欠測のあるデータに対する解析手法の基礎 (4) Imputation ??測のあるデータに対する解析 ... 参照 群(Placebo群 ... :時点 で分割した実薬群(上),参照群(下)の分散 共

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  • 2015 estimand

    (4)placeboMultipleImputation

    TF4(JPMA )

    12015

    Contents

    Introduction EfficacyEffectiveness Estimand6

    pMI(placeboMultipleImputation)

    22015

    Estimand

    Efficacy Perprotocol dejure Estimand

    Effectiveness ITTdefacto Estimand

    NRC(2010 5

    Mallinckrodtetal.(2012), Mallinckrodt(2013) NRC+16

    Mallinckrodtetal.(2014) Mallinckrodtetal.(2012)3 pickupEstimand 136

    32015

    NRC(2010)Mallinckrodt(2013)6EstimandIII

    Estimand Rescue

    Medication

    1 Effectiveness

    2 Efficacy

    3 Efficacy

    4 Effectiveness

    5 Effectiveness

    6 Effectiveness

    42015

  • NRC(2010)Mallinckrodt(2013)6EstimandEstimand 6

    Effectiveness

    RescueMedication RescueMedication

    placeboMultipleImputation(pMI)

    52015

    Estimand 6

    RescueFollow Up

    RescueFollowUp

    RescueFollowUp

    FollowUp

    FollowUp

    Rescue

    Rescue Medication

    62015

    placeboMultipleImputation(pMI)

    MARMultipleImputation Efficacy

    MIMAR

    placeboMultipleImputation Effectiveness

    Placebo

    Effectiveness

    Efficacy

    1 2 3 4

    72015

    pMIMI

    Carpenteretal.(2013) JumptoReference(J2R) Lastmeancarriedforward(LMCF) Copyincrementsinreference(CIR) Copyreference(CR)

    DIAmissingdata.org.uk Averagelastmeancarriedforward(ALMCF) Ownlastmeancarriedforward(OLMCF)

    1 2 3 4

    82015

  • pMIAyele etal.,2014

    Effectiveness

    Effectiveness

    Efficacy Efficacy

    LOCFBOCFAyele etal.(2014)J2R

    MNAR

    92015

    Carpenteretal.,2013

    pMIJointModelingSchafer,1997

    1. MARUNMMRMMCMCPrior

    2. 1.3. 2.

    4. 13MM5.

    Rubin

    3.pMI

    102015

    2

    TypeI

    pMI

    pMIMIMAR

    112015

    122015

  • J2RJumptoReference

    132015

    CIR(CopyIncrementsinReference)

    142015

    CR(CopyReference)

    J2R CRJ2R

    152015

    MARMI

    ProcMIREG FullyConditionalSpecification (FCS)

    (vanBuuren etal.,2006) MCMC

    162015

  • ,2014

    1

    2

    3

    4

    20.0(4.0)

    18.0(5.0)

    15.0(5.0)

    12.0(6.0)

    9.0(6.0)

    20.0(4.0)

    18.0(5.0)

    16.0(5.0)

    14.0(6.0)

    12.0(6.0)

