COMPARATIVE DIAGNOSTIC TEST ACCURACY OF MRI VERSUS CT SCAN IN ASSESSMENT OF ADULT PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): A Structured Systematic Review Protocol
Background: The quantitative computed tomography (CT) is currently the standard diagnostic imaging modality for evaluating clinical stages and exacerbation risk in patients with chronic obstructive pulmonary disease (COPD). Magnetic resonance imaging (MRI) techniques are now being adopted as alternative imaging modalities to the routine quantitative CT.
Aim and objectives: This review will identify and synthesize high-quality clinical evidence on the diagnostic efficacy of MRI versus the routine quantitative CT in the assessment of pulmonary functional loss and clinical staging in adult patients with COPD.
Methods/design: Electronic searches will be performed in four evidence-based medicine databases: MEDLINE (Ovid), PubMed, EMBASE and CENTRAL using appropriate keywords, text words and MeSH terms for the target population (COPD patients), index test (MRI), comparator test (quantitative CT), reference standard (spirometric pulmonary function tests or quantitative CT) and outcome (lung/respiratory function diagnosis). Only comparative quantitative studies will be included. Grey literature/unpublished studies will not be searched. The methodological quality will be evaluated using the dedicated Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2) tool. MRI diagnostic test outcome of will be compared with CT-based functional lung volumes and correlated with percentage predicted forced expiratory volume in 1 second (%FEV1).
Conclusion: This review will for the first time provide clinical evidence to support or refute the evidence suggesting MRI as the efficacious imaging modality for clinical staging and risk assessment of exacerbations in COPD patients.
Chronic obstructive pulmonary disease (COPD) and asthma are the most prevalent chronic respiratory diseases with overlapping clinical presentations (Ambrosino & Paggiaro, 2012; Yawn, 2009). Both asthma and smoking-related COPD are clinically characterised by difficulties in breathing, shortness in breath, episodic coughing and wheezing. However, unlike asthma air flow obstruction in COPD is usually not fully reversible following inhaled bronchodilators (Gjevre et al. 2006). By this account, asthma and COPD have different recommended treatment and management guidelines (Miravitlles et al., 2012; Yawn, 2009) therefore, differential diagnosis of COPD and asthma is important to ensure proper guideline-recommended management strategies (Yawn, 2009). For instance, guideline-recommended management strategies for COPD require proper COPD staging based on the pulmonary functional loss assessment. Computed tomography (CT) is currently the standard imaging modality for evaluating pulmonary functional loss of patients with COPD because it is regarded as having adequate technical capabilities of showing detailed anatomical features and morphological changes of lungs that can be quantitatively correlated with lung function status (Guan, et al. 2014; Ohno et al. 2012). Following advances in diagnostic radiologic imaging technology, there is growing evidence that magnetic resonance imaging (MRI) has better imaging capabilities for evaluating COPD patients than the conventional CT, claiming that it can reveal regional morphologic changes and the degree of perfusion and ventilation in lungs of COPD patients (Fan et al. 2013; Xia et al. 2014). However, individual clinical evidence supporting this claim appears superficial, therefore warranting a systematic synthesis of such evidences.
The smoking-related COPD is evaluated based on whole-lung pulmonary function tests coupled with radiologic imaging. The degree of pulmonary functional loss and severity of COPD can be clinically classified based on the degree of circulation (perfusion) and breathing (ventilation) in lungs (Ohno et al. 2008). Classification and staging of COPD has for the long time largely based on spirometry criteria specified by the guidelines recommended by the American Thoracic Society–European Respiratory Society (ATS/ERS), the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the UK National Institute for Health and Clinical Excellence (NICE) (Gruffydd-Jones & Loveridge, 2011; Hansen, Sun & Wasserman, 2007; Hur et al. 2007). The 2004 GOLD and ATS/ERS spirometry guidelines defined airway obstruction as below 0.7 (<70%) ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) (Hansen et al. 2007). However, this spirometric criterion has inadequate sensitivity and generally lacks statistical justifications because it tends to underestimate and overestimate airway obstruction in younger and older adults, respectively (Gruffydd-Jones & Loveridge, 2011; Hansen, et al., 2007). Even after this spirometry definition was partially updated in NICE COPD guidelines specifying post-bronchodilator FEV1/FVC% (Gruffydd-Jones & Loveridge, 2011), it still correlate poorly with histological abnormalities of the lungs, patient symptoms and outcomes in COPD (Sin, Leipsic & Man, 2011).
