Archives of Academic Emergency Medicine. 2022; 10(1): e82 REV I EW ART I C L E Point-of-Care Tests’ Role in Time Metrics of Urgent Inter- ventions in Emergency Department; a Systematic Review of Literature Sara Rahsepar1, Mohammad Sadegh Sanie Jahromi2, Samaneh Abiri2, Reza Akhavan3, Hossein Akhavan4, Bita Abbasi5, Fatemeh Maleki6, Somayyeh Ahmadnezhad7, Behrang Rezvani Kakhki3, Navid Kalani8∗, Pourya Adibi9 † 1. Department of Dermatology, Mashhad University of Medical sciences, Mashhad, Iran. 2. Research Center for Non-Communicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran. 3. Department of Emergency Medicine, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 4. Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 5. Department of Radiology, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 6. Department of Emergency Medicine, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran. 7. Department of Emergency Medicine, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran. 8. Research Center for Social Determinants of Health, Jahrom University of Medical Sciences, Jahrom, Iran. 9. Anesthesiology, Critical Care and Pain Management Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Received: July 2022; Accepted: August 2022; Published online: 10 October 2022 Abstract: Introduction: Point-of-Care Testing (POCT) could be helpful in clinical decisions, treatment selection, monitor- ing, prognostication, operational decision-making, and resource utilization. This study aimed to review the role of POCT in time metrics of performing urgent interventions in the emergency department (ED) or disposition time to proper care. Methods: This was a systematic review of the literature based on the PRISMA statement. PubMed, Scopus, Web of Science, and EMBASE databases were searched for studies reporting the application of the POCT in the ED with outcomes of the time to intervention or disposition. Results: After reviewing 3708 articles, 16 studies with 100,224 participants were included in this systematic review. There were 5 randomized clinical trials (RCTs), 5 retrospective cohorts, 2 prospective cohorts, and 4 before-after studies. All studies were performed in an ED setting except for one study of prehospital EMS air medical transport. Different panels, ultrasound, cardiac parameters, echocardiography, and polymerase chain reaction (PCR) POCTs were used in the studies. Regarding the outcome measures, studies with many types of patients referring to ED used different indices of time to intervention or time to disposition. Studies on different shock circumstances used the time to the first bolus of hydration or vasopressor or intravenous antibiotics for septic shock patients and central venous catheterization (CVC) placement time in one study. Time to imaging was considered as the outcome in some studies. Overall, there was a high risk of bias, especially in case of the randomization methods, and non-blinded designs in RCTs. There was lower possibility of bias in non-randomized studies but the studies did not have enough follow-ups and in case of studies using advanced panels of POCT, results do not seem to be easily ap- plicable to public health care in many countries. Conclusion: In synthesis of the evidence, all included studies were reporting the benefits of the POCT in decreasing the time to proper interventions and increasing the time to negative interventions in the last lines of critical care as well as the intubation and CVC placement. Keywords: Emergency medicine; point-of-care systems; point-of-care testing; emergency treatment Cite this article as: Rahsepar S, Sanie Jahromi MS, Abiri S, Akhavan R, Akhavan H, Abbasi B, et al. Point-of-Care Tests’ Role in Time Metrics of Urgent Interventions in Emergency Department; a Systematic Review of Literature. Arch Acad Emerg Med. 2022; 10(1): e82. https://doi.org/10.22037/aaem.v10i1.1817. ∗Corresponding Author: Navid Kalani; Research Center for Social Determi- nants of Health, Jahrom University of Medical Sciences, Jahrom, Iran. Email: This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Rahsepar et al. 2 1. Introduction Traditional public health systems are suffering from lim- ited, delayed, and inefficient medical services, especially when confronted with crowdedness, disasters, and the ag- ing population (1). In the face of ever-increasing public de- mand, emergency departments (EDs) face many challenges in maintaining consistent quality care (2, 3). Improved sur- vival of critically ill patients in the emergency department is directly related to advances in early identification and treat- ment (4). Frequent overcrowding and extended waiting times strain emergency departments’ capacity and compromise patient