Risk Of Incidental Findings Research Articles

Modeled residual current cancer risk after clinical investigation of a positive multicancer early detection test result.

Positive results of a multi-cancer early detection (MCED) test require confirmatory diagnostic workup. Here, residual current cancer risk (RR) during the process of diagnostic resolution, including situations where the initial confirmatory test does not provide resolution, was modeled. A decision-tree framework was used to model conditional risk in a patient's journey through confirmatory diagnostic options and outcomes. The diagnostic journey assumed that cancer signal detection (a positive MCED test result) had already led to a transition from screening to diagnosis and began with an initial positive predictive value (PPV) from the positive result. Evaluation of a most probable (top) predicted cancer signal origin (CSO) and then a second-most probable predicted CSO followed. Under the assumption that the top- and second-predicted CSOs were each followed by a targeted confirmatory test, the RR was estimated for each subsequent scenario. For an initial MCED test result with typical performance characteristics modeled (PPV, 40%; top-predicted CSO accuracy, 90%), after a negative initial confirmatory test (sensitivity, 70%, 90%, or 100%) the RR ranged from 6% to 20%. A second-predicted CSO (accuracy, 50%), after a negative second confirmatory test, still provided a significant RR (3%-18%) in comparison with the National Institute for Health and Care Excellence-recommended cancer risk threshold warranting investigation in symptomatic individuals (3%). With a 40% PPV for an MCED test and 90% specificity for a confirmatory test, the risk of incidental findings after one or two confirmatory tests was 6% and 12%, respectively. These results may illustrate the impact of a positive MCED test on follow-up decision-making.

PoCUS: Just because we can doesn't mean we should.

PoCUS: Just because we can doesn't mean we should.

Preventive screening for intracranial aneurysms.

BackgroundSubarachnoid hemorrhage from rupture of an intracranial aneurysm (aneurysmal subarachnoid hemorrhage) is a devastating subset of stroke. Since brain damage from the initial hemorrhage is a major cause for the poor outcome after aneurysmal subarachnoid hemorrhage, prevention of aneurysmal subarachnoid hemorrhage has the highest potential to prevent poor outcome from aneurysmal subarachnoid hemorrhage.AimIn this review, we describe the groups at high risk of aneurysmal subarachnoid hemorrhage who may benefit from preventive screening for unruptured intracranial aneurysms followed by preventive treatment of unruptured intracranial aneurysms found. Furthermore, we describe the advantages and disadvantages of screening and advise how to perform counseling on screening.Summary of reviewModeling studies show that persons with two or more affected first-degree relatives with aneurysmal subarachnoid hemorrhage and patients with autosomal dominant polycystic kidney disease (ADPKD) are candidates for screening for unruptured intracranial aneurysms. One modeling study also suggests that persons with only one affected first-degree relative with aneurysmal subarachnoid hemorrhage are also likely candidates for screening. Another group who may benefit from screening are persons ≥35 years who smoke(d) and are hypertensive, given their high lifetime risk of aneurysmal subarachnoid hemorrhage of up to 7%, but the prevalence of unruptured intracranial aneurysms in such persons and the efficiency and cost-effectiveness of screening in this group are not yet known. The ultimate goal of screening is to increase the number of quality years of life of the screening candidates, and therefore the benefits but also many downsides of screening –such as risk of incidental findings, very small unruptured intracranial aneurysms that require regular follow-up, preventive treatment with inherent risk of complications and anxiety – should be discussed with the candidate so that an informed decision can be made before intracranial vessels are imaged.ConclusionsSeveral groups of persons who may benefit from screening have been identified, but since these constitute only a minority of all aneurysmal subarachnoid hemorrhage patients, additional high-risk groups still need to be identified. Further research is also needed to identify persons at low or high risk of aneurysmal development and rupture within the groups identified thus far to improve the efficiency of screening. Moreover, if new medical treatment strategies that can reduce the risk of rupture of unruptured intracranial aneurysm become available, the groups of persons who may benefit from screening could increase considerably.

Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity.

