Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants.

We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling. We assessed key outcomes among the first cohort of individuals recruited. Over 14 months, 20,478 participants enrolled, and 14,053 samples were collected. The majority selected at-home sample collection followed by clinical sample collection and collection at community events. Participants were predominately female, White (self-identified), non-Hispanic, and between the ages of 40-49. Participants enrolled through community events were the most racially diverse and the youngest. Half of those enrolled completed the program. We identified 137 individuals with pathogenic or likely pathogenic variants for CDC Tier 1 conditions. The majority (77.4%) agreed to genetic counseling, and of those that agreed, 80.2% completed counseling. Twelve clinics participated, and we conducted 108 collection events. Participants enrolled at home were most likely to return their sample for sequencing. Through this evaluation, we identified facilitators and barriers to implementation of our state-wide PWGS program. Standardized reporting using implementation science frameworks can help generalize strategies and improve the impact of PWGS.

Population screening shows risk of inherited cancer and familial hypercholesterolemia in Oregon.

The Healthy Oregon Project (HOP) is a statewide effort that aims to build a large research repository and influence the health of Oregonians through providing no-cost genetic screening to participants for a next-generation sequencing 32-gene panel comprising genes related to inherited cancers and familial hypercholesterolemia. This type of unbiased population screening can detect at-risk individuals who may otherwise be missed by conventional medical approaches. However, challenges exist for this type of high-throughput testing in an academic setting, including developing a low-cost high-efficiency test and scaling up the clinical laboratory for processing large numbers of samples. Modifications to our academic clinical laboratory including efficient test design, robotics, and a streamlined analysis approach increased our ability to test more than 1,000 samples per month for HOP using only one dedicated HOP laboratory technologist. Additionally, enrollment using a HIPAA-compliant smartphone app and sample collection using mouthwash increased efficiency and reduced cost. Here, we present our experience three years into HOP and discuss the lessons learned, including our successes, challenges, opportunities, and future directions, as well as the genetic screening results for the first 13,670 participants tested. Overall, we have identified 730 pathogenic/likely pathogenic variants in 710 participants in 24 of the 32 genes on the panel. The carrier rate for pathogenic/likely pathogenic variants in the inherited cancer genes on the panel for an unselected population was 5.0% and for familial hypercholesterolemia was 0.3%. Our laboratory experience described here may provide a useful model for population screening projects in other states.

Population Screening in Health Systems.

Applications of genomics to population screening are expanding in the United States and internationally. Many of these programs are being implemented in the context of healthcare systems, mostly in a clinical research setting, but there are some emerging examples of clinical models. This review examines these genomic population screening programs to identify common features and differences in screened conditions, genomic technology employed, approach to results disclosure, health outcomes, financial models, and sustainability. The diversity of approaches provides opportunities to learn and better understand the optimal approach to implementation based on the contextual setting.

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.

Frequency and characteristics of errors by artificial intelligence (AI) in reading screening mammography: a systematic review.

PURPOSE: Artificial intelligence (AI) for reading breast screening mammograms could potentially replace (some) human-reading and improve screening effectiveness. This systematic review aims to identify and quantify the types of AI errors to better understand the consequences of implementing this technology. METHODS: Electronic databases were searched for external validation studies of the accuracy of AI algorithms in real-world screening mammograms. Descriptive synthesis was performed on error types and frequency. False negative proportions (FNP) and false positive proportions (FPP) were pooled within AI positivity thresholds using random-effects meta-analysis. RESULTS: Seven retrospective studies (447,676 examinations; published 2019-2022) met inclusion criteria. Five studies reported AI error as false negatives or false positives. Pooled FPP decreased incrementally with increasing positivity threshold (71.83% [95% CI 69.67, 73.90] at Transpara 3 to 10.77% [95% CI 8.34, 13.79] at Transpara 9). Pooled FNP increased incrementally from 0.02% [95% CI 0.01, 0.03] (Transpara 3) to 0.12% [95% CI 0.06, 0.26] (Transpara 9), consistent with a trade-off with FPP. Heterogeneity within thresholds reflected algorithm version and completeness of the reference standard. Other forms of AI error were reported rarely (location error and technical error in one study each). CONCLUSION: AI errors are largely interpreted in the framework of test accuracy. FP and FN errors show expected variability not only by positivity threshold, but also by algorithm version and study quality. Reporting of other forms of AI errors is sparse, despite their potential implications for adoption of the technology. Considering broader types of AI error would add nuance to reporting that can inform inferences about AI's utility.