care. Until a few decades ago, the patient or his/her sample had to be sent to the laboratory, and it took hours or days for the results to reach the physician, and during this time, the patient’s care had to continue without the infor- mation needed by the physician (5). Bedside tests are sim- ple medical diagnostic tests that can be performed at the time and place of patient care. Their simplicity is due to the advancement in technology. In recent decades, more and more trials have been performed on Point-of-Care testing (POCT). POCT enables faster clinical decisions during diag- nosis, treatment selection and monitoring, prognostication and operational decision-making, and resource utilization (6, 7). POCT has been shown to decrease the time to throm- bolysis in stroke by as much as half an hour (8). Also, as its aim of creation was, POCT improves test turnaround times in emergency departments (9). Therefore, with regard to all of the above, the role of POCT can be considered to help cope with the stress of overcrowding of ED (10). While many re- view studies have been conducted on the efficacy of differ- ent commercially available POCTs in case of diagnostic ac- curacy of different medical conditions (11-13), and logically it should provide faster results and better test turnaround times, no previous study has evaluated its final effects on the time-critical patients of emergency department. Alter et al. evaluated the effect of applying POCT on the destination of the ED patients and drew a conclusion that these devices decreased the total length of hospital stay (14). But no in- hospital timing studies are provided in the literature. So, the aim of this study was to review the role of POCT in time met- rics for performing urgent interventions in the ED or dispo- sition time to proper care. navidkalani@ymail.com, ORCID: https://orcid.org/0000-0003-1900-4215. † Corresponding Author: Pourya Adibi; Anesthesiology, Critical Care and Pain Management Research Center, Hormozgan University of Medi- cal Sciences, Bandar Abbas, Iran. Email: adibip@hums.ac.ir , ORCID: https://orcid.org/0000-0003-2296-2166. 2. Methods 2.1. Study design and setting The present study is a systematic review that was carried out in accordance with the items mentioned in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (15). A PICO model was used to structure the study question. Pop- ulation of interest was patients referring to ED. Patients re- ferring to ED are classified based on various triage models to address the urgency of the medical condition in litera- ture. Siegfried et al. classified patients of ED into 3 groups; simple, complex, and critical (16). Simple group would re- ceive only simple care and point-of-care tests along with only oral medications. Complex patients would undergo labora- tory and imaging studies, receive intravenous medications, and remain under observation in ED or be admitted to a ward. Critical patients would be admitted to intensive care unit (ICU) from the ED and receive resuscitative care in ED, urgent cardiac interventions, gastrointestinal bleeding care, and other urgent surgeries or invasive diagnostic studies. In- tervention/Exposure of interest was POCT application in ED. Comparison was done with the main standard of care test. Outcome was considered as time to critical care intervention. Critical care intervention included admission to ICU, cardiac interventions, urgent gastrointestinal (GI) interventions, and urgent surgeries. 2.2. Search strategy A systematic electronic search in PubMed, Scopus, Web of Science and EMBASE databases using the keywords "emer- gency medicine", "point of care", " "Point of care testing", "POCT", "rapid testing", "bedside testing", "emergency care" and all selected POCTs was done. A detailed search strat- egy of “((emergency medicine) OR (EMS) OR (emergency care) OR (Emergency Department) OR (Emergency Room) OR (ED) OR (pre-hospital) ) AND ((Point of care testing) OR (POCT) OR (Bedside Testing) OR (lactate POCT) OR (rapid testing))” was conducted in PubMed. If there was a system- atic review about POCT in the emergency setting, that study was also included in our review and the years after the search conducted in the included study were searched. This was used when the review focused on a single POCT item. The main text of the articles was also evaluated for additional ref- erences. In case of need for further data, contact with study authors to identify additional data was planned, which was not performed/needed. All searches were conducted from inception to August 2022. 