Extended Family Outreach in Hereditary Cancer Using Web-Based Genealogy, Direct-to-Consumer Ancestry Genetics, and Social Media: Mixed Methods Process Evaluation of the ConnectMyVariant Intervention.

BACKGROUND: Cascade screening, defined as helping at-risk relatives get targeted genetic testing of familial variants for dominant hereditary cancer syndromes, is a proven component of cancer prevention; however, its uptake is low. We developed and conducted a pilot study of the ConnectMyVariant intervention, in which participants received support to contact at-risk relatives that extended beyond first-degree relatives and encourage relatives to obtain genetic testing and connect with others having the same variant through email and social media. The support that participants received included listening to participants' needs, assisting with documentary genealogy to find common ancestors, facilitating direct-to-consumer DNA testing and interpretation, and assisting with database searches. OBJECTIVE: We aimed to assess intervention feasibility, motivations for participating, and engagement among ConnectMyVariant participants and their families. METHODS: We used a mixed methods design including both quantitative and qualitative evaluation methods. First, we considered intervention feasibility by characterizing recruitment and retention using multiple recruitment mechanisms, including web-based advertising, dissemination of invitations with positive test results, provider recruitment, snowball sampling, and recruitment through web-based social networks and research studies. Second, we characterized participants' motivations, concerns, and engagement through project documentation of participant engagement in outreach activities and qualitative analysis of participant communications. We used an inductive qualitative data analysis approach to analyze emails, free-text notes, and other communications generated with participants as part of the ConnectMyVariant intervention. RESULTS: We identified 84 prospective participants using different recruitment mechanisms; 57 participants were ultimately enrolled in the study for varying lengths of time. With respect to motivations for engaging in the intervention, participants were most interested in activities relating to genealogy and communication with others who had their specific variants. Although there was a desire to find others with the same variant and prevent cancer, more participants expressed an interest in learning about their genealogy and family health history, with prevention in relatives considered a natural side effect of outreach. Concerns about participation included whether relatives would be open to communication, how to go about it, and whether others with a specific variant would be motivated to help find common ancestors. We observed that ConnectMyVariant participants engaged in 6 primary activities to identify and communicate with at-risk relatives: sharing family history, family member testing, direct-to-consumer genealogy genetic testing analysis, contacting (distant) relatives, documentary genealogy, and expanding variant groups or outreach. Participants who connected with others who had the same variant were more likely to engage with several extended family outreach activities. CONCLUSIONS: This study demonstrated that there is an interest in extended family outreach as a mechanism to improve cascade screening for hereditary cancer prevention. Additional research to systematically evaluate the outcomes of such outreach may be challenging but is warranted.

Diagnostic yield of genetic screening in a diverse, community-ascertained cohort.

BACKGROUND: Population screening for genetic risk of adult-onset preventable conditions has been proposed as an attractive public health intervention. Screening unselected individuals can identify many individuals who will not be identified through current genetic testing guidelines. METHODS: We sought to evaluate enrollment in and diagnostic yield of population genetic screening in a resource-limited setting among a diverse population. We developed a low-cost, short-read next-generation sequencing panel of 25 genes that had 98.4% sensitivity and 99.98% specificity compared to diagnostic panels. We used email invitations to recruit a diverse cohort of patients in the University of Washington Medical Center system unselected for personal or family history of hereditary disease. Participants were sent a saliva collection kit in the mail with instructions on kit use and return. Results were returned using a secure online portal. Enrollment and diagnostic yield were assessed overall and across race and ethnicity groups. RESULTS: Overall, 40,857 people were invited and 2889 (7.1%) enrolled. Enrollment varied across race and ethnicity groups, with the lowest enrollment among African American individuals (3.3%) and the highest among Multiracial or Other Race individuals (13.0%). Of 2864 enrollees who received screening results, 106 actionable variants were identified in 103 individuals (3.6%). Of those who screened positive, 30.1% already knew about their results from prior genetic testing. The diagnostic yield was 74 new, actionable genetic findings (2.6%). The addition of more recently identified cancer risk genes increased the diagnostic yield of screening. CONCLUSIONS: Population screening can identify additional individuals that could benefit from prevention, but challenges in recruitment and sample collection will reduce actual enrollment and yield. These challenges should not be overlooked in intervention planning or in cost and benefit analysis.

Iris anomalies and the incidence of ACTA2 mutation.

