease and genetic markers. American Journal of Epidemiology, 144(7), 696–703.

NONCONVENTIONAL EPIDEMIOLOGIC STUDIES (p. 573) 26 w $BTFPOMZTUVEJFT w $BTFQBSFOUTUVEJFT

CASE-ONLY STUDIES (p. 573) 27 $BTFPOMZEFTJHOʹ͍ͭͯ͸ɼ%S,*%ઌੜͷαΠτΛࢀߟʹͤͯ͞ ͍͖ͨͩ·ͨ͠ $BTF0OMZ%FTJHOʹ͍ͭͯʦҨ఻Ӹֶʧʛ(FOF&OWJSPONFOUBM*OUFSBDUJPO ʢIUUQTXXXESLJEOFUDBTFPOMZHFOFQJʣ w
$BTFͷΈΛର৅ʹݚڀΛ͓͜ͳ͏ํ๏ w (FOFHFOF (FOFFOWJSPONFOUBMJOUFSBDUJPOΛධՁͰ͖Δ Exposure Genotype Cases - - A00 - + A01 + - A10 + + A11 Case-only odds ratio = (A11A00)/(A10A01) ΑΓେ͖͍ͱ͖ɼ ަޓ࡞༻ͷՄೳੑ͕ࣔࠦ͞ΕΔ w .BJOF⒎FDUʢҨ఻ࢠ΍؀ڥ͕Ξ΢τΧϜʹ௚઀༩͑ΔӨڹʣ͸Θ͔Βͳ͍ w Ҩ఻ࢠͱ؀ڥཁҼ͕ಠཱ͍ͯ͠Δඞཁ͕͋Δ

CASE-PARENT STUDIES (p. 575) 28 $BTF $POUSPM w ࣬ױΛൃ঱ͨ͠$BTFͷ਌Λ$POUSPMͱ͢ΔσβΠϯ w
ਓछɼຽ଒ɼҨ఻తഎܠͱ͍ͬͨަབྷҼࢠΛऔΓআ͘͜ͱ͕Ͱ͖Δ w $BTFDPIPSUσβΠϯͷྨܕ Genotype + - Case A B Control C D

EXAMPLE 1: COLORECTAL CANCER (p. 575) 29 ߴස౓ͷ೑ͷઁऔ େ௎͕Μ )FUFSPDZMJDBNJOFT
)$"T ൃ͕Μੑ෺࣭ ैདྷͷӸֶ Ո଒ྺ հೖʹΑΓϦεΫ௿Լ Ҩ఻ࢠมҟ ΑΓऑ͍Ҩ఻ࢠมҟ ؀ڥཁҼ º Ҩ఻Ӹֶɾ෼ࢠӸֶ Ҩ఻ࢠ εΫϦʔχϯά ศதͷಛҟతͳ Ҩ఻ࢠมҟ ૣظൃݟ Ҩ఻ࢠϓϩϑΝΠϦϯά w αϒλΠϓʹ෼ྨ w ద੾ͳ࣏ྍΛબ୒

EXAMPLE 2: INFLAMMATORY BOWEL DISEASE (1) (p. 577) 30 w
Ԍ঱ੑ௎࣬ױͱͯ͠Ϋϩʔϯපͱ௵ᙾੑେ௎ԌΛѻ͏ w (8"4͕੒ޭΛऩΊͨ࣬ױ w (8"4ͷ݁Ռ͸ɼൃ঱ػংͷ࠶ߟΛଅͨ͠ w ૊৫ଛইΛҾ͖ى͜͢৽ͨͳ෺࣭ͷൃݟ w Ϋϩʔϯපͷ࣏ྍ๏ͱͯ͠ *-ʹର͢ΔϞϊΫϩφʔϧ߅ମΛ࢖༻ͨ͠ྟচࢼݧͷ࣮ࢪΛଅͨ͠ ؔ࿈όϦΞϯτͷ਺ ࣬ױ 2007೥ΑΓલʹಉఆ͞Εͨ όϦΞϯτ 2007೥͔Β2013೥த·Ͱʹಉఆ ͞ΕͨόϦΞϯτ Ϋϩʔϯප 3 (NOD2, IBD5, IL23R) 140 ௵ᙾੑେ௎Ԍ 1 (IL23R) 133 ଟൃੑߗԽ঱ 0 52 ݪൃੑ୾ोੑ؊ߗม 0 28 ؔઅϦ΢Ϛν 2 (PAD14, CTLA4) 30 શ਎ੑΤϦςϚτʔσε 2 (PTPN22, IR5) 31 1ܕ౶೘ප 3 (INS, PTPN22, IRF5) 40 ೥ʹ࠷ॳͷ(8"4͕ൃද͞Εͨ Tom Strachan et al., ༁ʢੁ໺७෉, & ෱ౢٛޫʣ. Genetics and Genomics in MedicineʢήϊϜҩֶʣ, 2016.ͷද8.10Λࢀߟʹ࡞੒