Chest X-ray, chest CT, and pulmonary ventilation/perfusion (VQ) studies are the key radiologic modalities for assessing the morphologic and local pulmonary functional changes in smoking-related COPD (Ohno et al. 2008). Chest CT scan possesses adequate technical capabilities of revealing detailed anatomic features and morphologic changes of lungs that can be quantitatively correlated with lung function status in COPD staging (Guan, et al. 2014; Ohno et al. 2012). While CT has remained the standard radiologic modality for routine clinical evaluation of smoking-related COPD, MRI is increasingly being used for COPD evaluation. The parameters of oxygen-enhanced and hyperpolarized noble gas (3He) MRI have been demonstrated to correlate positively with the spirometric FEV1 measurement and the diffusing capacity of the lung for carbon monoxide (DLCO) (Hur et al. 2007; Kirby et al. 2014). The oxygen-enhanced MRI can also quantify gas diffusion rate between alveoli and capillaries and therefore, provide spirometrically-congruent information on the degree of airway obstruction and lung function (Hur et al. 2007). On the other hand, hyperpolarized 3He MR imaging can help identify COPD patients at increased risk of exacerbations based on the ventilation defect percentage (VDP) (Kirby et al. 2014).
The level of high quality evidence base supporting diagnostic superiority claim of oxygen-enhanced and hyperpolarized 3He MRI over the routine quantitative CT is yet to be established. Two recent comparative clinical studies have made invaluable attempt to compare the diagnostic capabilities of the oxygen-enhanced MRI (Ohno et al. 2012) and hyperpolarized 3He MRI (van Beek et al. 2009) versus quantitative CT for functional loss assessment and clinical staging in smoking-related COPD. The two studies have demonstrated that MRI is equally accurate as the routine quantitative CT in evaluation of COPD patients (Ohno et al. 2012; van Beek et al. 2009). However, evidences from individual studies are in most cases not sufficient to inform clinical decision making in healthcare management and policy development (Lavis et al. 2005). This limitation is usually due to varied methodological quality (with respect to internal and external validity) of clinical studies evaluating a given clinical question (Bornhoft et al. 2006). The methodological quality of a diagnostic test accuracy study depends on whether; an appropriate spectrum of patients (similar to that a clinician would encounter in actual clinical practice) was enrolled, a reference (or gold) standard of a given diagnostic test was clearly defined, the reference standard was applied regardless of diagnostic outcome of the index test, the diagnostic tests were truly validated through independent group of patients (blind comparison) (BMJ Clinical Evidence, 2014; Bossuyt et al. 2003). Evidence form diagnostic test accuracy studies that do not fulfil one or more of these four criteria should be closely scrutinized to ascertain the validly of the results in the real clinical practice (BMJ Clinical Evidence, 2014).
To ascertain the current state of evidence-base radiologic practice for clinical evaluation of COPD, it was important to conduct a preliminary literature search to check whether there are existing Evidence Based Medicine Reviews (EBMR) on comparative studies assessing the diagnostic accuracy of CT versus MRI in evaluating COPD patients. The preliminary electronic searches were performed in six electronic bibliographic databases: National Library of Medicine and National Institutes of Health (Medline), Excerpta Medica dataBASE (EMBASE), Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effectiveness (DARE), and Google Scholar. The searches yielded no published systematic review on the proposed review question. Therefore, a structured systematic review is warranted to identify and summarise high-quality evidence on the comparative diagnostic accuracy of MRI versus quantitative CT in evaluating adult patients with COPD. The proposed systematic review is likely to delineate the comparative diagnostic value of MRI versus quantitative CT in clinical staging of COPD, which would be useful in fine-tuning evidence-based clinical practice and informing clinical policy development.