BACKGROUND: Central cysts of the iris pigment epithelium, or iris flocculi, are frequently reported in the literature in association with thoracic aortic aneurysm and dissection due to smooth muscle alpha-actin 2 (ACTA2) mutations. Children with ACTA2 mutations may also present with congenital mydriasis. We report our experience regarding the frequency of ACTA2 mutation in children with the above iris anomalies. METHODS: This is a retrospective, consecutive case series of all children presenting for iris flocculi or congenital mydriasis at a single tertiary centre from October 2012 to December 2016. RESULTS: 13 children with iris flocculi and 3 with congenital mydriasis presented during the study period. 10 children with iris flocculi completed genetic testing, and none were positive for ACTA2 mutation. All children with congenital mydriasis presented with a multisystem smooth muscle dysfunction syndrome; two of these three children tested positive for missense R179 ACTA2 mutations. CONCLUSIONS: In this series, ACTA2 mutation or copy number variation was not detected in children presenting for iris flocculi, whereas congenital mydriasis was associated with R179 mutation in both cases that tested positive for ACTA2 mutation. The case of congenital mydriasis without typical cardiac features of the R179 ACTA2 phenotype or intracranial vasculopathy was negative for ACTA2 mutation. While all children presenting with these iris anomalies should be offered a genetic evaluation, incidence data should inform genetic counselling, particularly in the absence of a family history of aneurysm or sudden death, or systemic signs of smooth muscle dysfunction.

Syndromic and Systemic Diagnoses Associated With Isolated Sagittal Synostosis.

Reports of systemic associations in patients with Isolated Sagittal Synostosis (ISS) are sparse. Craniofacial surgeons, and other providers, should be aware that a significant proportion of patients with ISS may have syndromic or systemic involvement. This study investigates the incidence of systemic disease and syndromic diagnosis in a cohort of patients presenting with ISS (ie, patients with sagittal synostosis without other sutural involvement). METHODS: This study consists of a retrospective review of patients diagnosed with ISS between 2007 and 2017 at a single institution. Patients were divided according to onset (early <1 year, late >1 year) of ISS. Patient notes were examined for congenital anomalies, systemic conditions, and molecular testing. Only patients with isolated sagittal fusion-meaning, patients with sagittal synostosis and no other sutural involvement-were included. RESULTS: Three hundred seventy-seven patients met the inclusion criteria: systemic conditions were identified in 188/377 (50%) of them. One hundred sixty-one patients with early onset (Group A), and 216 patients with late onset ISS (Group B) were identified. Systemic involvement was identified in 38% of Group A and 60% of Group B, which was statistically significant (P < 0.001). Forty-eight of 377 (13%) of patients had a syndromic diagnosis, and 79% of these were confirmed via genetic testing. Thirty-five percent of patients were diagnosed with central nervous system anomalies and 16% had craniofacial anomalies. CONCLUSIONS: Nearly 50% of the patients initially diagnosed with ISS were found to have some form of systemic involvement. This supports affording full pediatric and genetic evaluation with molecular testing to these children.

Fast-track program vs traditional care in surgery for gastric cancer.

AIM: To systematically review the evidence for the effectiveness of fast-track program vs traditional care in laparoscopic or open surgery for gastric cancer. METHODS: PubMed, Embase and the Cochrane library databases were electronically searched for published studies between January 1995 and April 2013, and only randomized trials were included. The references of relevant studies were manually searched for further studies that may have been missed. Search terms included "gastric cancer", "fast track" and "enhanced recovery". Five outcome variables were considered most suitable for analysis: postoperative hospital stay, medical cost, duration to first flatus, C-reactive protein (CRP) level and complications. Postoperative hospital stay was calculated from the date of operation to the date of discharge. Fixed effects model was used for meta-analysis. RESULTS: Compared with traditional care, fast-track program could significantly decrease the postoperative hospital stay [weighted mean difference (WMD) = -1.19, 95%CI: -1.79--0.60, P = 0.0001, fixed model], duration to first flatus (WMD = -6.82, 95%CI: -11.51--2.13, P = 0.004), medical costs (WMD = -2590, 95%CI: -4054--1126, P = 0.001), and the level of CRP (WMD = -17.78, 95%CI: -32.22--3.35, P = 0.0001) in laparoscopic surgery for gastric cancer. In open surgery for gastric cancer, fast-track program could also significantly decrease the postoperative hospital stay (WMD = -1.99, 95%CI: -2.09--1.89, P = 0.0001), duration to first flatus (WMD = -12.0, 95%CI: -18.89--5.11, P = 0.001), medical cost (WMD = -3674, 95%CI: -5025--2323, P = 0.0001), and the level of CRP (WMD = -27.34, 95%CI: -35.42--19.26, P = 0.0001). Furthermore, fast-track program did not significantly increase the incidence of complication (RR = 1.39, 95%CI: 0.77-2.51, P = 0.27, for laparoscopic surgery; and RR = 1.52, 95%CI: 0.90-2.56, P = 0.12, for open surgery). CONCLUSION: Our overall results suggested that compared with traditional care, fast-track program could result in shorter postoperative hospital stay, less medical costs, and lower level of CRP, with no more complications occurring in both laparoscopic and open surgery for gastric cancer.