10. 研究疑問の定式化の事例
P : 12~18歳の慢性疲労症候群の患者を対象に,
I : インターネット⽀援型認知⾏動療法を受けた人は,
C : 通常の理学療法⼠による介⼊を受けた人と比べて,
O : 過去12日間における授業の完全出席率が高いか
T : 治療開始6か月時点
10
Nijhof SL et al: Lancet. 2012 Apr 14;379(9824):1412-8.
12. バイアス(真実からの乖離) へのリスク
15
バイアスの種類判断基準
選択バイアス乱数生成
割り付けの隠蔽化
実⾏バイアス患者と治療者の盲検化
検出バイアス評価者の盲検化
欠測バイアスアウトカム測定の完全性
報告バイアス事前設定したアウトカム報告
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook)
13. 選択バイアスによる過大評価,乱数生成
の不備11%,割り付けの隠蔽化の不備7%
vs. 不不 (112試試) 0.89 (0.82,0.96)
0.93 (0.87,0.99)
0.8 0.9 1.0 1.1 1.2
Ratio of Odds Ratio
乱乱乱乱: 不不不/不不 (832試試)
隠隠隠: 不不不/不不 (916試試)
vs. 不不 (376試試)
Savović J et al: Ann Intern Med. 2012 Sep 18;157(6):429-38. 16
14. バイアスへのリスクの評価法
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook) 17
15. 乱数生成の評価基準例
‘High risk’ of bias
介⼊の利⽤可能性により割り付け(allocated by availability of the
intervention)
患者の好みにより割り付け(allocation by preference of the participants)
‘Low risk’ of bias
コンピュータによる乱数生成(using a computer random number generator)
最小化法の使⽤(using minimization methods)
‘Unclear risk’ of bias
無作為に割り付け
(patients were randomly allocated)
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook) 18
16. 割り付けの隠蔽化の評価基準例
19
‘High risk’ of bias
封印されていない封筒の利⽤(assignment envelopes were used without
appropriate safeguards)
公開された割り付け予定乱数の利⽤(using an open random allocation
schedule)
‘Low risk’ of bias
中央登録⽅式の利⽤(using a method of central allocation)
不透明の封印された連続番号の封筒の利⽤(using a method of
sequentially numbered, opaque, sealed envelopes)
‘Unclear risk’ of bias
無作為に割り付け
(patients were randomly allocated)
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook)
17. 治療者と患者の盲検化の評価基準例
20
‘High risk’ of bias
治療者と患者の盲検化を試みたが,失敗している可能性がある(blinding
of key study participants and personnel attempted, but likely that the
blinding could have been broken)
‘Low risk’ of bias
治療者と患者の盲検化は確実である(blinding of participants and key
study personnel ensured)
‘Unclear risk’ of bias
判断するための十分な記載がない
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook)
18. 評価者の盲検化の評価基準例
‘High risk’ of bias
評価者の盲検化を⾏っておらず,盲検化の有無が測定結果に影響する可能
性がある(no blinding of outcome assessment, and the outcome
measurement is likely to be influenced by lack of blinding)
‘Low risk’ of bias
評価者の盲検化を確かに⾏っている(blinding of outcome assessment
ensured, and unlikely that the blinding could have been broken)
‘Unclear risk’ of bias
判断するための十分な記載がない
21
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook)
19. アウトカム測定の完全性の評価基準例
22
‘High risk’ of bias
欠測の理由が,真のアウトカムの値と関連する(reason for missing
outcome data likely to be related to true outcome)
不適切な単一代⼊法を利⽤する(potentially inappropriate application of
simple imputation)
‘Low risk’ of bias
アウトカム測定に欠測がない(no missing outcome data)
‘Unclear risk’ of bias
判断するための十分な記載がない
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook)
20. 事前設定したアウトカム報告の評価基準例
‘High risk’ of bias
一つ以上の主要評価項目が事前に設定されていない(one or more
reported primary outcomes were not pre-specified)
‘Low risk’ of bias
研究計画書が⼊⼿可能であり,すべての評価項目は事前設定と一致してい
る(the study protocol is available and all of the pre-specified (primary and
secondary) have been reported in the pre-specified way)
‘Unclear risk’ of bias
判断するための十分な記載がない
23
Chapter 8: Assessing risk of bias in included studies (http://www.cochrane.org/handbook)
50. ⼿始め,標題
系統的展望/メタ・アナリシス/両⽅
54
Liberati A et al: PLoS Med. 2009 Jul 21;6(7):e1000100
Fjorback LO et al: Acta Psychiatr Scand. 2011 Aug;124(2):102-19
Strauss C et al: PLoS One. 2014 Apr 24;9(4):e96110
