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Abstract
Background: Missing outcome data from randomized trials lead to greater uncertainty and possible bias in estimating the effect of an experimental treatment. An intention-to-treat analysis should take account of all randomized participants even if they have missing observations.
Purpose: To review and develop imputation methods for missing outcome data in meta-analysis of clinical trials with binary outcomes.
Methods: We review some common strategies, such as simple imputation of positive or negative outcomes, and develop a general approach involving `informative missingness odds ratios' (IMORs). We describe several choices for weighting studies in the meta-analysis, and illustrate methods using a meta-analysis of trials of haloperidol for schizophrenia.
Results: IMORs describe the relationship between the unknown risk among missing participants and the known risk among observed participants. They are allowed to differ between treatment groups and across trials. Application of IMORs and other methods to the haloperidol trials reveals the overall conclusion to be robust to different assumptions about the missing data.
Limitations: The methods are based on summary data from each trial (number of observed positive outcomes, number of observed negative outcomes and number of missing outcomes) for each intervention group. This limits the options for analysis, and greater flexibility would be available with individual participant data.
Conclusions: We propose that available reasons for missingness be used to determine appropriate IMORs. We also recommend a strategy for undertaking sensitivity analyses, in which the IMORs are varied over plausible ranges. Clinical Trials 2008; 5: 225—239. http://ctj.sagepub.com
|
Jüni P. , Altman DG , Egger M. Assessing the quality of controlled clinical trials .
BMJ 2001; 323:
42-46. Google Scholar | Crossref | Medline | |
|
Hollis S. , Campbell F. What is meant by intention to treat analysis? Survey of published
randomised controlled trials . BMJ 1999; 319:
670-74. Google Scholar | Crossref | Medline | |
|
Little Rja , Rubin DB Statistical Analysis with Missing Data. Hoboken, New
Jersey , Wiley,
2002. Google Scholar | Crossref | |
|
Wood AM , White IR , Thompson SG Are missing outcome data adequately handled? A review of published
randomized controlled trials in major medical journals .
Clin Trials 2004; 1:
368-76. Google Scholar | SAGE Journals | |
|
Whitehead A. , Whitehead J. A general parametric approach to the meta-analysis of randomised
clinical trials . Stat Med 1991 ; 10:
1665-77. Google Scholar | Crossref | Medline | ISI | |
|
Henderson R. , Diggle P. , Dobson A. Joint modeling longitudinal measures and event time
data . Biostatistics 2000; 4:
465-80. Google Scholar | Crossref | |
|
Kenward MG , Goetghebeur EJ , Molenberghs G. Sensitivity analysis for incomplete categorical data .
Statistical Modelling 2001; 1:
31-48. Google Scholar | SAGE Journals | ISI | |
|
Rubin DB Formalizing subjective notions about the effect of nonrespondents in
sample surveys . J Am Statist Assoc 1977 ; 72:
538-43. Google Scholar | Crossref | ISI | |
|
Forster JJ , Smith PWF. Model-based inference for categorical survey data subject to
non-ignorable nonresponse . J R Statist Soc B 1998; 60:
57-70. Google Scholar | Crossref | |
|
Thompson SG , Higgins JPT. How should meta-regression analyses be undertaken and
interpreted? Stat Med 2002; 21:
1559-74. Google Scholar | Crossref | Medline | ISI | |
|
Higgins JPT , Thompson SG Controlling the risk of spurious findings from
meta-regression . Stat Med 2004 ; 23:
1663-82. Google Scholar | Crossref | Medline | ISI | |
|
Rubin DB Multiple Imputation for Non Response in Surveys. New
York, NY, Wiley,
1987. Google Scholar | Crossref | |
|
Miller ME , Morgan TM , Espeland MA , Emerson SS Group comparisons involving missing data in clinical trials: a
comparison of estimates and power (size) for some simple
approaches . Stat Med 2001; 20:
2383-97. Google Scholar | Crossref | Medline | ISI | |
|
Gould AL A new approach to the analysis of clinical drug trials with
withdrawals . Biometrics 1980; 36:
721-27. Google Scholar | Crossref | Medline | ISI | |
|
Tashkin DP , Kanner R. , Bailey W. , et al. Smoking cessation in patients with chronic
obstructive pulmonary disease: a double-blind, placebo-controlled, randomised
trial . Lancet 2001; 357:
1571-75. Google Scholar | Crossref | Medline | ISI | |
|
Hajek P. , Stead LF Aversive smoking for smoking cessation .
Cochrane Database Syst Rev 2001; 3: CD000546 . Google Scholar | |
|
Gamble C. , Hollis S. Uncertainty method improved on best-worst case analysis in a binary
meta-analysis . J Clin Epidemiol 2005; 58:
579-88. Google Scholar | Crossref | Medline | ISI | |
|
Magder LS Simple approaches to assess the possible impact of missing outcome
information on estimates of risk ratios, odds ratios, and risk
differences . Controlled Clin Trials 2003; 24:
411-21. Google Scholar | Crossref | Medline | |
|
Rotnitzky A. , Robins JM , Scharfstein DO Semiparametric regression for repeated outcomes with nonignorable
nonresponse . J Am Statist Assoc 1998; 93:
1321-39. Google Scholar | Crossref | ISI | |
|
Little RJA. Pattern-mixture models for multivariate incomplete
data . J Am Statist Assoc 1993; 88:
125-34. Google Scholar | ISI | |
|
Nordheim EV Inference from nonrandomly missing categorical data: An example from a
genetic study on Turner's syndrome . J Am Statist
Assoc 1984; 79:
772-80. Google Scholar | Crossref | ISI | |
|
Kadane JB Subjective Bayesian analysis for surveys with missing
data . Statistician 1993; 42:
415-26. Google Scholar | Crossref | |
|
Scharfstein DO , Daniels MJ , Robins JM Incorporating prior beliefs about selection bias into the analysis of
randomized trials with missing outcomes .