Research questions and aims
The specific aim of the present structured diagnostic test accuracy review is to systematically identify high-quality clinical evidence on the diagnostic superiority of MRI versus the routine quantitative CT in the assessment of pulmonary functional loss and clinical staging in adult patients with COPD. However, given the different technical capabilities of MRI and CT for COPD evaluation the following are the specific objective of the present systematic review study:
1) To evaluate the correlation of diagnostic findings of oxygen-enhanced or hyperpolarized 3He MRI and quantitative CT with pulmonary function tests (FEV1/FVC%).
2) To determine the effect MRI technique choice (oxygen-enhanced or hyperpolarized 3He MRI) on the diagnostic accuracy of MRI in COPD staging.
3) To determine the most appropriate radiological modality with greatest patient access and throughput to inform evidence-based practice and policy development.
Perspective and Methodology
The primary goals of any systematic reviews of diagnostic test accuracy studies are to summarize the accuracy of diagnostic tests and whether the diagnostic tests of interest have sufficient sensitivity and specificity (with respect to an existing routine diagnostic test or a reference standard) to warrant their use in clinical practice. Importantly, systematic reviews of diagnostic test accuracy studies should also investigate possible sources of variations in diagnostic test outcomes and whether such variations reflects clinical situations that would be encountered in real clinical practice (Leeflang, 2014).
Conducting systematic reviews of diagnostic test accuracy studies can be methodologically challenging with regards to the choice of qualitative or quantitative approach to review of the comparative diagnostic test evidence (Leeflang et al. 2008). Most diagnostic test accuracy reviews with clear statistical diagnostic test outcome measures have both qualitative and quantitative aspects that can be evaluated together. Qualitative aspects can be evaluated by qualitative synthesis (meta-synthesis) while standardized statistical diagnostic test accuracy numerical data can be summarised by quantitative synthesis (meta-analysis). However, a meta-analysis is only possible when quantitative pooling or presentation of statistical diagnostic test outcome is possible in homogeneously presented diagnostic test outcome. For instance, a meta-analysis is only possible when diagnostic test outcome are presented as sensitivity and specificity with 95% confidence interval (Leeflang et al. 2008; Leeflang, 2014). While the present diagnostic test accuracy review is anticipated to review quantitative diagnostic test accuracy studies, only qualitative synthesis of evidence is possible. In this case, the quantitative approach will not be sought because quantitative pooling or presentation of diagnostic test outcome measures in the anticipated diagnostic test accuracy studies is not possible owing to heterogeneity of statistical diagnostic outcome.
Ideally, the diagnostic accuracy of a clinical diagnostic test is the ability of the test to differentiate patients with a given disease condition from healthy individuals. However, the accuracy of any given diagnostic test varies between sub-groups of patients owing to disease progression variability, patient population group (paediatrics, younger adults and geriatrics), clinical setting variation, and experience variability among radiographers and reviewers of diagnostic tests (Leeflang et al. 2008; Leeflang, 2014). Index tests under evaluation must be evaluated against a reference standard (definitive) diagnostic test using the same patient population sample that must be representative of the wider population of patients with the target disease condition (Leeflang et al. 2008). Assessing the quality of diagnostic test accuracy evidence should focus on possible sources of variation in the target patient population of interest, procedural risk of biases and applicability concerns. By this account, systematic reviews of diagnostic tests accuracy studies are ideally qualitative rather than quantitative.