Owing to recent technological advancements, using next-generation sequencing (NGS) and the accumulation of clinical experiences worldwide, more than 420 genes associated with inborn errors of immunity (IEI) have been identified, which exhibit large genotypic and phenotypic variations. Consequently, NGS-based comprehensive genetic analysis, including whole-exome sequencing (WES), have become more valuable in the clinical setting and have contributed to earlier diagnosis, improved treatment, and prognosis. However, these approaches have the following disadvantages that need to be considered: a relatively low diagnostic rate, high cost, difficulties in the interpretation of each variant, and the risk of incidental findings. Thus, the objective of this study is to review our WES results of a large number of patients with IEI and to elucidate patient characteristics, which are related to the positive WES result. We performed WES for 136 IEI patients with negative conventional screening results for candidate genes and classified these variants depending on validity of their pathogenicity. We identified disease-causing pathogenic mutations in 36 (26.5%) of the patients which were found in known IEI-causing genes. Although the overall diagnostic rate was not high and was not apparently correlated with the clinical subcategories and severity, we revealed that earlier onset with longer duration of diseases were associated with positive WES results, especially in pediatric cases. Most of the disease-causing germline mutations were located in the known IEI genes which could be predicted using patients' clinical characteristics. These results may be useful when considering appropriate genetic approaches in the clinical setting.

The Value of Ultrasound Monitoring of Adnexal Masses for Early Detection of Ovarian Cancer.

Although ultrasound has so far been found to be ineffective as a screening tool for ovarian cancer, it is commonly used as a means of evaluating or following ovarian or adnexal masses once they are detected. We review the use of serial ultrasound for the management of adnexal masses and propose an approach to monitoring based on an understanding of the overall risk of cancer among the population in question and an assessment of how the potential benefit of monitoring compares with potential risk. In our approach, masses that are symptomatic, large (>10 cm), associated with an elevated CA 125 level or overt signs of malignancy, or that are determined to have a worrisome appearance by stringent ultrasound criteria should be evaluated surgically. Women with masses that have none of these characteristics should be offered monitoring. Short-term initial ultrasound monitoring carries significant potential benefit in terms of aiding detection of early malignancy and avoidance of unnecessary surgery. However, if a mass remains stable but persistent, the potential benefit of ongoing monitoring wanes with time, whereas the potential harms, in terms of patient anxiety, cost, and the risk of incidental findings and unnecessary surgery increase. Therefore, monitoring of stable lesions should be limited in duration in order to limit potential harms from overtreatment and overdiagnosis.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

Abstract 3879: Patient preferences for disclosure of incidental genetic information discovered through high-throughput sequencing

Abstract INTRODUCTION: Several high throughput next generation sequencing platforms that search for targetable genetic alterations in cancer are now available in the clinic. However, a large number of germline variants may also be detected during testing, some of which may predispose a patient to diseases other than cancer. If, and how, to disclose these incidental genetic findings is controversial. The purpose of this study was to assess patient preferences regarding disclosure of incidental genetic findings. METHODS: We developed a cross-sectional questionnaire study of ambulatory breast oncology patients. Patients completed a 45 item questionnaire, including their disclosure preferences about various hypothetical scenarios of incidental genetic findings found during tumor profiling. Basic descriptive statistics and the proportional odds logistic regression were used for analysis. RESULTS: Of 351 patients approached between February-May 2014, 199 (56%) responded. Participants had a mean age of 55 (29-80), and most were Caucasian (75%), had Stage 0-III disease (61%), were college-educated (53%) and comfortable with basic genetic information (69%). Sixty-eight percent of respondents desired tumor profiling even if they were found to carry a mutation that could cause a disease other than cancer. While 74% initially indicated they would want to know all genetic information found, only 47% of respondents wanted to know about variants of uncertain significance when specifically questioned. Only 12% expressed preference not to learn about a mutation that was potentially heritable. Most patients (82%) preferred to know if they had a mutation that increased their risk of a serious but preventable illness (eg heart disease), but only 57% desired information for mutations that always caused a serious and unpreventable illness (eg Alzheimers dementia). Interestingly, 62% of patients desired tumor profiling even if there was only a 1% chance it would help their treatment, yet 54% endorsed significant concern about the potential risk of incidental findings impacting their ability to obtain health insurance. Ultimately, 59% of respondents indicated that they would agree to undergo tumor profiling if offered by their doctor; Caucasians (OR 4.1, CI 2-8.3) and those with prior knowledge of tumor profiling (OR 2.6, CI 1.3-5.1) were more likely to agree, while cancer stage, treatment, marital status, education, income, family history and other demographic factors were not significant. CONCLUSIONS: A majority of breast cancer patients express interest in pursuing tumor profiling. The potential for incidental genetic findings does not appear to significantly dissuade patients from pursuing this technology, nor does the potential for learning about germline traits that could impact family members. However, there is remarkable variability in disclosure preferences of specific types of incidental findings. Citation Format: Melinda L. Yushak, Sara Bouberhan, Gang Han, Lianne Epstein, Sarah Mougalian, Maysa Abu-Khalaf, Gina Chung, Michael DiGiovanna, Tara Sanft, Lajos Pusztai, Erin Hofstatter. Patient preferences for disclosure of incidental genetic information discovered through high-throughput sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3879. doi:10.1158/1538-7445.AM2015-3879