2.3. Eligibility criteria All observational or interventional clinical studies that were done in the emergency room and pre-hospital research envi- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e82 ronment were included in the study, when applying POCTs in the treatment process of time-critical diseases. Only studies on non-trauma patients were considered, as the classifica- tion of the severity of the trauma cannot be merged with clas- sifications of nontraumatic referrals of the ED due to the dif- ferent pathways of management. Applying the ABCD rule in traumatic patients, most time-critical interventions should be performed in seconds to minutes; in addition, the airway management and laboratory data are less diagnostic and are mostly used for disease severity evaluation. Studies were limited to adult populations to increase the ho- mogeneity between studies to be able to synthesize the re- sults. Studies conducted in various other departments in the hospital and at home or outside the hospital (except EMS) were not included in the study. Gray literature studies were not included as results that are not peer-reviewed might bias the final findings. Studies written in a language other than English were also excluded. Studies reporting accuracy and time to results of the test were not sought in this study as we were planning to evaluate the role of POCT in decreasing the test turnaround times. 2.4. Data collection After removing the duplicates, the remaining studies were in- dependently reviewed by two reviewers for eligibility to be included in the study. Any disagreement regarding study se- lection was resolved by consensus. The process of extract- ing data from included studies was done independently by two reviewers using the previously specified Excel form. The data extracted from each study included the name of the first author, the country, the number of subjects under investiga- tion, the disease of the population under investigation, and the type of POCT test and the final result. 2.5. Quality assessment The quality check was done using the appropriate checklist from The Scottish Intercollegiate Guidelines Network (SIGN) Methodology checklist and Risk of Bias 2 (RoB 2) tool check- list for RCTs (17). Two independent reviewers evaluated the studies based on the checklists and in case of non-agreement a third reviewer judged. 3. Results After reviewing 3708 article titles and removing 1035 items due to duplication, 2673 article titles were examined. After removing 1007 unrelated titles, among the remaining 666 ar- ticles that were reviewed in terms of abstracts, 487 cases were removed due to irrelevance. The full texts of the 179 remain- ing articles were reviewed. Studies that met the inclusion criteria of this study were selected. Finally, 16 studies were included in this systematic review (18-33). Figure 1 shows how the studies were selected. The baseline characteristics of these studies are shown in table 1. There were 5 RCT studies (18, 21, 25, 28, 29), 5 retrospective cohorts (22, 23, 30, 32, 33), 2 prospective cohorts (24, 31), and 4 before-after studies (19, 20, 26, 27). A total number of 100,224 participants were evaluated in these studies. All studies were conducted in the ED setting, except for one study of prehospital EMS air medical trans- port. Five studies used panels of POCT and 3 had eval- uated POCT Ultrasound for diagnosis of pericardiocentesis and hemodynamic instability. Three studies evaluated lac- tate as the POCT for diagnosis of sepsis and critically ill cir- cumstances. Cardiac parameters were used in 4 studies (20, 21, 26, 29). Renal function was assessed as POCT in 4 stud- ies (25, 27, 28, 31) and POCT echocardiography was used in one study (23). We only found one study about the POCT In- fluenza PCR that had reported the outcome of time to inter- vention (24). Regarding the outcome measures, studies with many types of patients referring to ED had used different indices of time to intervention or time to disposition. Studies on different shock circumstances had used time to first bolus of hydration or vasopressor or IV antibiotics for septic shock patients and central venous catheterization (CVC) placement time. Time to imaging was considered as the outcome in some stud- ies on the POCT echocardiography. Although there were no comparisons to non-POCT, since it is not possible in the set- ting of the resuscitation, we included the study and outcome was the occurrence of intracardiac thrombus during cardiac arrest, which can be considered as the time of the end of re- suscitation. In synthesis of the evidence, all included studies were re- porting the benefits of the POCT on decreasing the time to proper interventions ad increasing the time to negative inter- ventions in the last lines of critical care as well as intubation and CVC placement. Overall, Time to intervention was not homogenously re- ported