The most important methodological aspects in all systematic reviews of diagnostic tests accuracy are the risk of bias and applicability concerns that must be systematically appraised using QUADAS-2 quality appraisal checklist. This tool contains methodological quality domains tailored specifically for diagnostic test accuracy studies. The QUADAS-2 tool has four separable quality appraisal domains (patient selection, index tests, reference standard and diagnostic flow/timing), which are appraised separately for the risk of bias and applicability concerns. Based on the QUADAS-2 tool, the methodological domains in the present systematic review of diagnostic tests accuracy can be separated as follows: selection process of COPD patient population, index test (oxygen-enhanced MRI and hyperpolarized 3He MRI), comparator test (quantitative CT), reference standard (pulmonary function tests and CT-based functional lung volume) and outcome (lung/respiratory function diagnosis). Diagnostic test accuracy studies have cross-sectional design default where the tests of interests (index test and its comparator) are evaluated against a known well-validated diagnostic test as the reference standard (Leeflang et al. 2008). With respect to patient selection, the QUADAS-2 tool will be useful in assessing whether the selection process of COPD patients was biased. Based on this quality domain, a consecutive or random sample of patients enrolment approach will be considered of low risk of selection bias. By this account, prospective cohort and case-control studies are most likely to be identified and justified because of the consecutive nature of patient enrolment of patients with COPD. In addition, by design, cohort studies are anticipated to enrol only patients with the COPD to receive both index test (MRI) and comparator/reference standard test (quantitative CT, CT-based functional lung volume and pulmonary function tests) for clinical staging of COPD. On the other hand, diagnostic case–control studies (with two-gate design), are anticipated to enrol participants with COPD (as cases) and those without COPD (controls). By this account, in prospective cohort studies, COPD patients are categorised according to (severity of symptoms) thus, according to clinical stages of COPD. In contrast, case-control studies classify participants based on absolute diagnosis of COPD. While case–control designs are useful in delineating absolute diagnostic accuracy of a given clinical test, accuracy estimates from case-control design are generally not representative the diagnostic test accuracy in real clinical practice (Leeflang, 2014). However, the present diagnostic test accuracy review will include case-control studies but will be considered as having high risk of applicability concern.
Index test results must be interpreted without the knowledge of the reference standard results to avoid verification bias (Leeflang, 2008; Leeflang, 2014). On the other hand, CT-based functional lung volume and pulmonary function tests will be considered as the comparator and reference standard tests, respectively. However, CT-based functional lung volume can correctly classify patients in routine clinical practice and therefore, it can be considered as both reference standard and comparator tests. In the present systematic review of diagnostic test accuracy, the risk of verification and review biases will be evaluated based on the QUADAS-2 tool.
Methods: Literature Search Strategy
To ensure high quality radiologic evidence, the present systematic review study will search relevant diagnostic test accuracy studies in evidence-based medicine (EBM) resource databases, particularly: MEDLINE (Ovid), PubMed, The Cochrane Library, Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL). These databases host the trusted EBM resources. Search strategies for identifying diagnostic test accuracy studies are moving away from two-strand search strategy to multi-strand search strategy. The multi-strand approach tries to capture the complexly presented study components: target population, index tests, comparator tests, reference standard and outcome (Mann & Gilbody, 2012). Thus, as recommended by Mann & Gilbody (2012), a multi-strand electronic search strategy will be developed by separately combining keywords, textwords and MeSH terms related to patient population with target condition (adult COPD patients), index test (MRI), comparator test (quantitative CT), reference standard (Pulmonary function tests and CT-based functional lung volume) and outcome (lung/respiratory function diagnosis). Thus, the proposed search framework will be PICRO rather than the default PICO (Population, Intervention, Comparator and Outcome) search framework). While the default PICO search framework is frequently used for searching interventional studies that evaluate the efficacy of new clinical interventions against routine interventions (comparator), this search framework is not always sufficient for searching diagnostic test accuracy studies, with both comparator and reference standard tests (Mann & Gilbody, 2012). In this case, PICO is only sufficient for searching diagnostic test accuracy studies, where the comparator test also serves as the reference standard. By this account, the present diagnostic tests accuracy systematic review will adopt the novel PICRO search framework as described originally by Misso (2012) because, the comparator test (quantitative chest CT) and reference standard tests (pulmonary function tests or CT-based functional lung volume) are completely different and independent.