ࢀߟจݙ ,FOOFUI+3PUINBO ༁ʢຊా߶ ྛ༤Ұ ࠤ౻ت࿨ʣϩεϚϯͷӸֶୈ൛ ࣰݪग़ ൛৽ࣾ 5PN4USBDIBOFUBM
༁ʢੁ໺७෉ ෱ౢٛޫʣήϊϜҩֶ ϝσΟΧϧɾαΠΤϯεɾ Πϯλʔφγϣφϧ ਫౡੁ໺७ࢠʢஶʣɾαΩϚΠίʢ࡞ըʣϚϯΨͰΘ͔ΔήϊϜҩֶ ༽౔ࣾ "OESFB4'PVMLFT ؂༁ʢ੢ࢁؽʣ࣮ફͰΘ͔Δʂ3ʹΑΔ౷ܭҨ఻ֶ ؙળग़൛ ෌ా੣ ২໦༏෉ήϊϜσʔλղੳ ڞཱग़൛ ాٶݩ ২໦༏෉ খ৿ཧήϊϜҩֶͷͨΊͷҨ఻౷ܭֶ ڞཱग़൛ 31

Discussion!! 32

Genetic and Molecular Epidemiology (Modern epidemiology Chap. 28)

Genetic and Molecular Epidemiology (Modern epidemiology Chap. 28)

Shuntaro Sato

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Chapter 28 Genetic and Molecular Epidemiology Muin J. Khoury, Robert

Genome? Gene? Omic 2 ਫౡ-ੁ໺७ࢠʢஶʣɾαΩϚΠίʢ࡞ըʣʢ2018ʣʰϚϯΨͰΘ͔Δ ήϊϜҩֶʱ༽౔ࣾɹ Λࢀߟʹ࡞੒ ճ Λ 䎠

Genetic and Molecular Epidemiology 3 &YQPTVSFT 4VTDFQUJCJMJUZ 0VUDPNFT #JPMPHJDNBSLFST w

Overview 4 (FOF %JTFBTF %JTFBTF (FOF (FOF º (FOF &OWJSPONFOU

MULTIDISCIPLINARY APPROACHES TO THE EVALUATION OF BIOMARKERS (p. 566) 5

ANALYTIC VALIDITY (p. 566) 6 "OBMZUJDWBMJEJUZ ʢ෼ੳతଥ౰ੑʣ "DDVSBDZ ʢਖ਼֬ੑʣ

CLINICAL VALIDITY (p. 566) 7 ෼ੳతଥ౰ੑΛ্ཱ֬ͨ͠Ͱɼ ࣍͸ྟচతଥ౰ੑΛྟচ͓ΑͼӸֶݚڀͰධՁ͢Δඞཁ͕͋Δ Clinical Outcome Biomarker

CLINICAL UTILITY (p. 567) 8 ྟচత༗༻ੑͱ͸ɼݕࠪʹΑΓΞ΢τΧϜ͕ྑ͘ͳΔ֬཰Λࣔ͢ #VSLFFUBM Outcome Intervention Sick

ETHICAL, LEGAL, AND SOCIAL ISSUES (p. 567) 9 όΠΦϚʔΧʔʢಛʹҨ఻৘ใʣΛ࢖༻͢Δݚڀ͸ɼͨ͘͞Μͷ FUIJDBMʢྙཧతʣ

CONVENTIONAL EPIDEMIOLOGIC STUDIES (p. 568) 10 w $BTFDPOUSPMTUVEJFT w $PIPSUTUVEJFT

AlleleɾGenotype 11 છ৭ମ A - T T - A G

SNV (Single Nucleotide Variant) 12 *% MPDVT MPDVT MPDVT MPDVT

SNPɾMAF 13 δΣϊλΠϓ "" "B BB 5PUBM /

CASE-CONTROL STUDIES (1) (p. 568) 14 Ҩ఻ࢠϚʔΧʔ͸ײडੑҼࢠͱͯ҆͠ఆ͍ͯ͠ΔͨΊɼ DBTFDPOUSPMTUVEJFTʹద͍ͯ͠Δ 3FDBMMCJBT͸গͳ͍

