Horizon scanning for new genomic tests

PurposeThe development of health-related genomic tests is decentralized and dynamic, involving government, academic, and commercial entities. Consequently, it is not easy to determine which tests are in development, currently available, or discontinued. We developed and assessed the usefulness of a systematic approach to identifying new genomic tests on the Internet.MethodsWe devised targeted queries of Web pages, newspaper articles, and blogs (Google Alerts) to identify new genomic tests. We finalized search and review procedures during a pilot phase that ended in March 2010. Queries continue to run daily and are compiled weekly; selected data are indexed in an online database, the Genomic Applications in Practice and Prevention Finder.ResultsAfter the pilot phase, our scan detected approximately two to three new genomic tests per week. Nearly two thirds of all tests (122/188, 65%) were related to cancer; only 6% were related to hereditary disorders. Although 88 (47%) of the tests, including 2 marketed directly to consumers, were commercially available, only 12 (6%) claimed United States Food and Drug Administration licensure.ConclusionSystematic surveillance of the Internet provides information about genomic tests that can be used in combination with other resources to evaluate genomic tests. The Genomic Applications in Practice and Prevention Finder makes this information accessible to a wide group of stakeholders. Genet Med 2011:13(2):161–165     

Horizon scanning for translational genomic research beyond bench to bedside

PurposeThe dizzying pace of genomic discoveries is leading to an increasing number of clinical applications. In this report, we provide a method for horizon scanning and 1 year data on translational research beyond bench to bedside to assess the validity, utility, implementation, and outcomes of such applications.MethodsWe compiled cross-sectional results of ongoing horizon scanning of translational genomic research, conducted between 16 May 2012 and 15 May 2013, based on a weekly, systematic query of PubMed. A set of 505 beyond bench to bedside articles were collected and classified, including 312 original research articles; 123 systematic and other reviews; 38 clinical guidelines, policies, and recommendations; and 32 articles describing tools, decision support, and educational materials.ResultsMost articles (62%) addressed a specific genomic test or other health application; almost half of these (n = 180) were related to cancer. We estimate that these publications account for 0.5% of reported human genomics and genetics research during the same time.ConclusionThese data provide baseline information to track the evolving knowledge base and gaps in genomic medicine. Continuous horizon scanning of the translational genomics literature is crucial for an evidence-based translation of genomics discoveries into improved health care and disease prevention.Genet Med16 7, 535–538.     

Venous thromboembolism and its prophylaxis in elective knee arthroplasty: An international perspective

IntroductionPatients undergoing knee arthroplasty are at high risk of developing post-operative deep vein thrombosis (DVT) or a pulmonary embolus (PE). Despite best efforts, the best prophylaxis for thromboembolic disease remains controversial. This article aims to update the reader on the newest guidelines concerning venous thromboembolism (VTE) prophylaxis for elective knee arthroplasty, highlighting their inconsistencies and why variations in recommendations exist.MethodsThe Medline database and the Internet were searched for VTE prophylaxis guidelines in English. 12 guidelines were found and compared. The comparison looked at the recommendations made, the grade of recommendation, the level of evidence available for these recommendations and any inconsistencies between the guidelines.ResultsNearly all the guidelines advocate the use of low molecular weight heparin (LMWH) and Fondaparinux. There is little consensus in terms of other recommended drugs, the doses, duration and their recommendation grades. There are marked differences in the methodologies adopted by the different guideline working-groups.ConclusionThere is still uncertainty about the optimal methods of thromboprophylaxis in elective knee arthroplasty. Although there are always going to be disagreements about the endpoints amongst guideline makers, guidelines should achieve uniformity in their reporting of end-points, criteria for levels of evidence and recommendation grades, facilitating the clinician's decision-making process.Level of evidenceIIa.     

FORM: An Australian method for formulating and grading recommendations in evidence-based clinical guidelines

Background  

Clinical practice guidelines are an important element of evidence-based practice. Considering an often complicated body of evidence can be problematic for guideline developers, who in the past may have resorted to using levels of evidence of individual studies as a quasi-indicator for the strength of a recommendation. This paper reports on the production and trial of a methodology and associated processes to assist Australian guideline developers in considering a body of evidence and grading the resulting guideline recommendations.     