The proposed keywords for the electronic searches include: “adult patients with COPD”, “adults with smoking-related COPD”, “magnetic resonance imaging”, “MR imaging”, “computed tomography”, “pulmonary function tests”, “CT-based functional lung volume”, “Lung function diagnosis”, “respiratory function diagnosis”, “sensitivity” and “specificity.” Appropriate Medical Subject Headings (MeSH) terms will be identified based on two relevant primary diagnostic accuracy studies indexed in PubMed database. A multi-strand electronic search will be performed by combining keywords/text words and MeSH terms using Boolean operators (AND, OR, NOT) based on PICRO search framework. To locate recent evidence, the electronic searches will be limited to studies published in the last seven years (from January 2008 to December, 2014). Importantly, the present review will be limited to studies published in English language. This is because acquiring professional translation service for scientific manuscripts is a complex process (Meneghini & Packer, 2007), which is costly and may result in significant delays. Furthermore, most translated scientific manuscripts are likely to be of poor quality due to mistranslations and loss of tacit meaning. This systematic review will not be conducting a comprehensive search of grey literature resources, because only published articles will be considered for review. While not including unpublished articles will result in undesirable publication bias (McAuley et al. 2000; Hopewell et al. 2007), unpublished manuscripts are in most cases not peer-reviewed (Conn et al. 2003). Thus including evidence from grey literature is not suitable for systematic reviews intended to inform clinical management and policy development. To locate other potentially eligible peer-reviewed studies not indexed in the searched EBM databases, the electronic searches will be supplemented with manual bibliographic hand searches of relevant reviews, editorials, and the included studies. A preliminary PubMed PICRO search strategy is shown in table 1 below.
Table 1: PubMed PICRO search strategy (from 1st January 2008 to 31st December, 2014)
Definition Keywords and MeSH Terms for PubMed search Hits
Population /condition (P) Adults with COPD (≥18 yrs) (((“pulmonary disease, chronic obstructive/diagnosis”[MeSH Terms]) OR “pulmonary disease, chronic obstructive/etiology”[MeSH Terms]) OR “smoking/adverse effects”[MeSH Terms] AND ((((“adult”[MeSH Terms]) OR aged[MeSH Terms]) AND males[MeSH Terms]) OR females[MeSH Terms]) AND humans[MeSH Terms]) Filters: Publication date from 2008/01/01 to 2014/12/31
Index test (I) MR imaging technique (“magnetic resonance imaging/methods”[MeSH Terms]) OR “oxygen/diagnostic use”[MeSH Terms]) Filters: Publication date from 2008/01/01 to 2014/12/31
Comparator test (C) Quantitative CT scan OR CT-based functional lung volume ((“tomography, x ray computed/methods”[MeSH Terms]) OR (“tomography, x ray computed/statistics and numerical data”[MeSH Terms])) Filters: Publication date from 2008/01/01 to 2014/12/31
Reference Standard (R) Pulmonary function tests (((“pulmonary function tests”[Text Word]) OR “pulmonary function tests forced expiratory volume”[Text Word]) OR “diffusing capacity for carbon monoxide”[Text Word]) Filters: Publication date from 2008/01/01 to 2014/12/31
Outcomes (O) Lung/respiratory function diagnosis
(((((((((((“respiratory function tests”[MeSH Terms]) OR “risk assessment/classification”[MeSH Terms]) OR “risk assessment”[MeSH Terms]) OR (“risk assessment/statistics and numerical data”[MeSH Terms])) OR “risk factors”[MeSH Terms]) OR “risk management/classification”[MeSH Terms]) OR (“sensitivity and specificity”[MeSH Terms])) OR “reproducibility of results”[MeSH Terms])))) Filters: Publication date from 2008/01/01 to 2014/12/31
P and I and C and R and O Combined search /narrowed down to comparative studies published in English within the last 7 years from 1st January 2008 to 31st December, 2014) 5