in the literature but all POCT utilizations were asso- ciated with more rapid decision-making. The possibility of adverse events or complications due to the unnecessary interventions in cases of false positive or nega- tive results of the POCT remains the major problem in draw- ing the final conclusion in the review. This raises the question whether samples should be sent for laboratory testing at the same time as performing the POCT or after a positive POCT. 3.1. Quality assessment Risk of Bias 2 (RoB 2) tool checklist was used for 5 RCT stud- ies (table 2). None of these RCTs were blinded. There was an overall high risk of bias, especially in case of the random- ization methods, and non-blinded designs. The effects of This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Rahsepar et al. 4 the false negative POCT care were not accurately addressed in the evaluated literature, increasing the possibility of non- investigated potential harms. SIGN checklist was used for other cohorts and before-after studies (table 3). Most stud- ies’ quality was compromised by some points. Diagnosis of most diseases is/was made based on clinical findings, imag- ing, and laboratory findings. In studies with mixed types of patients, study results might have been affected by the diag- nosis based on other clinical findings, rather than the labora- tory finding alone (bias of having an outcome in enrolment). Only Singer et al. b, Lau et al. (PREDICT Study), Perlitz et al., Deledda et al., and Hoch et al. had homogenous patients regarding the type of the disease. 4. Discussion Many systematic review studies have focused on the advan- tages and disadvantages of using POCT in the emergency room. The belief that drives POCT is to make the test con- venient and fast for the patient. These devices make it more likely that the patient, physician, and care team will receive results more quickly, thus allowing "clinical management" decisions to be made immediately. This assumption was as- sessed in our study. Various POCTs have been marketed: glu- cometers, blood gas and electrolyte analyzers, etc. POCTs are cheaper, faster, and smarter and, by making POCT more af- fordable, the tendency to use them for many diseases has in- creased (6, 7). The accuracy of established diagnoses based on POCT was not taken into account in our investigation, but overall, out- comes of interest, i.e. times to the intervention, were not consistently reported by literature. However, all POCT uti- lizations were associated with a quicker decision-making process, which would be highly interesting to both health- care providers and policy-makers. The likelihood of adverse events or consequences from unneeded procedures when POCT findings are falsely positive or negative still poses a se- rious obstacle to making a definitive decision. This raises the question whether samples should be sent for laboratory test- ing at the same time as performing the POCT or following a positive POCT. This problem raises questions regarding the treatment’s ultimate results, but it should be evaluated ac- cording to each patient’s unique medical situation and the available POCT. These results were not comparable to any study as there was no study with similar objectives. Major benefits are achieved when POCT device output is readily available to the care team in an electronic medical record (reduced turnaround time or TAT), and mortality is reduced when goal-directed therapy (GDT) is combined with POCT and use of electronic medical records. But our review has indicated the need for treatment confirmation as a factor limiting the application of POCT, especially in new POCTs. Singer et al. (2015) provided the evidence that in time- critical patients with severe conditions, using the POCT of Hemoglobin (Hb), international normalized ratio (INR), tro- ponin, and some other tests decreased the time to computed tomography (CT) with intravenous contrast injection, while their utilized POCT did not included any parameters needed for the estimation of the kidney function. But other stud- ies that had evaluated renal function POCTs had not evalu- ated the time to CT scan metrics except for Bargnoux et al. (27). In addition, POCT has become established worldwide and plays a vital role in critical care. Best POCT known to the public is the blood sugar (BS) assessment tool. A review by Beik et al. evaluated the POCT in hyper/hypoglycemic state. Their results were supporting the application of the POC β-Hydroxybutyrate and BS tests in patients with sus- pected diabetes-related ketoacidosis (34). Assessment of blood sugar is one of the vitals of the critical care, for which POCT has been routinely made available. But the application of the other new POCTs is also