    1

    2

    3

    4

    1 0.3 0.3 0.2 0.1

    1 1 0.6 0.55 0.52 1 0.6 0.553 1 0.64 1

    SD

    2

    100/ 4

    4

    4

    172015

    MAR

    ,2014

    1 2 3 45% 10% 13% 15%

    1 2 3 4

    1

    2

    3

    4

    5

    5 11

    4 3

    7 7

    1 4

    83 75

    182015

    J2RDIA

    100

    1

    2

    1

    23

    1

    23

    4

    1

    23

    4

    2

    3

    4

    5

    3

    4

    5

    4

    5

    5

    1 2 3 4

    Placebo

    1

    2

    1

    23

    1

    2

    3

    4

    1

    23

    4

    2

    3

    4

    534

    5

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    5

    5

    1 2 3 4

    Active

    -15

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    -5

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    m b

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    e

    192015

    CRDIA

    100

    1

    2

    1

    23

    1

    23

    4

    1

    23

    4

    2

    3

    4

    5

    3

    4

    5

    4

    5

    5

    1 2 3 4

    Placebo

    1

    2

    1

    23

    1

    2

    3

    4

    1

    2

    3

    4

    2

    3

    4

    534

    5

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    1 2 3 4

    Active

    -15

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    202015

  • CIRDIA

    DIA 1

    DIAExampleplot1 CIR1

    1 2 3 4

    1

    2

    3

    4

    5

    DIACIR

    212015

    MARMCMCDIA

    100

    1

    2

    1

    23

    1

    23

    4

    1

    23

    4

    2

    3

    4

    5

    3

    4

    5

    4

    5

    5

    1 2 3 4

    Placebo

    1

    2

    1

    2

    3

    1

    2

    3

    4

    1

    23

    4

    2

    3

    4

    534

    5

    4

    5

    5

    1 2 3 4

    Active

    -15

    -10

    -5

    0

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    e

    222015

    MARREG

    100

    1

    2

    1

    23

    1

    23

    4

    1

    2

    3

    4

    2

    3

    4

    5

    3

    4

    5

    4

    5

    5

    1 2 3 4

    Placebo

    1

    2

    1

    23

    1

    2

    3

    4

    1

    2

    3

    4

    2

    3

    4

    534

    5

    4

    5

    5

    1 2 3 4

    Active

    -15

    -10

    -5

    0

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    232015

    SequentialModelingAyele etal.,2014

    Bayesian SASProcMIREGpMIJ2R ActiveBayesian

    100

    1

    2

    1

    23

    1

    2

    3

    4

    1

    2

    3

    4

    2

    3

    4

    5

    3

    4

    5

    4

    5

    5

    1 2 3 4

    Placebo

    1

    2

    1

    23

    1

    2

    3

    4

    1

    2

    3

    4

    2

    3

    4

    534

    5

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    -15

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    24

  • :

    pMIJ2RCRMARMI J2RCR

    () SE

    95%CIt p

    LCL UCL

    J2R 2.82 1.06 4.89 0.75 2.67 0.0077

    CR 2.84 1.05 4.90 0.78 2.71 0.0068

    CIR DIA

    MARMCMC 3.37 1.05 5.43 1.32 3.22 0.0013

    MARREG 3.35 1.06 5.42 1.28 3.18 0.0015

    SequentialModeling

    J2R2.79 1.17 5.08 0.50 2.39 0.0172

    4

    252015

    placeboMultipleImputationpMI Estimand 6Effectiveness

    JumptoReference(J2R) CopyIncrementsinReference(CIR) CopyReference(CR)

    Effectiveness Efficacy

    MNAR1

    Sequential ModelingAyele etal.,2014 Bayesian pMI

    pMIMARMI J2RCR

    262015

    Ayele,B.T.,Lipkovich,I.,Molenberghs,G.&Mallinckrodt,C.H.(2014).Amultipleimputationbasedapproachtosensitivityanalysisandeffectivenessassesments inlongitudinalclinicaltrials.JournalofBiopharmaceuticalStatistics.24,211228.

    Carpenter,J.R., Roger,J.H.& Kenward,M.G.(2013).Analysisoflongitudinaltrialswithprotocoldeviation:Aframeworkforrelevant,accessibleassumption,andinferenceviamultipleimputation.JournalofBiopharmaceuticalStatistics.23,13521371.

    Mallinckrodt,C.H.(2013).PreventingandTreatingMissingDatainLongitudinalClinicalTrials.CambridgePress.

    Mallinckrodt,C.H.,ChuangStein,C.,Molenberghs,G.,OKelly,M.,Ratitch,B.,Janssens,M.,&Bunouf,P.(2014).Recentdevelopmentinthepreventionandtreatmentofmissingdata,TherapeuticInnovation&regulatoryScience. 48,6880.

    Mallinckrodt,C.H.,Lin,Q.,Lipkovich,I.,andMolenberghs,G.(2012).Astructuredapproachtochoosingestimands andestimatorsinlongitudinalclinicaltrials,PharmaceuticalStatistics,11,456461.

    NationalResearchCouncil.(2010).ThePreventionandTreatmentofMissingDatainClinicalTrials.TheNationalAcademiesPress.

    VanBuuren,S.,Brand,J.P.L.,GroothuisOudshoorn,C.G.M.&Rubin,D.B.(2006).Fullyconditionalspecificationinmultipleimputation.JournalofStatisticalComputationandSimulation.76,10491064.

    272015

    Schafer,J.L.(1997).Analysisofincompletemultivariatedata.NewYork:ChapmanandHall.

    .(2014). .SAS.

    .(2015). estimand (7)2

    282015

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