The final search hits from the searched databases will be imported into EndNote (Version X7.1 for Windows, Thomson Reuters) citation manager and screened based on titles, author names, and abstracts to remove duplicates. Full-text articles of potentially relevant citation will be retrieved and further screened for methodological consistency to ensure only comparative studies are included. This systematic review study will consider all comparative diagnostic test accuracy studies assessing the efficacy of oxygen-enhanced MRI and hyperpolarized 3He MRI compared to the routine quantitative CT in evaluating adult COPD patients. Pulmonary function tests, particularly %FEV1 and the “percentage predicted diffusing capacity of the lung for carbon monoxide per unit of alveolar volume (%DLCO/VA)” are spirometric measures widely recognized as gold standard for evaluating clinical stage and exacerbation risk in COPD patients (Ip et al. 2007; Ohno et al. 2008). However, CT-based functional lung volume has remained standard diagnostic approach to COPD evaluation and therefore, will be suitable both as a comparator test and a reference standard test (Ohno et al. 2008). Thus, only studies basing on %DLCO/VA or CT-based functional lung volume as the reference standard will be included in the review. The proposed inclusion and exclusion criteria are presented in table 2 below.
Table 2: inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
Comparative studies evaluating the diagnostic accuracy of oxygen- enhanced MRI or hyperpolarized 3He MRI versus CT Non-comparative studies evaluating only technical capabilities of MRI or CT in COPD evaluation, such as reviews, editorials and letters.
Studies evaluating adult patients (≥18 yrs) with COPD Studies evaluating children ( Studies evaluating only COPD patients Studies evaluating mixed population of patients with COPD, asthma and other unclassified chronic respiratory diseases
Studies using quantitative CT as the comparator or reference standard test or %DLCO/VA as the reference standard. Studies using other reference standards other than quantitative CT and %DLCO/VA
Studies that report diagnostic accuracy outcome as sensitivity and specificity relative reference standard. Studies not reporting relative sensitivity and specificity
Studies published in English language Studies published in languages other than English
Methods: Quality Assessment
The consistency of methodological quality of studies included in any systematic review of healthcare interventions determines the final quality and reliability of clinical evidence summarized. Most diagnostic test accuracy reviews often yield heterogeneous results owing to different study designs and methodological quality of the included studies. Therefore, it is essential to assess the methodological quality consistency of the included studies as a yardstick of applicability and generalizability of the summarized evidence (Whiting et al. 2011). Therefore, the present systematic review will evaluate the methodological quality of the included diagnostic test accuracy studies using the updated version of Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2) tool (appendix 1) developed recently (Whiting et al. 2011; NICE, 2012a). This tool is now considered as the standard methodological quality assessment tool for diagnostic test accuracy studies, because it contains14 items assessing the risk of bias and applicability concerns in four separable methodological domains (patient selection process, index tests, reference standard and flow/timing). Importantly, this stool is quantitative in nature and therefore, useful for evaluating the quantitative aspects/outcomes of the diagnostic test accuracy studies (Whiting et al. 2011; Maheux-Lacroix et al. 2013).
Based on QUADAS-2 quality appraisal tool, studies will be considered as having low risk of patient selection bias if prospective COPD patients are recruited randomly or consecutively to receive the interventions. By this account only prospective cohort and case-control studies will be considered as of low risk of patient-selection bias. An interval of no more than four weeks between the index test (oxygen enhanced MRI or hyperpolarized 3He MRI) and comparator or reference standard (spirometric pulmonary function tests or quantitative CT) will be considered appropriate diagnostic flow and timing. Studies must interpret index tests without the knowledge of reference standard results. In this case, lack of blinding of interpreters to index and reference standard results, will be considered as high risk of bias. To be considered as truly quantitative, the selected studies must present diagnostic test results expressed as the degree of correlation between MRI or quantitative CT in COPD diagnosis with the pulmonary function tests (%DLCO/VA or CT-based functional lung volume).