growing. Our review included many new POCT items, all of which satis- fied the needs of the ED for quick disposition and decision- making for patients. We compared the care with and without the POCT in the ED setting. Some ongoing trials with good power were not included in our study due to being limited to the comparison framework; a trial of the LAPHSUS was not included in our study as they had not compared POCT with non-POCT-based care (35, 36). One of the most com- mon uses of POCT in ED is for patients with suspected sepsis, for whom timely intervention is of great importance. While we did not assess the safety issues, the systematic review of Kruse et al. only focused on the accuracy of lactate POCT in sepsis care and showed promising results (37). Morris et al. conducted the most similar review to our study. They in- cluded 8 studies about sepsis but only 2 of the studies had reported time to intervention indices (38). While our review showed positive results in decreasing the time to interven- tion of almost all evaluated interventions in different medical circumstances of POCT application, a study showed that ac- celerating the speed of the laboratory analysis in stroke care did not change door-to-needle time (39); yet, there were not using the bedside tests and only the laboratory works were speeded up. Our review included many new POCT items, all of which sat- isfied the needs of the ED for quick disposition and decision- making for patients. This study revealed the methodological and conceptual limitations of the POCT literature in the time metric studies in the ED. 5. Limitations Since there were multiple diverse reported outcomes based on utilizing different POCTs in diverse types of diseases, we This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e82 were not able to conduct any meta-analysis. Also, the quality of the included studies was not satisfactory and most stud- ies suffered from significant methodological limitations that warrant the need for randomized trials or protocols for stan- dard evaluation of the exposure and outcomes in the cohorts, for minimizing the risk of bias. Outcome level risk of bias as- sessment in this study is complex due to diverse outcomes. Most studies’ quality was compromised by some points. Di- agnosis of most diseases was made based on clinical findings, imaging, and laboratory findings. In studies with mixed types of patients, study results might have been affected by the di- agnosis based on other clinical findings, rather than the lab- oratory finding alone (bias of having an outcome in enrol- ment). Only Singer et al. b, Lau et al. (PREDICT Study), Per- litz et al., Deledda et al., and Hoch et al. had homogenous patients regarding the type of the disease. Although we used a comprehensive literature review, there might be some studies that were not found by our study due to incomplete retrieval of identified research or some studies might not have been published due to negative results or any other publishing issues, causing reporting bias. 6. Conclusion In synthesis of the evidence, all included studies were report- ing the benefits of POCT in decreasing the time to proper in- terventions and increasing the time to negative interventions in the last lines of critical care as well as the intubation and CVC placement. 7. Declarations 7.1. Acknowledgments We appreciate Clinical Research Development Unit of Pey- manieh Educational and Research and Therapeutic Center of Jahrom University of Medical Sciences for providing facilities for this work. 7.2. Authors’ contribution SR and PA designed the study. SR, MSJ, SA, and RA wrote the protocol. HA, PA, BA, and FM conducted the literature re- view and data extraction. SAh, BRK, NK, and SR wrote the draft of the article. All authors contributed to revisions and confirmed the final version of the article. 7.3. Funding None. 7.4. Conflict of interest None. References 1. Luppa PB, Müller C, Schlichtiger A, Schlebusch H. 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Point-of-care lactate testing for sep- sis at presentation to health care: a systematic review of patient outcomes. Brit J of Genral Pract. 2017 Dec 1;67(665):e859-70. 39. Trongnit S, Reesukumal K, Kost GJ, Nilanont Y, Pra- tumvinit B. Reducing Laboratory Turnaround Time in Pa- tients With Acute Stroke and the Lack of Impact on Time to Reperfusion Therapy. Arch Pathol Lab Med. 2021 May 2. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Rahsepar et al. 8 Table 1: The basic characteristics of included studies ID Design Setting N POCT type Patients Comparison Result of time to intervention Mullen et al. (18) RCT pre hospital 59 Fingerstick lactate Critically ill POCT vs. No test Higher time to central venous catheter (CVC) placement Singer et al. A (19) Before-after study ED 160 Hand-held lactate POCT (i-STAT) Sepsis suspected POCT vs. Standard care Lower time to IV fluids, ICU admissions; similar time to IV antibiotics Singer et al. B (20) Before-after study ED 23 86 Panel of Hb and HCT, troponin I, BNP, lactate, and INR Critical patients POCT vs. Standard care Lower time to contrast CT (only for Hb and HCT) Goodacre et al. (21) RCT ED 22 43 CK-MB, myoglobin, troponin I [Siemens] MI suspected POCT vs. Standard care Higher rate of cardiac intervention in first 24 hours Hoch et al. (22) Retrospective cohort ED 25 7 Ultrasound Pericardiocentesis POCT vs. No test Lower time to intervention Lau et al. (PREDICT Study) (23) Retrospective cohort ED 56 Resuscitative echocardiography Intracardiac Thrombus during cardiac arrest POCT positive vs. Negative Immediate termination of resuscitation Perlitz et al. (24) Cross-over design, prospective ED 82 8 Influenza PCR Influenza suspected POCT vs. Standard care Lower admission time to antiviral therapy Lee et al. (25) RCT ED 23 23 Liver, renal, pancreas enzymes, and lipid panels, electrolytes, and blood gases ED patients POCT vs. Standard care Lower time to intervention in almost all interventions Deledda et al. (26) Before-after study ED 54,41 9 Cardiac troponin I MI suspected POCT vs. Standard care Lower disposition time Bargnoux et al. (27) Before-after study ED 17 8 Creatinine Contrast- enhanced computed tomography scan POCT vs. Standard care Lower waiting time for imaging Chaisirin et al. (28) RCT ED 26 0 Panel of metabolic, electrolyte, BUN, creatinine, CO2 ED patients POCT vs. Standard care Lower disposition time Mogensen et al. (29) RCT ED 22 2 D-dimer, troponin i, CK-MB, CRP ED patients POCT vs. Standard care Lower time to intervention only for acute bacterial infection (CRP) Kankaanpää et al. (30) Retrospective cohort ED 17 59 Blood gases and chemistry panel, CBC, and CRP Non-ambulatory ED patients POCT vs. Standard care Lower time to imaging Jarvis et al. (31) Prospective cohort ED 25 70 9 Renal function analysis ED patients POCT vs. Standard care Lower time to intervention Mosier et al. (32) Retrospective cohort ED 5,4 41 Ultrasound Hemodynamic instability POCT before IV therapy or vasopressor vs. No POCT No POCT group had the least time of intubation, followed by group of POCT after bolus water or vasopressor Hall et al. (33) Retrospective cohort ED 38 34 Ultrasound Shock POCT vs. Standard care Lower disposition time POCT: Point-of-Care testing; RCT: randomized clinical trial; N: sample size; ED: emergency department; Hb: Hemohlobolin; INR: The international normalized ratio; CK-MB: Creatine Kinase MB; BUN: Blood Urea Nitrogen; CT: computed tomography; ICU: intensive care unit; IV: intravenous; PCR: polymerase chain reaction; HCT: hematocrit; MI: myocardial infarction; BNP: B-type natriuretic peptide; CRP: c-reactive protein; CBC: complete blood count. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2022; 10(1): e82 Figure 1: PRISMA flowchart of articles included in the review study. POCT: Point-of-Care testing. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S. Rahsepar et al. 10 Table 2: Critical appraisal of randomized clinical trials included in the review Study Randomization Concealment Imbalance Suggest Problem? Risk of Bias Mullen et al. Probably no No Yes High Goodacre et al. Yes Yes Yes Low Lee et al. Yes Probably no Yes Some concerns Chaisirin et al. Yes Yes Yes Low Mogensen et al. Yes Yes Yes Low Table 3: Critical appraisal of cohort studies included in the review Character Singer et al. Singer et al. Singer et al. Hoch et al. Lau et al. Perlitz et al. Deledda et al. Bargno- ux et al. Kanka- anpää et al. Jarvis et al. Mosier et al. Hall et al. Clear question Y Y Y Y Y Y Y Y Y Y Y Y Comparable source popula- tions Y Y Y Y Y Y Y Y Y Y Y Y Bias of having outcome in en- rolment Y Y Y Y Y Y Y Y Y Y Y Y Lost to follow-up reported and compared? N N N Y N N N N N N N N Clear outcomes Y Y Y Y Y Y Y Y Y Y Y Y Blinding N N N N N N N N N N N N Knowledge of exposure status Y Y Y Y Y Y Y Y Y Y Y Y Reliable exposure assessment Y Y Y Y Y Y Y Y Y Y Y Y Validity and reliability of assessment based on other sources N N N N Y N N N N N N N Exposure repeated assess- ment N N N N Y N N N N N N N Identified confounders Y Y Y Y Y N Y Y Y Y Y Y Confidence intervals re- ported? Y N Y Y Y N Y N Y Y Y Y Risk of bias? ** * 0 0 0 ** 0 ** ** ** 0 0 Association between expo- sure and outcome? Y Y Y Y Y Y Y Y Y Y Y Y Clinical application Y Y Y Y Y N Y Y Y Y Y Y N: No; Y: Yes. Risk of bias has 3 levels of 0, *, **, where ** is showing the highest risk of bias and 0 for low source of bias. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References