Goyal M et al: JAMA Intern Med. 2014 Mar;174(3):357-68
51. ⼿始め,要旨,背景
A previous Cochrane review (James 2005) showed that cognitive
behavioural therapy (CBT) was effective in treating childhood anxiety
disorders; however, questions remain regarding (1) the relative efficacy of
CBT versus non-CBT active treatments; (2) the relative efficacy of CBT
versus medication and the combination of CBT and medication versus
placebo; and (3) the long-term effects of CBT.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 55
52. ⼿始め,要旨,目的
To examine (1) whether CBT is an effective treatment for childhood and
adolescent anxiety disorders in comparison with (a) wait-list controls; (b)
active non-CBT treatments (i.e. psychological placebo, bibliotherapy and
treatment as usual (TAU)); and (c) medication and the combination of
medication and CBT versus placebo; and (2) the long-term effects of CBT.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 56
53. ⼿始め,要旨,データ源と適格基準
データ源
Searches for this review included the Cochrane Central Register of
Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and
Neurosis Group Register, which consists of relevant randomised controlled
trials from the bibliographic databases-The Cochrane Library (1970 to
July 2012), EMBASE, (1970 to July 2012) MEDLINE (1970 to July 2012) and
PsycINFO (1970 to July 2012).
適格基準
All randomised controlled trials (RCTs) of CBT versus waiting list, active
control conditions, TAU or medication were reviewed. All participants must
have met the criteria of the Diagnostic and Statistical Manual (DSM) or the
International Classification of Diseases (ICD) for an anxiety diagnosis,
excluding simple phobia, obsessive-compulsive disorder, post-traumatic
stress disorder and elective mutism.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 57
54. ⼿始め,要旨,研究評価と統合⽅法
The methodological quality of included trials was assessed by three
reviewers independently. For the dichotomous outcome of remission of
anxiety diagnosis, the odds ratio (OR) with 95% confidence interval (CI)
based on the random-effects model, with pooling of data via the inverse
variance method of weighting, was used. Significance was set at P < 0.05.
Continuous data on each child's anxiety symptoms were pooled using the
standardised mean difference (SMD).
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 58
55. ⼿始め,要旨,結果
①ー(a) CBT vs Waiting list
Forty-one studies consisting of 1806 participants were included in the
analyses. The studies involved children and adolescents with anxiety of
mild to moderate severity in university and community clinics and school
settings. For the primary outcome of remission of any anxiety diagnosis for
CBT versus waiting list controls, intention-to-treat (ITT) analyses with 26
studies and 1350 participants showed an OR of 0.13 (95% CI 0.09 to 0.19, Z
= 10.26, P < 0.0001), but with evidence of moderate heterogeneity (P =
0.04, I² = 33%). The number needed to treat (NNT) was 6.0 (95% CI 7.5 to
4.6). No difference in outcome was noted between individual, group and
family/parental formats.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 59
56. ⼿始め,要旨,結果
①ー(b) CBT vs active non-CBT
ITT analyses revealed that CBT was no more effective than non-CBT active
control treatments (six studies, 426 participants) or TAU in
reducing anxiety diagnoses (two studies, 88 participants).