Adherence to colonoscopy recommendations for first-degree relatives of young patients diagnosed with colorectal cancer

OBJECTIVES:Colorectal cancer is the third leading cause of cancer death in the United States. The American College of Gastroenterology recommends screening for first-degree relatives of patients diagnosed with colorectal cancer before the age of 50. A colonoscopy is one of the most commonly recommended exams due to its specificity and the possibility to resect pre-malignant lesions. Nevertheless, the rate of physician adherence to this recommendation is unknown.METHODS:This transversal study was performed at a major cancer center in Brazil with 62 patients, aged 18 to 50, who completed a questionnaire on information received from their physicians regarding screening their first-degree relatives. We used the answers from patients who provided explicit consent.RESULTS:Two hundred and three patients were eligible to participate and 93 (45.8%) agreed to complete the questionnaire. Twenty-three questionnaires (24.73%) were returned and 39 were completed by telephone. Of the patients who answered the questionnaire, 39 (62.9%) had received a colonoscopy recommendation for their first-degree relatives and 23 (37.1%) were not informed of the recommendation. Among the patients who received the recommendations, 20.51% affirmed that all relatives completed the exam and 51.28% stated that no relatives completed the exam.DISCUSSION:The adherence rate of our physicians to the ACG guideline recommendations was 62.9%. Considering that our study was performed at a leading center for cancer treatment in Latin America, we had expected better adherence. The results show that adherence to the colorectal cancer screening recommendations for high-risk patients must be improved.     

Making the GRADE in anaphylaxis management: Toward recommendations integrating values,preferences, context,and shared decision making

ObjectiveTo review GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methods and discuss the clinical application of conditional recommendations in clinical guidelines, specifically in the context of anaphylaxis.Data SourcesArticles that described GRADE, evidence synthesis, evidence to recommendation frameworks, and shared decision making were used to discuss conditional recommendations of the 2020 Anaphylaxis GRADE guideline.Study SelectionsA narrative review detailing concepts of GRADE and approaches to translate conditional recommendations to individualized and contextualized patient care.ResultsGRADE methods encourage a nuanced relationship between certainty of evidence and strength of recommendations. Strength of recommendation must incorporate key factors, including the balance between benefits and harms, patient values and preferences, and resource allocation (costs), with equity, feasibility, and acceptability also often included as considerations. GRADE guidelines provide recommendations that are characterized by directionality (for or against) and strength (strong or conditional). A conditional recommendation is tailored to context and primarily applied through a lens of patient preferences related to the likelihood of outcomes of importance and a shared decision-making approach. Although the 2020 Anaphylaxis GRADE guideline better informs the practice of anaphylaxis prevention through (1) identification and mitigation of risk factors for biphasic anaphylaxis and (2) evaluation of the use of glucocorticoid and/or antihistamine pretreatment, all GRADE recommendations, although directional, are conditional and as such should not be universally applied to every circumstance.ConclusionClinical guidelines provide an important opportunity to critically appraise evidence and translate evidence to practice. Patients, practitioners, and policy makers should appreciate the strength of recommendation and certainty of evidence and understand how this affects guideline applicability and implementation.     

Comparative efficacy of lithium and aducanumab for cognitive decline in patients with mild cognitive impairment or Alzheimer’s disease: A systematic review and network meta-analysis

BackgroundIn 2021, the US Food and Drug Administration granted an accelerated approval to aducanumab for patients with mild cognitive impairment (MCI) and mild dementia caused by Alzheimer’s disease (AD); however, the cost of aducanumab is high, at approximately $28,000 for one year per person. On the other hand, lithium is much cheaper at $40 a year, and has been reported to be effective for the cognitive decline observed in both patients with MCI and AD. In contrast to acetylcholinesterase inhibitors and N-methyl D-aspartate receptor antagonists, aducanumab and lithium may be disease-modifying drugs. Therefore, we focused on aducanumab and lithium and compared the effects of these drugs on the cognitive decline in MCI and AD patients using a network meta-analysis.MethodsPubMed, the Cochrane Library, CINHAL, and ClinicalTrials.gov were searched for randomized controlled trials testing lithium or aducanumab for the treatment of cognitive decline in patients with MCI or AD, up to January 31, 2022. A frequentist fixed-effect network meta-analysis was performed to estimate direct and indirect effects. The primary outcome was change scores in cognitive decline measured by Mini-Mental State Examination. This study has been registered with PROSPERO (number CRD42022304807).ResultsNetwork meta-analysis demonstrated that lithium was significantly more effective than aducanumab in the primary outcome.ConclusionAlthough there were various limitations in this study, lithium may be a more cost-effective treatment than aducanumab for MCI and AD.     