The overall risk or bias and applicability concerns will be used as a yardstick of the effect of methodological quality of the included studies on the summarized clinical evidence. Studies not fulfilling more than two methodological domains will be considered as having high risk of bias and of poor quality. Such studies will be excluded because they are likely to skew the final results in a biased manner.
Data Extraction Tool
Inconsistent reporting of outcome data is one of the most probable reporting issues in clinical research yet it can significantly affect the quality and validity of summarized clinical evidences presented in systematic reviews of healthcare/clinical interventions (Kirkham et al. 2013; Smith et al. 2014). Therefore, data collection from primary studies included in any given systematic review must be standardized to avoid selective or biased reporting. In this case, a standardized core outcome set (COS) to be extracted from all studies must be prespecified and a standardized data extraction tool developed (Kirkham et al. 2013). The present diagnostic test accuracy review will employ one data extraction tool. The tool is the standard evidence table for diagnostic test accuracy studies developed by the UK’s NICE (NICE, 2012b), adapted with slight modifications (Appendix 2). The following qualitative information will be extracted from each of the included studies to aid in qualitative synthesis: Study characteristics, particularly: study design (type), study quality, sample size, prevalence, patient demographic characteristics, type(s) of index tests, comparator test or reference standard, calculated sensitivity/specificity values, and sources of funding. Information on the technical specifications of the MRI index test (oxygen enhanced or hyperpolarized 3He) chosen and the quantitative CT as comparator test or reference standard will be collected. Collection of these qualitative data will be useful in assessing methodological consistency of the included studies based on QUADAS-2 tool.
While the a 2 X 2 contingency table frequently used for collecting data on sensitivity and specificity of diagnostic test accuracy reviews (Maheux-Lacroix et al. 2013; Rahman et al. 2013; Hutting et al. 2013), this data collection tool will be irrelevant in the present review study, because the anticipated diagnostic test accuracy studies will only classify patients with the COPD. The diagnostic accuracy will be measured as the correlation of the index test results with pulmonary function tests (%DLCO/VA or CT-based functional lung volume).
Timetable (100 words)
Following the approval of the proposed diagnostic accuracy review protocol by GCU university reviewers, a structured schedule for conducting the actual systematic review will be developed with special consideration of other university programs offered during the same university calendar. This review is estimated to take at least three months after approval of this protocol. This time-frame is somewhat short considering other academic programs that will be going on during the same review period. However, this can be achieved by adhering to the following Gaant chart starting from May 11th 2015 to august 21st 2015.
Table 3: The proposed Gaant chart for review process
Review activities Wk1 Wk2 Wk3 Wk4 Wk4 Wk7 Wk8 Wk9 Wk10 Wk11 Wk12
Electronic literature searches
Screening based on inclusion/exclusion criteria
Methodological quality screening
Data extraction (qualitative)
Data extraction (quantitative)
*Wk1= Week one …
Budget and likely funding sources
Significant costs in many literature reviews occur due to purchasing of relevant articles and acquiring translation services. The present diagnostic test accuracy review will not incur such costs because only articles published in English language will be accessed free via the GCU library. Licensure of all statistical software needed in the review will be requested via the GCU university library at student price and this may be funded by the university library. Other costs related to printing and binding of the review drafts and final review report will be settled by the GCU library. Costs associated with personal travels during the study period will be negligible and will be incurred as normal personal expenditure.