(2) long-term effect
The few controlled follow-up studies (n = 4) indicate that treatment gains
in the remission of anxiety diagnosis are not statistically significant.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 60
57. ⼿始め,要旨,結論
Cognitive behavioural therapy is an effective treatment for childhood and
adolescent anxiety disorders; however, the evidence suggesting that CBT is
more effective than active controls or TAU or medication at follow-up, is
limited and inconclusive.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 61
60. 研究疑問は理にかなっているか︖
65
疑問患者介入アウト
カム
① がん治療死亡
② 前⽴腺がん化学療法死亡
③ 去勢抵抗性前⽴腺がんドセタキセル死亡
④ 転移性去勢抵抗性
前⽴腺がん
ドセタキセル死亡
焦点化
「患者」「介⼊」「アウトカム」の定義が研
究間で広がりのある中,その介⼊の効果が等
しいと思えるか︖
61. 事例,研究疑問の評価
P...19歳未満の全般性不安障害/社交不安障害/パ
ニック障害(PTSD/強迫性障害は除外)
I...認知⾏動療法(集団療法や家族への介⼊も含む)
O...不安障害の寛解(ADIS-P/ADIS-C/
DISCAP/CGI-I)
疾病間に相違はないか︖
集団認知⾏動療法を含めて良いか︖
臨床全般印象改善度(CGI-I) を含めて良いか︖
66
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690
62. 包括的に文献検索しているか︖
基準
①文献データベースを複数利⽤
(例: MEDLINE/EMBASE/Cochrane Central Register of
Controlled Trials)
②追加検索を実施
(例: 臨床試験登録/引⽤文献/学会発表/専門家への聴取/
製薬会社や規制当局データベースの検索)
Murad MH et al: JAMA. 2014 Jul;312(2):171-9 67
63. 事例,包括的文献検索の評価
文献データベースを複数利⽤
We identified all studies that might describe RCTs of CBT for anxiety
disorders in children and adolescents from the Depression, Anxiety and
Neurosis Cochrane Review Group Trials Registers (CCDANCTR) (most
recent search, 01/05/2012). ...(中略)... Reports of trials for inclusion in the
Group’s registers are collated from routine (weekly), generic searches of
MEDLINE (1950-), EMBASE (1974-) and PsycINFO (1967-), from quarterly
searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
and from review-specific searches of additional databases.
追加検索を実施
The WHO Trials portal (ICTRP) and ClinicalTrials.gov were also searched to
identify additional unpublished and/or ongoing studies.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 68
65. 事例,再現性の評価
独⽴評価(研究選択)
All citations identified by searching were separately inspected by four
reviewers (ACJ, FAC, GJ and AS) to ensure reliability. All articles that
possibly met our inclusion criteria were obtained so that the full text could
be independently assessed as to whether they met review criteria. Authors
were not blinded to the names of authors, institutions, journals of
publication and results, when they applied the inclusion criteria. Any
disagreement on the eligibility of a study was discussed with the other
review authors, and, where necessary, the authors of the studies were
contacted for further information.
独⽴評価(バイアスへのリスクの評価)
For each included study, three review authors (ACJ, FAC and GJ)
independently assessed risk of bias... (後略)
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 70
66. 事例,再現性の評価
独⽴評価(データの抽出)
Data extraction forms were developed a priori and included information
regarding study methods, participant details, treatment details and
adherence to treatment protocol and outcome measures. Data were
extracted and assessed by FAC, GJ and ACJ independently. Consensus was
reached through discussion. In cases of disagreement, the other review
authors were consulted.
評定者一致の指標
記載なし
71
厳密な独⽴評価
評定者一致の指標はないが,合意形成で代替
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690
68. 事例,解釈可能性の評価
必要治療症例数(NNT) の利⽤
The review used ORs and 95% CIs based on the random-effects model,
with pooling of data via the inverse variance method of weighting.
Significance was set at P < 0.05. Where available, data from an interview
with the child or adolescent were used; otherwise data from interviews
with the parents were used. Where both endpoint and change data were
available for the same outcome, the endpoint was presented. The number
needed to treat (NNT) with 95% CIs was calculated (STATA 2009). For each
comparison, a summary statistic of all those responding to treatment was
calculated as a percentage of the total number of participants.
