Alexander Ginsburg

Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver, usually developing in persons with chronic liver disease. Worldwide, it is the fifth most common type of cancer and the third most common cause of death from cancer (1). There were 25000 deaths attributed to liver and intrahepatic bile duct cancer in the United States in 2011 (2). Common causes of HCC are hepatitis C virus infection, hepatitis B virus infection, and alcohol abuse, although a substantial proportion of cases have no identifiable cause (35). Imaging modalities for HCC include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Although CT and MRI provide higher-resolution images than ultrasonography, they are also more costly and, in the case of CT, are associated with radiation exposure (5). Because HCC is typically a hypervascular lesion, CT and MRI are performed with arterial-enhancing contrast agents. Microbubble-enhanced ultrasonography can also be performed, although agents are not yet approved by the U.S. Food and Drug Administration for this purpose, and microbubbles are present in the liver for only a limited duration (6). Other technical, patient, and tumor factors may also affect test performance (712). This article reviews the test performance of ultrasonography, MRI, and CT for detection of HCC and for evaluation of focal liver lesions. This was conducted as part of a larger review commissioned by the Agency for Healthcare Research and Quality (AHRQ) on HCC imaging (13). Supplement. Original Version (PDF) Methods Scope of the Review The protocol was developed by using a standardized process with input from experts and the public and was registered in the PROSPERO database (CRD42014007016) (14). The review protocol included key questions on the comparative test performance of imaging for detection of HCC and for evaluation of focal liver lesions. Detailed methods and data for the review, including search strategies, inclusion criteria, and abstraction and quality ratings tables, are available in the full report, which also includes further key questions, full sensitivity and subgroup analyses, and an additional imaging modality (positron emission tomography) (13). Data Sources and Searches A research librarian searched multiple electronic databases, including MEDLINE (1998 to December 2013 for the full report; the update search for the review in this article was performed in December 2014), the Cochrane Library, and Scopus. Additional studies were identified by reviewing reference lists and from peer review suggestions. Study Selection Two investigators independently evaluated each study at the title/abstract and full-text article stages to determine inclusion eligibility (Appendix Table 1). We included studies on the test performance of ultrasonography, CT, or MRI against a reference standard for detection of HCC in surveillance or nonsurveillance settings (for example, imaging performed in patients undergoing treatment for liver disease or in whom HCC was previously diagnosed) or for further evaluation of focal liver lesions. Reference standards were histopathologic examination based on explanted liver or nonexplant histologic specimens, imaging plus clinical follow-up (for example, lesion growth), or a combination of these. Appendix Table 1. Inclusion and Exclusion Criteria We selected studies of ultrasonography (with or without contrast) and contrast-enhanced CT and MRI that met minimum technical criteria (non-multidetector or multidetector spiral CT, or 1.5- or 3.0-T MRI) (7). We excluded studies published before 1998 and those in which imaging began before 1995, unless the imaging methods met minimum technical criteria; studies of MRI with contrast agents no longer commercially produced (for example, superparamagnetic iron oxide [ferumoxides or ferucarbotran] or mangafodipir); and studies of CT arterial portography, CT hepatic angiography, and intraoperative ultrasonography. We included studies of ultrasonography microbubble contrast agents because they are commercially available and commonly used outside the United States, and efforts to obtain approval from the U.S. Food and Drug Administration are ongoing (1517). We excluded studies of diagnostic accuracy for non-HCC malignant lesions, including liver metastases. We included studies that reported results for HCC and cholangiocarcinoma together if cholangiocarcinoma lesions comprised less than 10% of the total. Studies on the accuracy of imaging for distinguishing HCC from a specific type of liver lesion (such as hemangioma or pseudolesion) and on the accuracy of imaging tests used in combination are addressed in the full report (13). We excluded studies published only as conference abstracts and included only English-language articles. The literature flow diagram is shown in Appendix Figure 1. Appendix Figure 1. Summary of evidence search and selection. * Studies of positron emission tomography; effects on clinical decisions, clinical outcomes, or staging; and accuracy for distinguishing hepatocellular carcinoma lesions from another specific type of liver lesion are addressed in the full report (13). Data Abstraction and Quality Rating One investigator abstracted details on the study design, dates of imaging and publication, patient population, country, sample size, imaging method and associated technical factors (Appendix Table 2), and results. Two investigators independently applied the approach recommended in the AHRQ Methods Guide for Medical Test Reviews to assess risk of bias as high, moderate, or low (18, 19). Appendix Table 2. Technical Factors Abstracted, by Imaging Modality Data Synthesis We conducted meta-analysis with a bivariate logistic mixed random-effects model that incorporated the correlation between sensitivity and specificity, using SAS software, version 9.3 (SAS Institute) (20). We assumed bivariate normal distributions for sensitivity and specificity. Statistical heterogeneity was measured with the random-effect variance (2). We calculated