CASE-CONTROL STUDIES (2) (p. 568) 15 ͭͷόϦΞϯτͱ࣬ױͱͷؔ࿈͚ͩͰ͸ͳ͘ɼ ଞͷόϦΞϯτ΍ཁҼͱڞʹ࣬ױͱͷؔ࿈Λ୳ࡧͰ͖Δ w

CASE-CONTROL STUDIES (3) (p. 568) 16 0VUDPNF : $PWBSJBUF &

COHORT STUDIES (p. 568) 17 ͋Γ;Εͨ࣬ױͱؔ࿈͢ΔҨ఻ࢠΛൃݟ͢ΔͨΊʹ໾ཱͭ w ॎஅతͳඇৗʹେن໛ͳूஂ w όΠΦόϯΫͷཱ֬

CROSS-SECTIONAL STUDIES (p. 569) 18 ௐࠪ࣌఺ʹ͓͚Δ࣬ױͷ༗ප཰΍ͦͷ࣬ױʹؔ࿈͢ΔҨ఻ࢠΛ୳ࡧͰ͖Δ

METHODOLOGIC ISSUES CONFOUNDING (p. 570) 19 ڵຯͷ͋ΔόϦΞϯτ ࣬ױ 3BDFFUIOJDJUZ ʢਓछຽ଒ੑʣ

GENOTYPE AND EXPOSURE MISCLASSIFICATION (1) (p. 570) 20 /POEJ⒎FSFOUJBMNJTDMBTTJpDBUJPOʢඇࠩҟޡ෼ྨʣ͸ όΠΦϚʔΧʔʢ஋ʣͱΞ΢τΧϜͱͷؔ࿈Λرऍ͢Δ

GENOTYPE AND EXPOSURE MISCLASSIFICATION (2) (p. 570) 21 w ࿈࠯ෆฏߧঢ়ଶ͕ڧ͍όϦΞϯτ͸ɼ࣬ױͱͷؔ࿈͕ڧ͘ͳΔ

GENE-ENVIRONMENT INTERACTION (1) (p. 570) 22 (FOFUJDGBDUPS ( EJTFBTF &OWJSPONFOUBMGBDUPS

GENE-ENVIRONMENT INTERACTION(2) (p. 570) 23 Exposure Geno- type Cases Controls

EMERGING ANALYTIC COMPLEXITY(1) (p. 571) 24 ِཅੑͷ੍ޚʢଟॏੑͷ໰୊ʣ w (8"4Ͱ͸ଟ͘ͷ4/7ʹ͍ͭͯݕఆΛ͓͜ͳ͏ˠଟॏੑͷ໰୊ w

EMERGING ANALYTIC COMPLEXITY(2) (p. 571) 25 /PWFMBOBMZUJDTUSBUFHJFT w ֊૚ܕճؼ෼ੳ w

NONCONVENTIONAL EPIDEMIOLOGIC STUDIES (p. 573) 26 w $BTFPOMZTUVEJFT w $BTFQBSFOUTUVEJFT

CASE-ONLY STUDIES (p. 573) 27 $BTFPOMZEFTJHOʹ͍ͭͯ͸ɼ%S,%ઌੜͷαΠτΛࢀߟʹͤͯ͞ ͍͖ͨͩ·ͨ͠ $BTF0OMZ%FTJHOʹ͍ͭͯʦҨ఻Ӹֶʧʛ(FOF&OWJSPONFOUBMOUFSBDUJPO ʢIUUQTXXXESLJEOFUDBTFPOMZHFOFQJʣ w

CASE-PARENT STUDIES (p. 575) 28 $BTF $POUSPM w ࣬ױΛൃ঱ͨ͠$BTFͷ਌Λ$POUSPMͱ͢ΔσβΠϯ w

EXAMPLE 1: COLORECTAL CANCER (p. 575) 29 ߴස౓ͷ೑ͷઁऔ େ௎͕Μ )FUFSPDZMJDBNJOFT

EXAMPLE 2: INFLAMMATORY BOWEL DISEASE (1) (p. 577) 30 w

ࢀߟจݙ ,FOOFUI+3PUINBO ༁ʢຊా߶ ྛ༤Ұ ࠤ౻ت࿨ʣϩεϚϯͷӸֶୈ൛ ࣰݪग़ ൛৽ࣾ 5PN4USBDIBOFUBM

Discussion!! 32