Low-Dose CT Lung Cancer Screening Practices and Attitudes among Primary Care Providers at an Academic Medical Center.

Low-dose computed tomography (LDCT) screening reduces lung cancer-specific and overall mortality. We sought to assess lung cancer screening practices and attitudes among primary care providers (PCPs) in the era of new LDCT screening guidelines. In 2013, we surveyed PCPs at an academic medical center (60% response) and assessed: lung cancer screening use, perceived screening effectiveness, knowledge of screening guidelines, perceived barriers to LDCT use, and interest in LDCT screening education. Few PCPs (n = 212) reported ordering lung cancer screening: chest X-ray (21%), LDCT (12%), and sputum cytology (3%). Only 47% of providers knew three or more of six guideline components for LDCT screening; 24% did not know any guideline components. In multiple logistic regression analysis, providers who knew three or more guideline components were more likely to order LDCT (OR, 7.1; 95% confidence intervals, 2.0-25.6). Many providers (30%) were unsure of the effectiveness of LDCT. Mammography, colonoscopy, and Pap smear were rated more frequently as effective in reducing cancer mortality compared with LDCT (all P values < 0.0001). Common perceived barriers included patient cost (86.9% major or minor barrier), harm from false positives (82.7%), patients' lack of awareness (81.3%), risk of incidental findings (81.3%), and insurance coverage (80.1%). LDCT lung cancer screening is currently an uncommon practice at an academic medical center. PCPs report ordering chest X-ray, a nonrecommended screening test, more often than LDCT. PCPs had a limited understanding of lung cancer screening guidelines and LDCT effectiveness. Provider educational interventions are needed to facilitate shared decision-making with patients. This study describes some of the first data available about PCPs' use of lung cancer screening tests since the publication of multiple professional guidelines endorsing LDCT. Knowledge gaps were identified that may hinder the uptake of evidence-based lung cancer screening guidelines.

Research participants in NGS studies want to know about incidental findings.

Following the implementation of high-throughput sequencing legal and ethical issues are discussed intensively. The management of incidental findings (IFs) in a research setting have been investigated but there is a lack of literature concerning research participant's perspective. The aim of this study was to investigate whether research participants want disclosure of IFs and what kind of IFs they want to know about. One hundred and twenty-seven research participants in a study of gastrointestinal polyps were informed about whole-exome sequencing and the risk of IFs. They were asked to decide whether they (A) wanted disclosure of IFs no matter whether the variants were associated with a non-treatable or non-preventable condition, (B) wanted disclosure of variants associated with treatable or preventable conditions or (C) wanted no disclosure at all. Participants who wanted disclosure of all the IFs (A) accounted for the majority (n=78), 45 of the participants only wanted disclosure of variants, which could lead to surveillance or treatment (B) and 4 participants did not want IFs to be disclosed at all (C). The study showed that almost all research participants wanted disclosure of at least some types of IFs.

Bad News about Bad News: The Disclosure of Risks to Insurability in Research Consent Processes

One of the phenomena associated with research is “incidental findings,” that is, unexpected findings made during the research, and outside the scope of the research, which have potential health importance. One underappreciated risk of incidental findings is the potential loss of the research subject's insurability; or if a research subject fails to disclose incidental findings when applying for insurance, the insurance contract may be voidable by the insurer. In this article, we seek to explain the insurability risks associated with incidental findings and to make recommendations for how researchers and research ethics committees should address the issue of disclosure of these risks.