Clinical utility of gene-expression profiling in women with early breast cancer: an overview of systematic reviews

PurposeThis overview systematically evaluates the clinical utility of using Oncotype DX and MammaPrint gene-expression profiling tests to direct treatment decisions in women with breast cancer. The findings are intended to inform an updated recommendation from the Evaluation of Genomic Applications in Practice and Prevention Working Group.MethodsEvidence reported in systematic reviews evaluating the clinical utility of Oncotype DX and MammaPrint, as well as the ability to predict treatment outcomes, change in treatment decisions, and cost-effectiveness, was qualitatively synthesized.ResultsFive systematic reviews found no direct evidence of clinical utility for either test. Indirect evidence showed Oncotype DX was able to predict treatment effects of adjuvant chemotherapy, whereas no evidence of predictive value was found for MammaPrint. Both tests influenced a change in treatment recommendations in 21 to 74% of participants. The cost-effectiveness of Oncotype DX varied with the alternative compared. For MammaPrint, lack of evidence of the predictive value led to uncertainty in the cost-effectiveness.ConclusionNo studies were identified that provided direct evidence that using gene-expression profiling tests to direct treatment decisions improved outcomes in women with breast cancer. Three ongoing studies may provide direct evidence for determining the clinical utility of gene-expression profiling testing.Genet Med 17 7, 519–532.     

The economic value of personalized medicine tests: what we know and what we need to know

PurposeThere is uncertainty about when personalized medicine tests provide economic value. We assessed evidence on the economic value of personalized medicine tests and gaps in the evidence base.MethodsWe created a unique evidence base by linking data on published cost–utility analyses from the Tufts Cost-Effectiveness Analysis Registry with data measuring test characteristics and reflecting where value analyses may be most needed: (i) tests currently available or in advanced development, (ii) tests for drugs with Food and Drug Administration labels with genetic information, (iii) tests with demonstrated or likely clinical utility, (iv) tests for conditions with high mortality, and (v) tests for conditions with high expenditures.ResultsWe identified 59 cost–utility analyses studies that examined personalized medicine tests (1998–2011). A majority (72%) of the cost/quality-adjusted life year ratios indicate that testing provides better health although at higher cost, with almost half of the ratios falling below $50,000 per quality-adjusted life year gained. One-fifth of the results indicate that tests may save money.ConclusionMany personalized medicine tests have been found to be relatively cost-effective, although fewer have been found to be cost saving, and many available or emerging medicine tests have not been evaluated. More evidence on value will be needed to inform decision making and assessment of genomic priorities.Genet Med 2014:16(3):251–257     

"Black box" 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk

A prominently displayed boxed warning, the so-called "black box," is added to the labeling of drugs or drug products by the Food and Drug Administration when serious adverse reactions or special problems occur, particularly those that may lead to death or serious injury. Healthcare providers are often not knowledgeable about the origin, meaning, and implications of these "black box" warnings. In this review, our goal is to provide insight into how the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk. We discuss drug labeling, the emphasis on safety throughout the drug approval process, legislative initiatives for safe use of drugs in children, and postmarketing safety surveillance. In addition, we encourage health care providers to report drug reactions to the Food and Drug Administration's MedWatch program. A discussion of new Food and Drug Administration initiatives to improve drug safety processes and methods to serve the public better are highlighted.     