positive and negative likelihood ratios by using the summarized sensitivity and specificity (21, 22). We analyzed data separately for each imaging modality; ultrasonography with and without contrast were also analyzed separately. We also separately analyzed studies in which imaging was performed for detection of HCC and for evaluation of focal liver lesions; studies on HCC detection were further stratified by setting (surveillance or nonsurveillance). We separately analyzed test performance by using patients with HCC or by using HCC lesions (one patient can have multiple lesions) as the unit of analysis. Other sensitivity and subgroup analyses were conducted on the reference standard, factors related to risk of bias, country, technical factors (Appendix Table 2), tumor factors (such as HCC lesion size or degree of tumor differentiation), and patient characteristics (for example, severity of underlying liver disease, underlying cause of liver disease, and body mass index). We performed separate analyses on the subset of studies that directly compared 2 or more imaging modalities or techniques in the same population against a common reference standard (23). We used the same bivariate logistic mixed-effects model as described above, with an added indicator variable for imaging modalities. We also performed meta-analyses for within-study comparisons on lesion size, degree of tumor differentiation, and (when data were available) technical factors. We graded the strength of each body of evidence as high, moderate, low, or insufficient on the basis of the aggregate risk of bias, consistency, precision, and directness (24). Role of the Funding Source This research was funded by the AHRQ Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the review protocol. The AHRQ staff had no role in conducting the review, and the investigators are solely responsible for the content of the manuscript and the decision to submit for publication. Results Of the 5202 citations identified at the title and abstract level, 890 articles seemed to meet inclusion criteria and were selected for further full-text review. After full-text review, 241 studies (Appendix Table 3) met inclusion criteria for the key questions and imaging modalities addressed in this review (Appendix Figure 1). Appendix Table 3. References to Articles That Met the Inclusion Criteria Appendix Table 3Continued. Appendix Table 3Continued. Sixty-eight studies evaluated ultrasonography (Appendix Table 3), 131 evaluated CT (25153), and 125 evaluated MRI (Appendix Table 3). Almost all studies reported sensitivity, but specificity was available in only 139 studies. We rated 5 studies as having low risk of bias (56, 99, 128, 132, 154), 199 as having moderate risk of bias, and 89 as having high risk of bias (13). One hundred twenty-five studies avoided use of a casecontrol design, 160 used blinded design, and 75 were prospective. More studies were conducted in Asia (190 studies) than in Australia, Canada, the United States, or Europe (95 studies in total for these regions). In 166 studies, imaging began in or after 2003 (13). Twenty-eight studies evaluated CT using methods that met minimum technical specifications (8-row multidetector CT; contrast rate 3 mL/s; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm), and 67 studies evaluated MRI using methods that met minimum technical specifications (1.5- or 3.0-T MRI; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm). Seventy-three MRI studies evaluated use of hepatic-specific contrast (for example, gadoxetic acid or gadobenate). Forty-seven ultrasonography studies evaluated use of

Impact of contacting study authors to obtain additional data for systematic reviews: diagnostic accuracy studies for hepatic fibrosis

BackgroundSeventeen of 172 included studies in a recent systematic review of blood tests for hepatic fibrosis or cirrhosis reported diagnostic accuracy results discordant from 2 × 2 tables, and 60 studies reported inadequate data to construct 2 × 2 tables. This study explores the yield of contacting authors of diagnostic accuracy studies and impact on the systematic review findings.MethodsSixty-six corresponding authors were sent letters requesting additional information or clarification of data from 77 studies. Data received from the authors were synthesized with data included in the previous review, and diagnostic accuracy sensitivities, specificities, and positive and likelihood ratios were recalculated.ResultsOf the 66 authors, 68% were successfully contacted and 42% provided additional data for 29 out of 77 studies (38%). All authors who provided data at all did so by the third emailed request (ten authors provided data after one request). Authors of more recent studies were more likely to be located and provide data compared to authors of older studies. The effects of requests for additional data on the conclusions regarding the utility of blood tests to identify patients with clinically significant fibrosis or cirrhosis were generally small for ten out of 12 tests. Additional data resulted in reclassification (using median likelihood ratio estimates) from less useful to moderately useful or vice versa for the remaining two blood tests and enabled the calculation of an estimate for a third blood test for which previously the data had been insufficient to do so. We did not identify a clear pattern for the directional impact of additional data on estimates of diagnostic accuracy.ConclusionsWe successfully contacted and received results from 42% of authors who provided data for 38% of included studies. Contacting authors of studies evaluating the diagnostic accuracy of serum biomarkers for hepatic fibrosis and cirrhosis in hepatitis C patients impacted conclusions regarding diagnostic utility for two blood tests and enabled the calculation of an estimate for a third blood test. Despite relatively extensive efforts, we were unable to obtain data to resolve discrepancies or complete 2 × 2 tables for 62% of studies.

Imaging Techniques for the Diagnosis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver, usually developing in persons with chronic liver disease. Worldwide, it is the fifth most common type of cancer and the third most common cause of death from cancer (1). There were 25000 deaths attributed to liver and intrahepatic bile duct cancer in the United States in 2011 (2). Common causes of HCC are hepatitis C virus infection, hepatitis B virus infection, and alcohol abuse, although a substantial proportion of cases have no identifiable cause (35). Imaging modalities for HCC include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Although CT and MRI provide higher-resolution images than ultrasonography, they are also more costly and, in the case of CT, are associated with radiation exposure (5). Because HCC is typically a hypervascular lesion, CT and MRI are performed with arterial-enhancing contrast agents. Microbubble-enhanced ultrasonography can also be performed, although agents are not yet approved by the U.S. Food and Drug Administration for this purpose, and microbubbles are present in the liver for only a limited duration (6). Other technical, patient, and tumor factors may also affect test performance (712). This article reviews the test performance of ultrasonography, MRI, and CT for detection of HCC and for evaluation of focal liver lesions. This was conducted as part of a larger review commissioned by the Agency for Healthcare Research and Quality (AHRQ) on HCC imaging (13). Supplement. Original Version (PDF) Methods Scope of the Review The protocol was developed by using a standardized process with input from experts and the public and was registered in the PROSPERO database (CRD42014007016) (14). The review protocol included key questions on the comparative test performance of imaging for detection of HCC and for evaluation of focal liver lesions. Detailed methods and data for the review, including search strategies, inclusion criteria, and abstraction and quality ratings tables, are available in the full report, which also includes further key questions, full sensitivity and subgroup analyses, and an additional imaging modality (positron emission tomography) (13). Data Sources and Searches A research librarian searched multiple electronic databases, including MEDLINE (1998 to December 2013 for the full report; the update search for the review in this article was performed in December 2014), the Cochrane Library, and Scopus. Additional studies were identified by reviewing reference lists and from peer review suggestions. Study Selection Two investigators independently evaluated each study at the title/abstract and full-text article stages to determine inclusion eligibility (Appendix Table 1). We included studies on the test performance of ultrasonography, CT, or MRI against a reference standard for detection of HCC in surveillance or nonsurveillance settings (for example, imaging performed in patients undergoing treatment for liver disease or in whom HCC was previously diagnosed) or for further evaluation of focal liver lesions. Reference standards were histopathologic examination based on explanted liver or nonexplant histologic specimens, imaging plus clinical follow-up (for example, lesion growth), or a combination of these. Appendix Table 1. Inclusion and Exclusion Criteria We selected studies of ultrasonography (with or without contrast) and contrast-enhanced CT and MRI that met minimum technical criteria (non-multidetector or multidetector spiral CT, or 1.5- or 3.0-T MRI) (7). We excluded studies published before 1998 and those in which imaging began before 1995, unless the imaging methods met minimum technical criteria; studies of MRI with contrast agents no longer commercially produced (for example, superparamagnetic iron oxide [ferumoxides or ferucarbotran] or mangafodipir); and studies of CT arterial portography, CT hepatic angiography, and intraoperative ultrasonography. We included studies of ultrasonography microbubble contrast agents because they are commercially available and commonly used outside the United States, and efforts to obtain approval from the U.S. Food and Drug Administration are ongoing (1517). We excluded studies of diagnostic accuracy for non-HCC malignant lesions, including liver metastases. We included studies that reported results for HCC and cholangiocarcinoma together if cholangiocarcinoma lesions comprised less than 10% of the total. Studies on the accuracy of imaging for distinguishing HCC from a specific type of liver lesion (such as hemangioma or pseudolesion) and on the accuracy of imaging tests used in combination are addressed in the full report (13). We excluded studies published only as conference abstracts and included only English-language articles. The literature flow diagram is shown in Appendix Figure 1. Appendix Figure 1. Summary of evidence search and selection. * Studies of positron emission tomography; effects on clinical decisions, clinical outcomes, or staging; and accuracy for distinguishing hepatocellular carcinoma lesions from another specific type of liver lesion are addressed in the full report (13). Data Abstraction and Quality Rating One investigator abstracted details on the study design, dates of imaging and publication, patient population, country, sample size, imaging method and associated technical factors (Appendix Table 2), and results. Two investigators independently applied the approach recommended in the AHRQ Methods Guide for Medical Test Reviews to assess risk of bias as high, moderate, or low (18, 19). Appendix Table 2. Technical Factors Abstracted, by Imaging Modality Data Synthesis We conducted meta-analysis with a bivariate logistic mixed random-effects model that incorporated the correlation between sensitivity and specificity, using SAS software, version 9.3 (SAS Institute) (20). We assumed bivariate normal distributions for sensitivity and specificity. Statistical heterogeneity was measured with the random-effect variance (2). We calculated positive and negative likelihood ratios by using the summarized sensitivity and specificity (21, 22). We analyzed data separately for each imaging modality; ultrasonography with and without contrast were also analyzed separately. We also separately analyzed studies in which imaging was performed for detection of HCC and for evaluation of focal liver lesions; studies on HCC detection were further stratified by setting (surveillance or nonsurveillance). We separately analyzed test performance by using patients with HCC or by using HCC lesions (one patient can have multiple lesions) as the unit of analysis. Other sensitivity and subgroup analyses were conducted on the reference standard, factors related to risk of bias, country, technical factors (Appendix Table 2), tumor factors (such as HCC lesion size or degree of tumor differentiation), and patient characteristics (for example, severity of underlying liver disease, underlying cause of liver disease, and body mass index). We performed separate analyses on the subset of studies that directly compared 2 or more imaging modalities or techniques in the same population against a common reference standard (23). We used the same bivariate logistic mixed-effects model as described above, with an added indicator variable for imaging modalities. We also performed meta-analyses for within-study comparisons on lesion size, degree of tumor differentiation, and (when data were available) technical factors. We graded the strength of each body of evidence as high, moderate, low, or insufficient on the basis of the aggregate risk of bias, consistency, precision, and directness (24). Role of the Funding Source This research was funded by the AHRQ Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the review protocol. The AHRQ staff had no role in conducting the review, and the investigators are solely responsible for the content of the manuscript and the decision to submit for publication. Results Of the 5202 citations identified at the title and abstract level, 890 articles seemed to meet inclusion criteria and were selected for further full-text review. After full-text review, 241 studies (Appendix Table 3) met inclusion criteria for the key questions and imaging modalities addressed in this review (Appendix Figure 1). Appendix Table 3. References to Articles That Met the Inclusion Criteria Appendix Table 3Continued. Appendix Table 3Continued. Sixty-eight studies evaluated ultrasonography (Appendix Table 3), 131 evaluated CT (25153), and 125 evaluated MRI (Appendix Table 3). Almost all studies reported sensitivity, but specificity was available in only 139 studies. We rated 5 studies as having low risk of bias (56, 99, 128, 132, 154), 199 as having moderate risk of bias, and 89 as having high risk of bias (13). One hundred twenty-five studies avoided use of a casecontrol design, 160 used blinded design, and 75 were prospective. More studies were conducted in Asia (190 studies) than in Australia, Canada, the United States, or Europe (95 studies in total for these regions). In 166 studies, imaging began in or after 2003 (13). Twenty-eight studies evaluated CT using methods that met minimum technical specifications (8-row multidetector CT; contrast rate 3 mL/s; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm), and 67 studies evaluated MRI using methods that met minimum technical specifications (1.5- or 3.0-T MRI; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm). Seventy-three MRI studies evaluated use of hepatic-specific contrast (for example, gadoxetic acid or gadobenate). Forty-seven ultrasonography studies evaluated use of

Imaging Techniques for the Diagnosis of Hepatocellular CarcinomaA Systematic Review and Meta-analysisImaging Techniques for Diagnosis and Staging of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver, usually developing in persons with chronic liver disease. Worldwide, it is the fifth most common type of cancer and the third most common cause of death from cancer (1). There were 25000 deaths attributed to liver and intrahepatic bile duct cancer in the United States in 2011 (2). Common causes of HCC are hepatitis C virus infection, hepatitis B virus infection, and alcohol abuse, although a substantial proportion of cases have no identifiable cause (35). Imaging modalities for HCC include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Although CT and MRI provide higher-resolution images than ultrasonography, they are also more costly and, in the case of CT, are associated with radiation exposure (5). Because HCC is typically a hypervascular lesion, CT and MRI are performed with arterial-enhancing contrast agents. Microbubble-enhanced ultrasonography can also be performed, although agents are not yet approved by the U.S. Food and Drug Administration for this purpose, and microbubbles are present in the liver for only a limited duration (6). Other technical, patient, and tumor factors may also affect test performance (712). This article reviews the test performance of ultrasonography, MRI, and CT for detection of HCC and for evaluation of focal liver lesions. This was conducted as part of a larger review commissioned by the Agency for Healthcare Research and Quality (AHRQ) on HCC imaging (13). Supplement. Original Version (PDF) Methods Scope of the Review The protocol was developed by using a standardized process with input from experts and the public and was registered in the PROSPERO database (CRD42014007016) (14). The review protocol included key questions on the comparative test performance of imaging for detection of HCC and for evaluation of focal liver lesions. Detailed methods and data for the review, including search strategies, inclusion criteria, and abstraction and quality ratings tables, are available in the full report, which also includes further key questions, full sensitivity and subgroup analyses, and an additional imaging modality (positron emission tomography) (13). Data Sources and Searches A research librarian searched multiple electronic databases, including MEDLINE (1998 to December 2013 for the full report; the update search for the review in this article was performed in December 2014), the Cochrane Library, and Scopus. Additional studies were identified by reviewing reference lists and from peer review suggestions. Study Selection Two investigators independently evaluated each study at the title/abstract and full-text article stages to determine inclusion eligibility (Appendix Table 1). We included studies on the test performance of ultrasonography, CT, or MRI against a reference standard for detection of HCC in surveillance or nonsurveillance settings (for example, imaging performed in patients undergoing treatment for liver disease or in whom HCC was previously diagnosed) or for further evaluation of focal liver lesions. Reference standards were histopathologic examination based on explanted liver or nonexplant histologic specimens, imaging plus clinical follow-up (for example, lesion growth), or a combination of these. Appendix Table 1. Inclusion and Exclusion Criteria We selected studies of ultrasonography (with or without contrast) and contrast-enhanced CT and MRI that met minimum technical criteria (non-multidetector or multidetector spiral CT, or 1.5- or 3.0-T MRI) (7). We excluded studies published before 1998 and those in which imaging began before 1995, unless the imaging methods met minimum technical criteria; studies of MRI with contrast agents no longer commercially produced (for example, superparamagnetic iron oxide [ferumoxides or ferucarbotran] or mangafodipir); and studies of CT arterial portography, CT hepatic angiography, and intraoperative ultrasonography. We included studies of ultrasonography microbubble contrast agents because they are commercially available and commonly used outside the United States, and efforts to obtain approval from the U.S. Food and Drug Administration are ongoing (1517). We excluded studies of diagnostic accuracy for non-HCC malignant lesions, including liver metastases. We included studies that reported results for HCC and cholangiocarcinoma together if cholangiocarcinoma lesions comprised less than 10% of the total. Studies on the accuracy of imaging for distinguishing HCC from a specific type of liver lesion (such as hemangioma or pseudolesion) and on the accuracy of imaging tests used in combination are addressed in the full report (13). We excluded studies published only as conference abstracts and included only English-language articles. The literature flow diagram is shown in Appendix Figure 1. Appendix Figure 1. Summary of evidence search and selection. * Studies of positron emission tomography; effects on clinical decisions, clinical outcomes, or staging; and accuracy for distinguishing hepatocellular carcinoma lesions from another specific type of liver lesion are addressed in the full report (13). Data Abstraction and Quality Rating One investigator abstracted details on the study design, dates of imaging and publication, patient population, country, sample size, imaging method and associated technical factors (Appendix Table 2), and results. Two investigators independently applied the approach recommended in the AHRQ Methods Guide for Medical Test Reviews to assess risk of bias as high, moderate, or low (18, 19). Appendix Table 2. Technical Factors Abstracted, by Imaging Modality Data Synthesis We conducted meta-analysis with a bivariate logistic mixed random-effects model that incorporated the correlation between sensitivity and specificity, using SAS software, version 9.3 (SAS Institute) (20). We assumed bivariate normal distributions for sensitivity and specificity. Statistical heterogeneity was measured with the random-effect variance (2). We calculated positive and negative likelihood ratios by using the summarized sensitivity and specificity (21, 22). We analyzed data separately for each imaging modality; ultrasonography with and without contrast were also analyzed separately. We also separately analyzed studies in which imaging was performed for detection of HCC and for evaluation of focal liver lesions; studies on HCC detection were further stratified by setting (surveillance or nonsurveillance). We separately analyzed test performance by using patients with HCC or by using HCC lesions (one patient can have multiple lesions) as the unit of analysis. Other sensitivity and subgroup analyses were conducted on the reference standard, factors related to risk of bias, country, technical factors (Appendix Table 2), tumor factors (such as HCC lesion size or degree of tumor differentiation), and patient characteristics (for example, severity of underlying liver disease, underlying cause of liver disease, and body mass index). We performed separate analyses on the subset of studies that directly compared 2 or more imaging modalities or techniques in the same population against a common reference standard (23). We used the same bivariate logistic mixed-effects model as described above, with an added indicator variable for imaging modalities. We also performed meta-analyses for within-study comparisons on lesion size, degree of tumor differentiation, and (when data were available) technical factors. We graded the strength of each body of evidence as high, moderate, low, or insufficient on the basis of the aggregate risk of bias, consistency, precision, and directness (24). Role of the Funding Source This research was funded by the AHRQ Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the review protocol. The AHRQ staff had no role in conducting the review, and the investigators are solely responsible for the content of the manuscript and the decision to submit for publication. Results Of the 5202 citations identified at the title and abstract level, 890 articles seemed to meet inclusion criteria and were selected for further full-text review. After full-text review, 241 studies (Appendix Table 3) met inclusion criteria for the key questions and imaging modalities addressed in this review (Appendix Figure 1). Appendix Table 3. References to Articles That Met the Inclusion Criteria Appendix Table 3Continued. Appendix Table 3Continued. Sixty-eight studies evaluated ultrasonography (Appendix Table 3), 131 evaluated CT (25153), and 125 evaluated MRI (Appendix Table 3). Almost all studies reported sensitivity, but specificity was available in only 139 studies. We rated 5 studies as having low risk of bias (56, 99, 128, 132, 154), 199 as having moderate risk of bias, and 89 as having high risk of bias (13). One hundred twenty-five studies avoided use of a casecontrol design, 160 used blinded design, and 75 were prospective. More studies were conducted in Asia (190 studies) than in Australia, Canada, the United States, or Europe (95 studies in total for these regions). In 166 studies, imaging began in or after 2003 (13). Twenty-eight studies evaluated CT using methods that met minimum technical specifications (8-row multidetector CT; contrast rate 3 mL/s; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm), and 67 studies evaluated MRI using methods that met minimum technical specifications (1.5- or 3.0-T MRI; at least arterial, portal venous, and delayed-phase imaging; delayed-phase imaging performed >120 s after administration of contrast; and enhanced imaging section thickness 5 mm). Seventy-three MRI studies evaluated use of hepatic-specific contrast (for example, gadoxetic acid or gadobenate). Forty-seven ultrasonography studies evaluated use of