Saadi, Samer

Abstract Background Risk of bias (RoB) tools are critical in systematic reviews and affect subsequent decision‐making. RoB tools should have adequate interrater reliability and interconsensus agreement. We present an approach of post hoc evaluation of RoB tools using duplicated studies that overlap systematic reviews. Methods Using a back‐citation approach, we identified systematic reviews that used the Risk Of Bias In Nonrandomized Studies‐of Interventions (ROBINS‐I) tool and retrieved all the included primary studies. We selected studies that were appraised by more than one systematic review and calculated observed agreement and unweighted kappa comparing the different systematic reviews' assessments. Results We identified 903 systematic reviews that used the tool with 51,676 cited references, from which we eventually analyzed 171 duplicated studies assessed using ROBINS‐I by different systematic reviewers. The observed agreement on ROBINS‐I domains ranged from 54.9% (missing data domain) to 70.3% (deviations from intended interventions domain), and was 63.0% for overall RoB assessment of the study. Kappa coefficient ranged from 0.131 (measurement of outcome domain) to 0.396 (domains of confounding and deviations from intended interventions), and was 0.404 for overall RoB assessment of the study. Conclusion A post hoc evaluation of RoB tools is feasible by focusing on duplicated studies that overlap systematic review. ROBINS‐I assessments demonstrated considerable variation in interconsensus agreement among various systematic reviewes that assessed the same study and outcome, suggesting the need for more intensive upfront work to calibrate systematic reviewers on how to identify context‐specific information and agree on how to judge it.

Abstract Context Low vitamin D status is common and is associated with various common medical conditions. Objective To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. Methods We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. Results Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. Conclusion The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals’ and providers’ values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Background and Aims: Transient elastography (TE), shear wave elastography, and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). Approach and Results: A comprehensive search for studies assessing LSM by TE, shear wave elastography, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), using histopathology as the standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV coinfection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. Conclusions: LSM from TE, shear wave elastography, and MRE shows acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Background and Aims: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. Approach and Results: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR−) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66–6.25 and 0.23–0.80, 1.89–5.24 and 0.12–0.64, and 1.32–7.15 and 0.15–0.86, respectively; LR+ and LR− for NAFLD F2-4, F3-4, and F4 were 2.65–3.37 and 0.37–0.39, 2.25–6.76 and 0.07–0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. Conclusions: Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.

Background and Aims: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. Approach and Results: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database’s inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%–96% and specificity was 48%–50%, while at 25 kPa, its sensitivity and specificity were 57%–85% and 82%–93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. Conclusions: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Abstract Background Early-stage breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast-conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial-breast irradiation (PBI) compared with whole-breast irradiation (WBI). Methods A systematic review was completed to identify relevant randomized clinical trials and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs). Results Fourteen randomized clinical trials and 6 comparative observational studies with 17 234 patients evaluated the comparative effectiveness of PBI. PBI was not statistically significantly different from WBI for IBR at 5 years (RR = 1.34, 95% CI = 0.83 to 2.18; high strength of evidence [SOE]) and 10 years (RR = 1.29, 95% CI = 0.87 to 1.91; high SOE). Evidence for cosmetic outcomes was insufficient. Statistically significantly fewer acute AEs were reported with PBI compared with WBI, with no statistically significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and over than 10 years (high SOE) compared with WBI. Conclusions Ipsilateral breast recurrence was not statistically significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectiveness of PBI among selected patients with early-stage, favorable-risk breast cancer who are similar to those represented in the included studies.

AbstractContextHypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.ObjectiveTo support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults.MethodsWe searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence.ResultsWe reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.ConclusionThe evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients’ values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

AbstractContextIndividuals with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. Management of hyperglycemia in these patients is challenging.ObjectiveTo support development of the Endocrine Society Clinical Practice Guideline for management of hyperglycemia in adults hospitalized for noncritical illness or undergoing elective surgical procedures.MethodsWe searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence.ResultsWe included 94 studies reporting on 135 553 patients. Compared with capillary blood glucose, continuous glucose monitoring increased the number of patients identified with hypoglycemia and decreased mean daily blood glucose (BG) (very low certainty). Data on continuation of insulin pump therapy in hospitalized adults were sparse. In hospitalized patients receiving glucocorticoids, combination neutral protamine hagedorn (NPH) and basal-bolus insulin was associated with lower mean BG compared to basal-bolus insulin alone (very low certainty). Data on NPH insulin vs basal-bolus insulin in hospitalized adults receiving enteral nutrition were inconclusive. Inpatient diabetes education was associated with lower HbA1c at 3 and 6 months after discharge (moderate certainty) and reduced hospital readmissions (very low certainty). Preoperative HbA1c level &lt; 7% was associated with shorter length of stay, lower postoperative BG and a lower number of neurological complications and infections, but a higher number of reoperations (very low certainty). Treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors in hospitalized patients with type 2 diabetes and mild hyperglycemia was associated with lower frequency of hypoglycemic events than insulin therapy (low certainty). Caloric oral fluids before surgery in adults with diabetes undergoing surgical procedures did not affect outcomes (very low certainty). Counting carbohydrates for prandial insulin dosing did not affect outcomes (very low certainty). Compared with scheduled insulin (basal-bolus or basal insulin + correctional insulin), correctional insulin was associated with higher mean daily BG and fewer hypoglycemic events (low certainty).ConclusionThe certainty of evidence supporting many hyperglycemia management decisions is low, emphasizing importance of shared decision-making and consideration of other decisional factors.