Evidence synthesis and guideline development in genomic medicine: current status and future prospects

PurposeWith the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field.MethodsTo pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report “Clinical Practice Guidelines We Can Trust.”ResultsThe participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence.ConclusionOngoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.Genet Med advance online publication 19 June 2014     

Highly accurate molecular genetic testing for HFE hereditary hemochromatosis: results from 10 years of blinded proficiency surveys by the College of American Pathologists

PurposeThe College of American Pathologists offers blinded proficiency testing (PT) for laboratories performing HFE genetic tests for hereditary hemochromatosis (common C282Y and H63D variants). This study used 10 years of PT data to determine laboratory performance for HFE analytical genotyping and clinical interpretation.MethodsLaboratories were graded for accuracy of genotype determination (six possible C282Y/H63D genotypes) and clinical interpretation regarding whether the genotype was likely to have contributed to iron overload in a hypothetical patient.ResultsThe analytical genotyping error rate was low (0.73%) in 7,663 results (from 257 unique laboratories). Genotyping errors were significantly higher in C282Y heterozygous, H63D homozygous, and C282Y homozygous samples, in non-American laboratories, and in laboratories with lower testing volume. Analytical sensitivity and specificity were >98.5 and >99.5%. The interpretive error rate (4.3%) was higher than the genotyping error rate, with two problematic genotypes (C282Y heterozygous and H63D homozygous) accounting for 77% of total interpretive errors. There was a time-dependent improvement in the interpretation of the clinical significance of HFE genotypes.ConclusionsHFE molecular genetic testing, performed by non–US Food and Drug Administration–approved laboratory-developed tests, demonstrated excellent accuracy, sensitivity, and specificity. Clinical interpretations were more heterogeneous, probably owing to the low clinical penetrance of some common HFE genotypes.Genet Med 18 12, 1206–1213.     

Regulatory changes raise troubling questions for genomic testing

By 6 October 2014, many laboratories in the United States must begin honoring new individual data access rights created by recent changes to federal privacy and laboratory regulations. These access rights are more expansive than has been widely understood and pose complex challenges for genomic testing laboratories. This article analyzes regulatory texts and guidances to explore which laboratories are affected. It offers the first published analysis of which parts of the vast trove of data generated during next-generation sequencing will be accessible to patients and research subjects. Persons tested at affected laboratories seemingly will have access, upon request, to uninterpreted gene variant information contained in their stored variant call format, binary alignment/map, and FASTQ files. A defect in the regulations will subject some non-CLIA-regulated research laboratories to these new access requirements unless the Department of Health and Human Services takes swift action to avert this apparently unintended consequence. More broadly, all affected laboratories face a long list of daunting operational, business, compliance, and bioethical issues as they adapt to this change and to the Food and Drug Administration’s recently announced plan to publish draft guidance outlining a new oversight framework for lab-developed tests.Genet Med16 11, 799–803.     

The Yale Guideline Recommendation Corpus: A representative sample of the knowledge content of guidelines

Objective

To develop and characterize a large, representative sample of guideline recommendations that can be used to better understand how current recommendations are written and to test the adequacy of guideline models. We refer to this sample as the Yale Guideline Recommendation Corpus (YGRC).

Method

To develop the YGRC, we extracted recommendations from guidelines downloaded from the National Guideline Clearinghouse (NGC). We evaluated the representativeness of the YGRC by comparing the frequency of use of controlled vocabulary terms in the YGRC sample and in the NGC. We examined semantic and formatting indicators that were used to denote recommendation statements.

Results

In the course of reviewing 7527 recommendation statements, we extracted 1275 recommendations from the NGC and characterized the guidelines from which they were derived. Both semantic and formatting indicators were used inconsistently to denote recommendations. Recommendation statements were not reliably identifiable in 31.6% (310/982) of the guidelines and many recommendations were not executable as written. We also found variability and inconsistency in the way strength of recommendation is currently reported. Over half of the recommendations (52.7%), did not indicate strength, while 6.5% inaccurately indicated strength.

Conclusion

The YGRC provides a representative sample of current guideline recommendations and demonstrates considerable variability and inconsistency in the way recommendations are written and in the way the recommendation strength is currently reported.     

The Port Clearance Test: Why it is Important to the Clinician

In October 1990, the US Food and Drug Administration (FDA) Center for Devices and Radiological Health Office of Device Evaluation Division of Gastroenterology/Urology and General Use Devices, under the direction of Mr. Tim Ulatowski, published “Guidance on 510(k) Submissions for Implanted Infusion Ports” (Ports). The guidance contains a set of tests that any new implanted infusion port is to pass prior to submission of 510(k) clearance to market applications before clearance is granted. One of