PROSPERO International prospective register of systematic reviews
Sex difference in long-term outcomes of stroke in the INternational STroke oUtComes sTudy (INSTRUCT): a meta-analysis of individual patient data
Hoang Phan, Leigh Blizzard, Dominique Cadilhac, Amanda Thrift, Mathew Reeves, Jonathan Sturm, Seana Gall
Hoang Phan, Leigh Blizzard, Dominique Cadilhac, Amanda Thrift, Mathew Reeves, Jonathan Sturm, Seana Gall. Sex difference in long-term outcomes of stroke in the INternational STroke oUtComes sTudy (INSTRUCT): a meta-analysis of individual patient data.
Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016036723
Are there sex differences in long-term mortality and functional outcomes and health-related quality of life of stroke worldwide?
How much potential confounders will contribute to the sex differences seen in long term?
We will systematically search for population-based studies with long-term outcomes of stroke (at least 1 year of follow-up) from academic databases (PubMed, SCOPUS, EMBASE, Science Direct) from 2008 to 2015. Restriction: human studies only; article published in the English language only.
We also searched for studies with long-term outcomes of stroke in 56 population-based studies which previously identified by Feigin et al (1) and by Gall et al (2).
The search strategy was as follows:
(((("stroke"[Title] OR "isch(a)emic stroke"[Title] OR "intracerebral"[Title] OR "intraparenchymal"[Title] OR "subarachnoid"[Title] OR "h(a)emorrhage"[Title])) AND ("mortality"[Title] OR "morbidity"[Title] OR "fatality"[Title] OR "case fatality"[Title] OR "survival"[Title] OR "trends"[Title] OR "outcome(s)"[Title] OR "functional outcome(s)"[Title] OR "disability"[Title] OR "disabled"[Title] OR "functional status"[Title] OR "functional outcome"[Title] OR "functional limitation"[Title] OR "activities of daily living"[Title] OR "ADL"[Title] OR "basic activities of daily living"[Title] OR "BADL"[Title] OR "personal activities of daily living"[Title] OR "PADL"[Title] OR "instrumental activities of daily living"[Title] OR "IADL"[Title] OR "extended activities of daily living"[Title] OR "EADL"[Title] OR "health-related quality of life"[Title] OR "quality of life"[Title] OR "HRQoL"[Title] OR "QoL"[Title] OR "wellbeing"[Title] OR "life satisfaction"[Title] OR "health status"[Title])) AND ("population-based" OR "community-based" OR "community" OR "epidemiology" OR "epidemiological" OR "incidence" OR "attack rates" OR "survey" OR "surveillance" OR "ideal study")) AND (("long-term" OR "long term" OR "month(s)" OR "-month" OR "year(s)" OR "-year") AND ("2008/05/01"[PDat] : "2015/05/01"[PDat]) AND English[lang])
1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009 Apr;8(4):355-69.
2. Gall SL, Pham Lan T, Martin K, Blizzard L, Srikanth V. Sex Differences in Long-Term Outcomes After Stroke Functional Outcomes, Handicap, and Quality of Life. Stroke. 2012 Jul;43(7):1982-1987.
Types of study to be included
Population-based incidence stroke studies
Condition or domain being studied
Long-term outcomes of stroke including mortality, functional outcome and health-related quality of life will be studied
Subjects for this study were participants in ‘ideal’ stroke incidence studies conducted around the world. These studies gather all cases of first-ever-in-a-life-time stroke that occur within a defined population over a period of at least 12 months. This includes cases inside and outside of the hospital system. Therefore, all people irrespective of their age or sex that suffered a stroke within a given population will be included. The studies include both ischaemic and haemorrhagic and undetermined type of stroke.
Exclusions: Non-human studies, population with restrictions (e.g. elderly population).
These studies will be included must meet criteria of the ‘gold standard’ for assessing stroke incidence. (3)
- They have standardised methods to ensure high quality data, including: standard definitions for first-ever-in-a-lifetime stroke; a prospective design, population-based case ascertainment from multiple overlapping sources from inside and outside hospital systems; subtyping of a large proportion of events using imaging; a large and preferably stable population base; and surveillance over at least one year to control for seasonal variation in stroke occurrence.
- The follow-up for the studies to be included was completed at least 1 year
3. Sudlow C, Warlow C. Comparing Stroke Incidence Worldwide: What Makes Studies Comparable? Stroke. 1996;27:550-558
Mortality, functional outcome and health-related quality of life
For mortality outcome: The death data were collected from follow-up data and verification from death certificate in included studies.
For functional outcome: (level of disability or dependence) outcome measures among stroke survivors were assessed from follow-up data with any instrument such as modifies Rankin Scale, Barthel Index.
For health-related quality of life: quality of life scores among stroke survivors were assesed from follow-up data with any instrument such as EQ5D, SF36, AQoL.
Data extraction, (selection and coding)
Two independent reviewers, Hoang Phan and Seana Gall, will review the literature and systematically search for appropriate studies using the inclusion ans exclusion criteria.
Then we will invite chief investigators of each study to provide the individual patient data of socio-demographics, stroke-related factors, pre-stroke health and long-term outcomes of stroke.