Dissemination of results
Dissemination of findings of literature reviews in healthcare innervations is important to ensure they contribute to evidence-based clinical practice, clinical management and policy development. If approved by GCU university reviewers, the present diagnostic test accuracy review study will be disseminated to the GCU student fraternity via free access portal at GCU library both in electronic and print versions. After university review and grading, the manuscript will be rewritten and formatted according to the Cochrane systematic review of clinical interventions with the intention of submitting to the Cochrane library for peer-review. Importantly, this will be disseminated to the public via reputable medical magazine as a free informative article
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Appendix 1: the QUADAS-2 tool for studies of diagnostic test accuracy
QUADAS-2 is structured so that four key domains are each rated in terms of the risk of bias and the concern regarding applicability to the review question (as stated in Phase 1). Each key domain has a set of signalling questions to help reach the judgements regarding bias and applicability.
Domain 1: Patient selection
A. Risk of bias
Describe methods of patient selection:
Was a consecutive or random sample of patients enrolled? Yes / No / Unclear
Was a case-control design avoided? Yes / No / Unclear
Did the study avoid inappropriate exclusions? Yes / No / Unclear
Could the selection of patients have introduced bias?
Risk: Low / High / Unclear
B. Concerns regarding applicability
Describe included patients (prior testing, presentation, intended use of index test and setting):
Is there concern that the included patients do not match the review question?
Concern: Low / High / Unclear
Domain 2: Index test(s)
A. Risk of bias
Describe the index test and how it was conducted and interpreted:
Were the index test results interpreted without knowledge of the results of the reference standard? Yes / No / Unclear
If a threshold was used, was it pre-specified? Yes / No / Unclear
Could the conduct or interpretation of the index test have introduced bias?
Risk: Low / High / Unclear
B. Concerns regarding applicability
Is there concern that the index test, its conduct, or interpretation differ from the review question?
Concern: Low / High / Unclear
Domain 3: Reference standard
A. Risk of bias
Describe the reference standard and how it was conducted and interpreted:
Is the reference standard likely to correctly classify the target condition? Yes / No / Unclear
Were the reference standard results interpreted without knowledge of the results of the index test? Yes / No / Unclear
Could the reference standard, its conduct, or its interpretation have introduced bias?
Risk: Low / High / Unclear
B. Concerns regarding applicability
Is there concern that the target condition as defined by the reference standard does not match the review question?
Concern: Low / High / Unclear
Domain 4: Flow and timing
A. Risk of bias
Describe any patients who did not receive the index test(s) and/or reference standard or who were excluded from the 2×2 table (refer to flow diagram):
Describe the time interval and any interventions between index test(s) and reference standard:
Was there an appropriate interval between index test(s) and reference standard? Yes / No / Unclear
Did all patients receive a reference standard? Yes / No / Unclear
Did patients receive the same reference standard? Yes / No / Unclear
Were all patients included in the analysis? Yes / No / Unclear
Could the patient flow have introduced bias?
Risk: Low / High / Unclear
Appendix 2: An evidence table for studies of diagnostic test accuracy
Bibliographic reference Study type Study quality Number of patients Prevalence Patient characteristics Type of test Reference standard Correlation between index test results and pulmonary function tests Source of funding
         
 Bibliographic reference: author(s), year, article title, journal, volume, pages.
 Study type: for example, cross-sectional, cohort or case–control studies.
 Study quality: note particular strengths and weaknesses.
 Number of patients: total number of patients included in the study, with inclusion and exclusion criteria.
 Prevalence: proportion of people with the disease in the population at risk.
 Patient characteristics: characteristics relevant to the area of interest: age, sex, ethnic origin, comorbidity, disease status, community- or hospital-based.
 Type of test: description of the diagnostic test used in the study. Specify the test threshold where applicable.
 Reference standard: used as a measure of outcome. Specify if it is a ‘gold standard’ or ‘current best practice’.
 Correlation between index test results and pulmonary function tests
 Source of funding: government funding (for example, NHS), voluntary/charity (for example, Wellcome Trust), pharmaceutical company; and the role of funding organisations.
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