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 73
70. 事例,統合した結果の信頼性の評価
バイアスへのリスクの評価
For each included study, three review authors (ACJ, FAC and GJ)
independently assessed risk of bias using the seven domains set out below
from the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011), with ratings of ’low risk’, ’high risk’ and ’unclear risk’: (後略)
研究間の異質性の評価
The Chi2 test and the I2 statistic were used to assess statistical
heterogeneity for all analyses and between groups. Significance was set at
P < 0.1. The Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011) recommends using a range for I2 and a guide to
interpretation. For this review, if either moderate heterogeneity (I2 in the
range of 30% to 60%) or substantial heterogeneity (I2 in the range of 50%
to 90%) was found, subgroup and sensitivity analyses were used, with
meta-regression analyses (STATA 2009).
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 75
71. 研究間の異質性の評価法
76
評価法判断
コクランQ検定小さいp値→異質性
I2統計量0~40%→重要でない異質性
30~60%→中程度の異質性
50~90%→相当な異質性
75%~100%→重大な異質性
Higgins JPT, Green S: Cochrance handbook for systematic reviews of interventions. Wiley-Blackwell. 2008
77. 事例,バイアスへのリスクの評価
研究全体のバイアスへのリスクの評価
(⽅法) Those studies judged to be at high risk of bias for selection bias
were excluded from the main analysis.
(結果) A sensitivity analysis (not shown) for those studies reporting clear
processes of randomisation showed similar direction of results as the main
analysis with all studies included, with CBT being effective versus W/L
controls for the remission of anxiety diagnoses (OR 0.1, 95% CI 0.05 to
0.18, Z = 7.48, P < 0.00001).
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 83
78. 個々の研究結果は一貫しているか︖
基準
①フォレストプロットの確認
(例: 点推定値の「差」と信頼区間の「重なり」)
②研究間の異質性の評価結果
(例: コクランQ検定/I2統計量)
③異質性の説明要因の検討
(例: サブグループ分析/メタ回帰分析)
Murad MH et al: JAMA. 2014 Jul;312(2):171-9 84
79. 事例,フォレストプロットの確認
85
26研究(1350名) の
統合結果(CBT vs Waiting List)
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690
80. 事例,フォレストプロットの確認
個々の研究の
オッズ比と信頼区間
統合した
オッズ比と信頼区間
E is better C is better
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 86
81. 事例,研究間の異質性の評価結果
異質性の評価結果
The standard mean difference (SMD) was
0.98 with significant heterogeneity
E is better C is better
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 87
82. 事例,異質性の説明要因の検討
個人療法の結果
E is better C is better
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 88
83. 事例,異質性の説明要因の検討
集団療法の結果
E is better C is better
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 89
84. 事例,異質性の説明要因の検討
家族介⼊の結果
E is better C is better
James AC et al: Cochrane Database Syst Rev. 2013 Jun 3;6:CD004690 90
85. 信頼できるサブグループ分析
サブグループ間の効果の相違の⽅向性につい
て,最小限の仮説を事前に設定している
サブグループ間の効果が異なる(交互作⽤)
交互作⽤は,メタ・アナリシス*ではなく,
個々の研究から⽀持される
*個別患者データのメタ・アナリシスは例外
結果は,生物学的説明と整合性がある
交互作⽤に再現性がある(先⾏研究)
Sun X et al: JAMA. 2014 Jan 22-29;311(4):405-11. 91
86. 信頼区間は狭いか︖
92
基準
①上側と下側の信頼限界の解釈の同等性の評価
(同等であればエビデンスは正確と評価)
本質的に,主観的判断を伴う
Murad MH et al: JAMA. 2014 Jul;312(2):171-9
87. 事例,信頼区間の狭さの評価
The number needed to treat (NNT) using conservative ITT data is 6.0 (95%
CI 7.5 to 4.6), which means that for one additional participant to attain
remission from anxiety disorder using CBT, one needs to treat six
participants. In terms of medical and psychological treatments, this is an
acceptable finding (Laupacis 1988), allowing one to recommend CBT in
clinical practice.
5名(NNT=4.6) と8名(NNT = 7.5) は,実質的な
差がないと判断
93
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