Risk of bias (quality) assessment
Heterogeneity will be evaluated using chi-squared test-based Q-statistics and I-squared statistics with Mantel-Haenszel approach.
Publication bias will be assessed with Egger’s test and funnel plot using Begg’s test, with significant bias defined as P-value lower than 0.1.
Strategy for data synthesis
We will use a two-stage analysis method (4) where we will first estimate study-specific mortality, functional outcomes and health-related quality of life within each study and then combine using meta-analysis then estimate the pooled crude and adjusted sex differences in long-term outcomes of stroke.
Poisson modelling will estimate the mortality rate ratio (MRR) for women compared to men at long-term after stroke. Log binomial regression will estimate the relative risk (RR) of poor functional outcome for women compared to men after stroke. Linear regression estimated the mean difference of utility scores of health-related quality of life for women compared to men. Multivariable models will be adjusted for potential confounders such as age, pre-stroke dependency, stroke severity and comorbidities.
We intend to use STATA 12.1 to analyses the results of pooled data using random-effect meta-analysis for each outcome.
4. Stukel TA, Demidenko E, Dykes J, Karagas MR. Two-stage methods for the analysis of pooled data. Stat Med. 2001 Jul 30;20(14):2115-30.
Analysis of subgroups or subsets
Further analyses such as subgroup analysis or sensitivity analyses will also be performed as appropriate.
Sensitivity analyses will be used to examine whether study- or participant-level characteristics influenced the sex differences in long-term outcomes of stroke. Study level characteristics includes: geographic regions, mean age difference between women and men, severity instruments, linkage to National Death Registries, availability of person-years data, type of stroke, sample size, country income group, adequate of follow-up and type of functional outcome measurement. At the level of the participant, we will test an interaction between stroke type and sex on the outcomes using multilevel random-effects meta-analysis. Given the considerable variation in when the studies were conducted (1950 to 2015), we will examine whether year of stroke influenced the associations. We tested the interaction between sex and year of stroke on long-term outcomes of stroke.
Subgroup analyses among hospitalised patients will be carried out to see whether there were sex differences in treatment and management, and if any differences influenced the sex differences in outcome.
The burden of stroke in women is set to grow in coming years. This will place an enormous burden on health systems and communities. By determining those factors that explain sex differences our study will inform both interventions and future research to address these disparities. As the only pooled analysis of population-based studies designed to measure long-term outcomes our study will represent an important advance for the field. It will also help identify important limitations in stroke incidence studies so that new prospective studies can be designed to specifically address sex differences in outcomes. This proposal represents a significant collaboration between investigators for these studies and will establish a resource that could be used to address other important questions about long-term outcome after stroke. By using existing datasets, we will provide novel and important information on the causes of sex differences in long-term stroke outcomes for far less cost and in a much shorter time-frame than if a prospective study were to be established.
Contact details for further information
17 Liverpool Street. Hobart TAS 7000. Australia
Organisational affiliation of the review
Menzies Institute for Medical Research
Dr Hoang Phan, Menzies Institute for Medical Research Professor Leigh Blizzard, Menzies Institute for Medical Research Professor Dominique Cadilhac, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Vic., Australia Professor Amanda Thrift, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton Professor Mathew Reeves, Department of Epidemiology, Michigan State University, East Lansing, Michigan, USA Dr Jonathan Sturm, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Vic., Australia Dr Seana Gall, Menzies Institute for Medical Research
Emma Heeley, The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia Vemmos Konstantinos, Department of Medicine, Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece Craig Anderson, The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia Priya Parmar, National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies, Auckland, NZ Yannick Bejot, University of Burgundy, University Hospital of Dijon, Dijon, France Yannick Bejot, University of Burgundy, University Hospital of Dijon, Dijon, France Norberto Cabral, Clinica Neurológica de Joinville, Joinville Stroke Registry, University of Joinville Region-Univille, Joinville, Brazil Antonio Carolei, Department of Biotechnological and Applied Clinical Sciences, Neurological Institute, University of L'Aquila, Italy Simona Sacco, Department of Biotechnological and Applied Clinical Sciences, Neurological Institute, University of L'Aquila, Italy, Nicolas Chausson, Stroke Unit, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France Stephane Olindo, Department of Neurology, University Hospital of Martinique, Fort de France, Martinique French West Indies Peter Rothwell, Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom Carolina Silva, UNIFAI, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal Manuel Correia, UNIFAI, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal Rui Magalhães, UNIFAI, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal Peter Appelros, Department of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden Janika Korv, Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia Riina Vibo, Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia Cesar Minelli, Departamento de Neurologia, Psicologia e Psiquiatria, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil Petr Otahal, Menzies Institue for Medical Research
Anticipated or actual start date
01 May 2015
Anticipated completion date
01 June 2016
There is no cost for the review
Conflicts of interest
Subject index terms status
Subject indexing assigned by CRD
Subject index terms
Humans; Research Design; Sex Characteristics; Stroke
Stage of review
Date of registration in PROSPERO
21 March 2016
Date of publication of this revision
03 October 2016
Stage of review at time of this submission
Piloting of the study selection process
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
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