Deficient mismatch repair screening of advanced adenomas in the population screening program for colorectal cancer is not effective.

AIM: Currently, screening of colorectal cancers (CRC) by assessing mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is used to identify Lynch syndrome (LS) patients. Advanced adenomas are considered immediate precursor lesions of CRC. In this study we investigate the relevance of screening of advanced adenomas for LS in population screening. METHODS AND RESULTS: Advanced adenomas (n = 1572) were selected from the Dutch colorectal cancer population screening programme, based on one or more of the criteria: tubulovillous (n = 848, 54%) or villous adenoma (n = 118, 7.5%), diameter ≥ 1 cm (n = 1286, 82%) and/or high-grade dysplasia (n = 176, 11%). In 86 cases (5%), all three criteria were fulfilled at the same time. MMR-IHC and/or MSI analyses were performed on all cases. Only five advanced adenomas (0.3%) showed dMMR and MSI, including two cases with hypermethylation. In at least two patients a germline event was suspected based on allelic frequencies. No pathogenic explanation was found in the last case. CONCLUSION: Timely testing of precursor lesions would be preferable to detect new LS patients before CRC development. However, standard assessment of dMMR of advanced adenomas from the population screening is not effective.

Population-based BRCA germline mutation screening in the Han Chinese identifies individuals at risk of BRCA mutation-related cancer: experience from a clinical diagnostic center from greater Shanghai area.

BACKGROUND: Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group. METHODS: We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers. RESULTS: Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months). CONCLUSION: The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.

Editor's Choice - Systematic Review and Meta-Analysis of Contemporary Abdominal Aortic Aneurysm Growth Rates.

OBJECTIVE: To evaluate the contemporary growth rate of small abdominal aortic aneurysms (AAAs) in view of recent epidemiological changes, such as decreasing smoking rates and establishment of population screening programmes. DATA SOURCES: MEDLINE, CENTRAL, PsycINFO, Web of Science Core Collection, and OpenGrey databases. REVIEW METHODS: Systematic review following the PRISMA guidelines. In October 2021, databases were queried for studies reporting on AAA growth rates published from 2015 onwards. The primary outcome was contemporary AAA growth rates in mm/year. Data were pooled in a random effects model meta-analysis, and heterogeneity was assessed through the I2 statistic. GRADE assessment of the findings was performed. The protocol was published in PROSPERO (CRD42022297404). RESULTS: Of 8 717 titles identified, 43 studies and 28 277 patients were included: 1 241 patients from randomised controlled trials (RCTs), 23 941 from clinical observational studies, and 3 095 from radiological or translational research studies. The mean AAA growth rate was 2.38 mm/year (95% CI 2.16 - 2.60 mm/year; GRADE = low), with meta-regression analysis adjusted for baseline diameter showing an increase of 0.08 mm/year (95% CI 0.024 - 0.137 mm/year; p = .005) for each millimetre of increased baseline diameter. When analysed by study type, the growth rate estimated from RCTs was 1.88 mm/year (95% CI 1.69 - 2.06 mm/year; GRADE = high), while it was 2.31 mm/year (95% CI 1.95 - 2.67 mm/year; GRADE = moderate) from clinical observational studies, and 2.85 mm/year (95% CI 2.44 - 3.26 mm/year; GRADE = low) from translational and radiology based studies (p < .001). Heterogeneity was high, and small study publication bias was present (p = .003), with 27 studies presenting a moderate to high risk of bias. The estimated growth rate from low risk studies was 2.09 mm/year (95% CI 1.87 - 2.32; GRADE = high). CONCLUSION: This study estimated a contemporaneous AAA growth rate of 2.38 mm/year, being unable to demonstrate any clinically meaningful AAA growth rate reduction concomitant with changed AAA epidemiology. This suggests that the RESCAN recommendations on small AAA surveillance are still valid. However, sub-analysis results from RCTs and high quality study data indicate potential lower AAA growth rates of 1.88 - 2.09 mm/year, findings that should be validated in a high quality prospective registry.

Breast cancer screening and early diagnosis in China: a systematic review and meta-analysis on 10.72 million women.

BACKGROUND: The incidence of breast cancer among Chinese women has gradually increased in recent years. This study aims to analyze the situation of breast cancer screening programs in China and compare the cancer detection rates (CDRs), early-stage cancer detection rates (ECDRs), and the proportions of early-stage cancer among different programs. METHODS: We conducted a systematic review and meta-analysis of studies in multiple literature databases. Studies that were published between January 1, 2010 and June 30, 2023 were retrieved. A random effects model was employed to pool the single group rate, and subgroup analyses were carried out based on screening model, time, process, age, population, and follow-up method. RESULTS: A total of 35 studies, including 47 databases, satisfied the inclusion criteria. Compared with opportunistic screening, the CDR (1.32‰, 95% CI: 1.10‰-1.56‰) and the ECDR (0.82‰, 95% CI: 0.66‰-0.99‰) were lower for population screening, but the proportion of early-stage breast cancer (80.17%, 95% CI: 71.40%-87.83%) was higher. In subgroup analysis, the CDR of population screening was higher in the urban group (2.28‰, 95% CI: 1.70‰-2.94‰), in the breast ultrasonography (BUS) in parallel with mammography (MAM) group (3.29‰, 95% CI: 2.48‰-4.21‰), and in the second screening follow-up group (2.47‰, 95% CI: 1.64‰-3.47‰), and the proportion of early-stage breast cancer was 85.70% (95% CI: 68.73%-97.29%), 88.18% (95% CI: 84.53%-91.46%), and 90.05% (95% CI: 84.07%-94.95%), respectively. CONCLUSION: There were significant differences between opportunistic and population screening programs. The results of these population screening studies were influenced by the screening process, age, population, and follow-up method. In the future, China should carry out more high-quality and systematic population-based screening programs to improve screening coverage and service.

Preferences for Peer Support Amongst Families Engaged in Paediatric Screening Programmes: The Perspectives of Parents Involved in Screening for Type 1 Diabetes in Children Aged 3-13.

INTRODUCTION: This work describes a secondary analysis of a qualitative data set originally used to understand parent participants' preferences for the design and implementation of a screening programme for paediatric Type 1 diabetes (T1D). From this, their spontaneous preferences for peer support emerged, described here in the context of existing peer support programmes for the newly diagnosed alongside suggestions for their incorporation into screening programmes for T1D and a range of other conditions. METHODS: Data were collected from semi-structured interviews conducted with parents of children aged 3-13 years to explore their expectations, perceptions and preferences of a T1D paediatric screening programme. A secondary analysis of interviews from participants who spontaneously raised preferences for peer support was used to populate a novel framework informed by NHS England's key principles for the same, namely, Shared experiences and reciprocated support, Accessibility and inclusivity and Person-centred and integrated peer support. RESULTS: Parents in 29 of 33 interviews spontaneously described the potential value of peer support if receiving a result indicating a positive (presymptomatic T1D result) from a screening programme. Specifically, the value of 'Shared experiences and reciprocated support' in terms of emotional support and reassurance, and access to more directly interpretable and relevant information related to the condition; 'Accessibility and inclusivity' relating to access to a community of similar individuals, whether in person or online; 'Person-centred and integrated peer-support' and the need for support reflecting the changing need of the child and the integration of peer support with clinical care. CONCLUSIONS: The needs of peer support described by parents involved in T1D paediatric screening appear to be shared with those of families with children diagnosed with a range of life-altering conditions. Although the needs of peer support for paediatric screening may differ across conditions, our findings are a valuable starting point for its design both in T1D and other examples of similar population screening programmes. PATIENT OR PUBLIC CONTRIBUTION: Patients and the public have been involved throughout the design of the ELSA study and have worked with us to inform the study process. They contributed to the design and content of patient-facing materials, the content of our topic guides and the analysis and interpretation of our findings.

New-onset atrial fibrillation prediction: the HARMS2-AF risk score.

AIMS: Lifestyle risk factors are a modifiable target in atrial fibrillation (AF) management. The relative contribution of individual lifestyle risk factors to AF development has not been described. Development and validation of an AF lifestyle risk score to identify individuals at risk of AF in the general population are the aims of the study. METHODS AND RESULTS: The UK Biobank (UKB) and Framingham Heart Study (FHS) are large prospective cohorts with outcomes measured >10 years. Incident AF was based on International Classification of Diseases version 10 coding. Prior AF was excluded. Cox proportional hazards regression identified independent AF predictors, which were evaluated in a multivariable model. A weighted score was developed in the UKB and externally validated in the FHS. Kaplan-Meier estimates ascertained the risk of AF development. Among 314 280 UKB participants, AF incidence was 5.7%, with median time to AF 7.6 years (interquartile range 4.5-10.2). Hypertension, age, body mass index, male sex, sleep apnoea, smoking, and alcohol were predictive variables (all P < 0.001); physical inactivity [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.96-1.05, P = 0.80] and diabetes (HR 1.03, 95% CI 0.97-1.09, P = 0·38) were not significant. The HARMS2-AF score had similar predictive performance [area under the curve (AUC) 0.782] to the unweighted model (AUC 0.802) in the UKB. External validation in the FHS (AF incidence 6.0% of 7171 participants) demonstrated an AUC of 0.757 (95% CI 0.735-0.779). A higher HARMS2-AF score (≥5 points) was associated with a heightened AF risk (score 5-9: HR 12.79; score 10-14: HR 38.70). The HARMS2-AF risk model outperformed the Framingham-AF (AUC 0.568) and ARIC (AUC 0.713) risk models (both P < 0.001) and was comparable to the CHARGE-AF risk score (AUC 0.754, P = 0.73). CONCLUSION: The HARMS2-AF score is a novel lifestyle risk score which may help identify individuals at risk of AF in the general community and assist population screening.

Routine transabdominal cervical length screening in mid-pregnancy for the prevention of preterm birth: Is it good enough to use as a screening test?

BACKGROUND: Preterm birth (PTB) is a major pregnancy complication. There is evidence that a short cervical length in mid-pregnancy may predict women at increased risk of PTB. AIMS: To evaluate the utility of population-based, transabdominal cervical length (TACL) measurement screening in mid-pregnancy for PTB prediction in women. MATERIALS AND METHODS: A transabdominal approach was initially performed, with a transvaginal (TVCL) approach offered when the TACL was <35 mm, could not be accurately measured, or the pregnancy had risk factors for PTB. TACL was compared to the directly related TVCL, when both were performed at the same assessment. Women with risk factors of PTB were included when they had both TACL and TVCL measurements performed at the same visit. RESULTS: Data were provided for 9355 singleton pregnancies from 13 participating imaging centres. A transabdominal approach was used in 9006 (96.3%), including 682 (7.3%) TVCL combined with TACL. There were 349 (3.7%) women who had TVCL only. The median TACL was longer (40 mm) than the TVCL (38 mm). In 682 paired TACL and TVCL measurements, TACL <35 mm correctly identified 96.2% of pregnancies with TVCL <25 mm, compared with 65.4% of cases when using a TACL <30 mm. A TVCL <25 mm occurred in 59 (0.6%) women. A TACL <35 mm was associated with birth <37 weeks of gestation in 12.1% of women and birth <32 weeks of gestation in 3.9%. CONCLUSIONS: Universal TACL is a feasible option for population screening of cervical length in a low-risk population, progressing to TVCL if the TACL is <35 mm or the cervix cannot be transabdominally accurately measured.

Population Screening for Inherited Predisposition to Breast and Ovarian Cancer.

The discovery of genes underlying inherited predisposition to breast and ovarian cancer has revolutionized the ability to identify women at high risk for these diseases before they become affected. Women who are carriers of deleterious variants in these genes can undertake surveillance and prevention measures that have been shown to reduce morbidity and mortality. However, under current strategies, the vast majority of women carriers remain undetected until they become affected. In this review, we show that universal testing, particularly of the BRCA1 and BRCA2 genes, fulfills classical disease screening criteria. This is especially true for BRCA1 and BRCA2 in Ashkenazi Jews but is translatable to all populations and may include additional genes. Utilizing genetic information for large-scale precision prevention requires a paradigmatic shift in health-care delivery. To address this need, we propose a direct-to-patient model, which is increasingly pertinent for fulfilling the promise of utilizing personal genomic information for disease prevention.

VUS: Variant of uncertain significance or very unclear situation?

The advancements in population screening, including newborn screening, enables the identification of disease-causing variants and timely initiation of treatment. However, screening may also identify mild variants, non-disease variants, and variants of uncertain significance (VUS). The identification of a VUS poses a challenge in terms of diagnostic uncertainty and confusion. X-linked adrenoleukodystrophy (ALD) serves as an illustrative example of this complex issue. ALD is a monogenic neurometabolic disease with a complex clinical presentation and a lack of predictive tests for clinical severity. Despite the success of ALD newborn screening, a significant proportion (62%) of missense variants identified through newborn screening exhibit uncertainty regarding their pathogenicity. Resolving this issue requires ongoing efforts to accurately classify variants and refine screening protocols. While it is undisputable that ALD newborn screening greatly benefits boys with the disease, the identification of VUS underscores the need for continuous research and collaboration in improving screening practices.

Incidental findings in the bowel cancer population screening program: other polyps and malignancies - A nationwide study.

The introduction of bowel cancer population screening programs has had a profound impact on gastrointestinal pathology. While the focus is mainly on quality assurance of diagnoses relevant for the outcome of these programs (colorectal cancer and its precursors), incidental findings are increasingly diagnosed. The incidence of such findings is largely unknown. Therefore, we investigated the incidence of incidental findings within the national screening program of the Netherlands. From the Dutch nationwide pathology databank (PALGA), we retrieved all histological diagnoses of patients participating in the national bowel cancer screening program from the start in 2014 until 1/1/2021. Descriptive statistics were used. During these 7 years, in total 9407 other polyps and malignancies (262 per 10,000 colonoscopies) were diagnosed. The majority (65%) were classified as inflammatory polyps. The most common malignancies were neuroendocrine tumours (n = 198, 6 per 10,000 colonoscopies); less common were lymphomas (n = 64) and metastases (n = 33). Mesenchymal polyps, such as leiomyomas and lipomas, were relatively common (27 and 16 per 10,000 colonoscopies, respectively), in comparison with neural polyps such as perineuriomas, ganglioneuromas, and neurofibromas (respectively 3, 2, and 1 per 10,000 colonoscopies). This is the largest study into the incidence of nonconventional colorectal polyps and malignancies in a homogeneous cohort of asymptomatic patients. Several of these diagnoses may have consequences for treatment and follow-up, in particular the malignancies and detection of patients with hereditary cancer syndromes.

1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants.

BACKGROUND: The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders. RESULTS: We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis. CONCLUSION: A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9-1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account.

Implementation of a Population-Based Cancer Family History Screening Program for Lynch Syndrome.

OBJECTIVES: Lynch syndrome increases risks for colorectal and other cancers. Though published Lynch syndrome cancer risk-management guidelines are effective for risk-reduction, the condition remains under-recognized. The Cancer Genetics Program at an academic medical center implemented a population-based cancer family history screening program, Detecting Unaffected Individuals with Lynch syndrome, to aid in identification of individuals with Lynch syndrome. METHODS: In this retrospective cohort study, simple cancer family history screening questionnaires were used to identify those at risk for Lynch syndrome. Program navigators triaged and educated those who screened positive about hereditary cancer, and genetic counseling and testing services, offering genetic counseling if eligible. Genetic counseling was provided primarily via telephone. Genetic counselors performed hereditary cancer risk assessment and offered genetic testing via hereditary cancer panels to those eligible. Remote service delivery models via telephone genetic counseling and at-home saliva testing were used to increase access to medical genetics services. RESULTS: This program screened 212,827 individuals, over half of whom were considered underserved, and identified 133 clinically actionable genetic variants associated with hereditary cancer. Of these, 47 (35%) were associated with Lynch syndrome while notably, 70 (53%) were not associated with hereditary colorectal cancer. Of 3,344 patients offered genetic counseling after initial triage, 2,441 (73%) elected to schedule the appointment and 1,775 individuals (73%) completed genetic counseling. Among underserved patients, telephone genetic counseling completion rates were significantly higher than in-person appointment completion rates (P < .05). While remote service delivery improved appointment completion rates, challenges with genetic test completion using at-home saliva sample collection kits were observed, with 242 of 1592 individuals (15%) not completing testing. CONCLUSION: Population-based cancer family history screening and navigation can help identify individuals with hereditary cancer syndromes across diverse patient populations, but logistics of certain downstream service delivery models can impact outcomes.

Absence of NOTCH1 mutation and presence of CDKN2A deletion predict progression of esophageal lesions.

Currently, surveillance for esophageal squamous cell carcinoma (ESCC) runs a risk of underestimation of early lesions which show absence of iodine staining, with no or only mild histologic changes. The development of molecular markers that indicate risk of progression is thus warranted. We performed whole-exome sequencing on biopsies from two sequential endoscopies of a single esophageal lesion and matching blood samples. There were 27 pairs of age-, gender-, pathologic stage-, and sampling interval-matched progressors and non-progressors identified in a prospective community-based ESCC screening trial. Putative molecular progression markers for ESCC were first evaluated by comparing somatic mutation, copy number alteration (CNA), and mutational signature information among progressors and non-progressors. These markers were then validated with another 24 pairs of matched progressors and non-progressors from the same population using gene alteration status identified by target sequencing and quantitative PCR. Progressors had more somatic mutation and CNA burden, as well as apolipoprotein B mRNA editing catalytic polypeptide-like and age-related signature weights compared with non-progressors. A gene score consisting of somatic NOTCH1 mutation and CDKN2A deletion is predictive of risk of progression in lesions which show absence of iodine staining under endoscopy but have no or only mild dysplasia. This gene score was also validated in an external cohort of matched progressors and non-progressors. Absence of NOTCH1 mutation and presence of CDKN2A deletion are markers of progression in squamous lesions of the esophagus. This gene score would be an ideal indicator for assisting the pathologist in the identification of high-risk individuals who could be potentially 'missed' or subject to a risk underestimation by histologic analysis, and might improve the performance of ESCC surveillance. © 2022 The Pathological Society of Great Britain and Ireland.

Use of novel artificial intelligence computer-assisted detection (AI-CAD) for screening mammography: an analysis of 17,884 consecutive two-view full-field digital mammography screening exams.

BACKGROUND: Novel artificial intelligence computer-assisted detection (AI-CAD) systems based on deep learning (DL) promise to support screen reading. PURPOSE: To test a DL-AI-CAD system compared to human reading on consecutive screening mammograms. MATERIAL AND METHODS: In this retrospective study, 17,884 consecutive anonymized screening mammograms, double-read from January to November 2018, were processed by the DL-AI-CAD system. AI-CAD reading was considered positive if the AI-CAD case scores exceeded 30 (range = 1-100) and the lesion was correctly marked. Likewise, human reading (R1 or R2, respectively) was considered positive if the lesion was correctly identified and called. Receiver operating characteristic (ROC) analysis was performed and accuracy data were calculated. Ground truth for benign lesions: absence of malignancy after cancer registry matching (2022); for malignancy: histopathologic proof; evaluation was patient-based. RESULTS: In total, 114 screen-detected and 17 interval cancers (ICA) occurred. ROC analysis of screen-detected cancers yielded an AUC of 89% for AI-CAD. Sensitivity/specificity was 81.7%/80.2% for AI-CAD; 77.1%/91.7% for R1; 78.6/91.6% for R2. Combining each human reading with AI-CAD was as sensitive as human double-reading (all approximately 88%), but less specific (approximately 75%) compared to human double-reading (approximately 87%). These AI-CAD combinations required consensus readings for twice as many cases as the human combination. Four of 17 ICA exceeded a case score of 30; two of four CAD correctly marked the quadrant of the subsequent ICA. CONCLUSION: Including ICA cases, this AI-CAD achieved comparable sensitivity to human reading at lower specificity. Combining human reading and AI-CAD allows increasing sensitivity compared to single-reading.

Expanded carrier screening for reproductive risk assessment: An evidence-based practice guideline from the National Society of Genetic Counselors.

Expanded carrier screening (ECS) intends to broadly screen healthy individuals to determine their reproductive chance for autosomal recessive (AR) and X-linked (XL) conditions with infantile or early-childhood onset, which may impact reproductive management (Committee Opinion 690, Obstetrics and Gynecology, 2017, 129, e35). Compared to ethnicity-based screening, which requires accurate knowledge of ancestry for optimal test selection and appropriate risk assessment, ECS panels consist of tens to hundreds of AR and XL conditions that may be individually rare in various ancestries but offer a comprehensive approach to inherited disease screening. As such, the term "equitable carrier screening" may be preferable. This practice guideline provides evidence-based recommendations for ECS using the GRADE Evidence to Decision framework (Guyatt et al., BMJ, 2008, 336, 995; Guyatt et al., BMJ, 2008, 336, 924). We used evidence from a recent systematic evidence review (Ramdaney et al., Genetics in Medicine, 2022, 20, 374) and compiled data from peer-reviewed literature, scientific meetings, and clinical experience. We defined and prioritized the outcomes of informed consent, change in reproductive plans, yield in identification of at-risk carrier pairs/pregnancies, perceived barriers to ECS, amount of provider time spent, healthcare costs, frequency of severely/profoundly affected offspring, incidental findings, uncertain findings, patient satisfaction, and provider attitudes. Despite the recognized barriers to implementation and change in management strategies, this analysis supported implementation of ECS for these outcomes. Based upon the current level of evidence, we recommend ECS be made available for all individuals considering reproduction and all pregnant reproductive pairs, as ECS presents an ethnicity-based carrier screening alternative which does not rely on race-based medicine. The final decision to pursue carrier screening should be directed by shared decision-making, which takes into account specific features of patients as well as their preferences and values. As a periconceptional reproductive risk assessment tool, ECS is superior compared to ethnicity-based carrier screening in that it both identifies more carriers of AR and XL conditions as well as eliminates a single race-based medical practice. ECS should be offered to all who are currently pregnant, considering pregnancy, or might otherwise biologically contribute to pregnancy. Barriers to the broad implementation of and access to ECS should be identified and addressed so that test performance for carrier screening will not depend on social constructs such as race.