Biostatistics 2003; 4:
495-512. Google Scholar | Crossref | Medline | ISI | |
|
White IR , Higgins JPT , Wood AM Allowing for uncertainty due to missing data in meta-analysis, Part 1:
Two-stage methods . Stat Med 2008; 27:
711-727. Google Scholar | Crossref | Medline | ISI | |
|
Joy CB , Adams CE , Lawrie SM Haloperidol versus placebo for schizophrenia .
Cochrane Database Syst Rev 2006; 4: CD003082 . Google Scholar | |
|
Vichaiya V. Clinical trial of haloperidol in schizophrenia .
Journal of the Psychiatric Association of Thailand 1971; 16:
31-42. Google Scholar | |
|
Bechelli LP , Ruffino-Netto A. , Hetem G. A double-blind controlled trial of pipotiazine, haloperidol and
placebo in recently-hospitalized acute schizophrenic patients .
Braz J Med Biol Res 1983; 16:
305-11. Google Scholar | Medline | ISI | |
|
Durost H. , Lee H. , Arthurs D. An early evaluation of haloperidol. In: Lehmann HE , Ban TA. (eds). The Butyrophenones in Psychiatry Quebec Psychopharmacological
Research Association , 1964, pp.
70-71. Google Scholar | |
|
DerSimonian R. , Laird N. Meta-analysis in clinical trials . Controlled
Clin Trials 1986; 7:
177-88. Google Scholar | Crossref | Medline | |
|
Arvanitis LA , Miller BG Multiple fixed doses of `Seroquel` (quetiapine) in patients with acute
exacerbation of schizophrenia: a comparison with haloperidol and placebo. The
Seroquel Trial 13 Study Group . Biol Psychiatry 1997; 42:
233-46. Google Scholar | Crossref | Medline | ISI | |
|
Beasley C-MJ , Tollefson G. , Tran P. , et al. Olanzapine versus placebo and haloperidol: acute
phase results of the North American double-blind olanzapine trial
. Neuropsychopharmacology 1996; 14:
111-23. Google Scholar | Crossref | Medline | ISI | |
|
Borison RL , Pathiraja AP , Diamond BI , Meibach RC Risperidone: clinical safety and efficacy in
schizophrenia . Psychopharmacol Bull 1992; 28:
213-18. Google Scholar | Medline | |
|
Chouinard G. , Jones B. , Remington G. , et al. A Canadian multicenter placebo-controlled study of
fixed doses of risperidone and haloperidol in the treatment of chronic
schizophrenic patients . J Clin Psychopharmacol 1993; 13:
25-40. Google Scholar | Crossref | Medline | ISI | |
|
Garry JW , Leonard TJ Haloperidol: a controlled trial in chronic
schizophrenia . Br J Psychiatry 1962; 108:
105-07. Google Scholar | Crossref | |
|
Howard JS Haloperidol for chronically hospitalized psychotics: a double-blind
comparison with thiothixine and placebo; a follow-up open
evaluation . Dis Nerv Syst 1974; 35:
458-63. Google Scholar | Medline | |
|
Marder SR , Meibach RC Risperidone in the treatment of schizophrenia .
Am J Psychiatry 1994; 151:
825-35. Google Scholar | Crossref | Medline | ISI | |
|
Nishikawa T. , Tsuda A. , Tanaka M. , et al. Prophylactic effect of neuroleptics in symptom-free
schizophrenics . Psychopharmacology 1982; 77:
301-04. Google Scholar | Crossref | Medline | ISI | |
|
Nishikawa T. , Tsuda A. , Tanaka M. , et al. Prophylactic effect of neuroleptics in symptom-free
schizophrenics: a comparative dose-response study of haloperidol and
propericiazine . Psychopharmacology 1984 ; 82:
153-56. Google Scholar | Crossref | Medline | ISI | |
|
Reschke RW Parenteral haloperidol for rapid control of severe, disruptive
symptoms of acute schizophrenia . Dis Nerv Syst 1974 ; 35:
112-15. Google Scholar | Medline | |
|
Selman FB , McClure RF , Helwig H. Loxapine succinate: a double-blind comparison with haloperidol and
placebo in acute schizophrenics . Curr Ther Res Clin
Exp 1976; 19:
645-52. Google Scholar | Medline | ISI | |
|
Serafetinides EA , Collins S. , Clark ML Haloperidol, clopenthixol, and chlorpromazine in chronic
schizophrenia. Chemically unrelated antipsychotics as therapeutic
alternatives . J Nerv Ment Dis 1972; 154:
31-42. Google Scholar | Crossref | Medline | ISI | |
|
Simpson GM , Angus JW , Edwards JG A controlled study of haloperidol in chronic
schizophrenia . Curr Ther Res Clin Exp 1967; 9:
407-12. Google Scholar | Medline | ISI | |
|
Spencer EK , Kafantaris V. , Padron-Gayol MV , et al. Haloperidol in schizophrenic children: early findings
from a study in progress . Psychopharmacol Bull 1992 ; 28:
183-86. Google Scholar | Medline | |
|
Hollis S. A graphical sensitivity analysis for clinical trials with
non-ignorable missing binary outcome . Stat Med 2002; 21:
3823-34. Google Scholar | Crossref | Medline | ISI | |
|
Higgins JPT , Thompson SG , Deeks JJ , Altman DG Measuring inconsistency in meta-analysis .
BMJ 2003; 327:
557-60. Google Scholar | Crossref | Medline |
