Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Changes in breast cancer screening rates among 32 community health centers during the COVID-19 pandemic.

BACKGROUND: Breast cancer screening utilization steeply dropped at the start of the coronavirus disease 2019 (COVID-19) pandemic. However, the effects on breast cancer screening in lower income populations are unknown. This study examined changes in breast cancer screening rates (BCSRs) during the pandemic among 32 community health centers (CHCs) that provided health care to lower income populations. METHODS: Secondary data from 32 CHCs participating in an American Cancer Society grant program to increase breast cancer screening services were used. BCSRs were defined as the percentage of women aged 50 to 74 years who had a medical visit in the past 12 months (142,207 in 2018, 142,003 in 2019, and 150,630 in 2020) and received a screening mammogram within the last 27 months. BCSRs in July 2020, July 2019, and June 2018 were compared with screening rate ratios (SRRs) and corresponding 95% confidence intervals (CIs). RESULTS: BCSRs significantly rose by 18% between 2018 and 2019 (from 45.8% to 53.9%; SRR, 1.18; 95% CI, 1.17-1.18) and then declined by 8% between 2019 and 2020 (from 53.9% to 49.6%; SRR, 0.92; 95% CI, 0.92-0.93). If the 2018-2019 BCSR trends had continued through 2020, 63.3% of women would have been screened in 2020 in contrast to the 49.6% who were; this potentially translated into 47,517 fewer mammograms and 242 missed breast cancer diagnoses in this population. CONCLUSIONS: In this study of 32 CHCs, BCSRs declined by 8% from July 2019 to 2020, and this reversed an 18% improvement between July 2018 and 2019. Declining BCSRs among CHCs during the COVID-19 pandemic call for policies to support and resources to identify women in need of screening.

Using the consolidated framework for implementation research to understand safety net health system efforts to increase colorectal cancer screening rates.

Guided by the Consolidated Framework for Implementation Research (CFIR), this study aimed to identify factors that influence implementation of evidence-based provider and client-oriented strategies to promote colorectal cancer (CRC) screening in safety net health systems. