Ngoc Wasson

Blood Tests to Diagnose Fibrosis or Cirrhosis in Patients With Chronic Hepatitis C Virus Infection: A Systematic Review

BACKGROUND Many blood tests have been proposed as alternatives to liver biopsy for identifying fibrosis or cirrhosis. PURPOSE To evaluate the diagnostic accuracy of blood tests to identify fibrosis or cirrhosis in patients with hepatitis C virus (HCV) infection. DATA SOURCES MEDLINE (1947 to January 2013), the Cochrane Library, and reference lists. STUDY SELECTION Studies that compared the diagnostic accuracy of blood tests with that of liver biopsy. DATA EXTRACTION Investigators abstracted and checked study details and quality by using predefined criteria. DATA SYNTHESIS 172 studies evaluated diagnostic accuracy. For identifying clinically significant fibrosis, the platelet count, age-platelet index, aspartate aminotransferase-platelet ratio index (APRI), FibroIndex, FibroTest, and Forns index had median positive likelihood ratios of 5 to 10 at commonly used cutoffs and areas under the receiver-operating characteristic curve (AUROCs) of 0.70 or greater (range, 0.71 to 0.86). For identifying cirrhosis, the platelet count, age-platelet index, APRI, and Hepascore had median positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater (range, 0.80 to 0.91). The Göteborg University Cirrhosis Index and the Lok index had slightly lower positive likelihood ratios (4.8 and 4.4, respectively). In direct comparisons, the APRI was associated with a slightly lower AUROC than the FibroTest for identifying fibrosis and a substantially higher AUROC than the aspartate aminotransferase-alanine aminotransferase ratio for identifying fibrosis or cirrhosis. LIMITATION Only English-language articles were included, and most studies had methodological limitations, including failure to describe blinded interpretation of liver biopsy specimens and inadequate description of enrollment methods. CONCLUSION Many blood tests are moderately useful for identifying clinically significant fibrosis or cirrhosis in HCV-infected patients. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: A systematic review

BACKGROUND Multiple treatments are available for chronic hepatitis C virus (HCV) infection. PURPOSE To compare benefits and harms of antiviral regimens for chronic HCV infection in treatment-naive adults. DATA SOURCES English-language literature from MEDLINE (1947 to August 2012), the Cochrane Library Database, Embase, Scopus, PsychINFO, and clinical trial registries. STUDY SELECTION Randomized trials of antiviral treatments and cohort studies examining associations between sustained virologic response (SVR) after therapy and clinical outcomes. DATA EXTRACTION Several investigators abstracted study details and quality by using predefined criteria. DATA SYNTHESIS No trial evaluated effectiveness of treatment on long-term clinical outcomes. Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower likelihood of SVR than was pegylated interferon alfa-2a plus ribavirin (absolute difference, 8 percentage points [95% CI, 3 to 14 percentage points]) on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood of SVR than was therapy for 24 weeks, and lower doses of pegylated interferon alfa-2b were less effective than standard doses (2 to 4 fair-quality trials). For genotype 1 infection, fair-quality trials found that triple therapy with pegylated interferon, ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likelihood of SVR than was dual therapy (absolute difference, 22 to 31 percentage points). Compared with dual therapy, boceprevir triple therapy increased risk for hematologic adverse events and telaprevir triple therapy increased risk for anemia and rash. A large well-designed cohort study and 18 smaller cohort studies found that an SVR after antiviral therapy was associated with lower risk for all-cause mortality than was no SVR. LIMITATIONS Trials involved highly selected populations. Observational studies did not always adequately control for confounders. CONCLUSION SVR rates for genotype 1 infection are higher with triple therapy that includes a protease inhibitor than with standard dual therapy. An SVR after antiviral therapy appears associated with improved clinical outcomes. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Reducing Risk for Mother-to-Infant Transmission of Hepatitis C Virus: A Systematic Review for the U.S. Preventive Services Task Force

BACKGROUND Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States. PURPOSE To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV. DATA SOURCES MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV. DATA EXTRACTION Investigators abstracted and reviewed study details and quality using predefined criteria. DATA SYNTHESIS Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission. LIMITATIONS Only English-language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes. CONCLUSION No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Pressure Ulcer Treatment Strategies: A Systematic Comparative Effectiveness Review

BACKGROUND Pressure ulcers affect as many as 3 million Americans and are major sources of morbidity, mortality, and health care costs. PURPOSE To summarize evidence comparing the effectiveness and safety of treatment strategies for adults with pressure ulcers. DATA SOURCES MEDLINE, EMBASE, CINAHL, Evidence-Based Medicine Reviews, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database for English- or foreign-language studies; reference lists; gray literature; and individual product packets from manufacturers (January 1985 to October 2012). STUDY SELECTION Randomized trials and comparative observational studies of treatments for pressure ulcers in adults and noncomparative intervention series (n > 50) for surgical interventions and evaluation of harms. DATA EXTRACTION Data were extracted and evaluated for accuracy of the extraction, quality of included studies, and strength of evidence. DATA SYNTHESIS 174 studies met inclusion criteria and 92 evaluated complete wound healing. In comparison with standard care, placebo, or sham interventions, moderate-strength evidence showed that air-fluidized beds (5 studies [n = 908]; high consistency), protein-containing nutritional supplements (12 studies [n = 562]; high consistency), radiant heat dressings (4 studies [n = 160]; moderate consistency), and electrical stimulation (9 studies [n = 397]; moderate consistency) improved healing of pressure ulcers. Low-strength evidence showed that alternating-pressure surfaces, hydrocolloid dressings, platelet-derived growth factor, and light therapy improved healing of pressure ulcers. The evidence about harms was limited. LIMITATION Applicability of results is limited by study quality, heterogeneity in methods and outcomes, and inadequate duration to assess complete wound healing. CONCLUSION Moderate-strength evidence shows that healing of pressure ulcers in adults is improved with the use of air-fluidized beds, protein supplementation, radiant heat dressings, and electrical stimulation.

Screening for Hepatitis C Virus Infection in Adults: A Systematic Review for the U.S. Preventive Services Task Force

BACKGROUND Identification of hepatitis C virus (HCV)-infected persons through screening could lead to interventions that improve clinical outcomes. PURPOSE To review evidence about potential benefits and harms of HCV screening in asymptomatic adults without known liver enzyme abnormalities. DATA SOURCES English-language publications identified from MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION Randomized trials and cohort, case-control, and cross-sectional studies that assessed yield or clinical outcomes of screening; studies reporting harms from HCV screening; and large series reporting harms of diagnostic liver biopsies. DATA EXTRACTION Multiple investigators abstracted and checked study details and quality by using predefined criteria. DATA SYNTHESIS No study evaluated clinical outcomes associated with screening compared with no screening or of different risk- or prevalence-based strategies. Three cross-sectional studies in higher prevalence populations found that screening strategies that targeted multiple risk factors were associated with sensitivities greater than 90% and numbers needed to screen to identify 1 case of HCV infection of less than 20. Data on direct harms of screening were sparse. A large study of percutaneous liver biopsies (n = 2740) in HCV-infected patients with compensated cirrhosis reported no deaths and a 1.1% rate of serious adverse events (primarily bleeding and severe pain). LIMITATIONS Modeling studies were not examined. High or unreported proportions of potentially eligible patients in the observational studies were not included in calculations of screening yield because of unknown HCV status. CONCLUSION Although screening tests can accurately identify adults with chronic HCV infection, targeted screening strategies based on the presence of risk factors misses some patients with HCV infection. Well-designed prospective studies are needed to better understand the effects of different HCV screening strategies on diagnostic yield and clinical outcomes. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Blood Tests to Diagnose Fibrosis or Cirrhosis in Patients With Chronic Hepatitis C Virus Infection

This review examined evidence on the accuracy of blood tests to diagnose fibrosis in patients with chronic hepatitis C virus (HCV) infection. Evidence shows that platelet count, the age–platelet in...

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

Predictive Utility of the Total Glasgow Coma Scale Versus the Motor Component of the Glasgow Coma Scale for Identification of Patients With Serious Traumatic Injuries

Study objective The motor component of the Glasgow Coma Scale (mGCS) has been proposed as an easier‐to‐use alternative to the total GCS (tGCS) for field assessment of trauma patients by emergency medical services. We perform a systematic review and meta‐analysis to compare the predictive utility of the tGCS versus the mGCS or Simplified Motor Scale in field triage of trauma for identifying patients with adverse outcomes (inhospital mortality or severe brain injury) or who underwent procedures (neurosurgical intervention or emergency intubation) indicating need for high‐level trauma care. Methods Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Health and Psychosocial Instruments, and the Cochrane databases were searched through June 2016 for English‐language cohort studies. We included studies that compared the area under the receiver operating characteristic curve (AUROC) of the tGCS versus the mGCS or Simplified Motor Scale assessed in the field or shortly after arrival in the emergency department for predicting the outcomes described above. Meta‐analyses were performed with a random‐effects model, and subgroup and sensitivity analyses were conducted. Results We included 18 head‐to‐head studies of predictive utility (n=1,703,388). For inhospital mortality, the tGCS was associated with slightly greater discrimination than the mGCS (pooled mean difference in [AUROC] 0.015; 95% confidence interval [CI] 0.009 to 0.022; I2=85%; 12 studies) or the Simplified Motor Scale (pooled mean difference in AUROC 0.030; 95% CI 0.024 to 0.036; I2=0%; 5 studies). The tGCS was also associated with greater discrimination than the mGCS or Simplified Motor Scale for nonmortality outcomes (differences in AUROC from 0.03 to 0.05). Findings were robust in subgroup and sensitivity analyses. Conclusion The tGCS is associated with slightly greater discrimination than the mGCS or Simplified Motor Scale for identifying severe trauma. The small differences in discrimination are likely to be clinically unimportant and could be offset by factors such as convenience and ease of use.

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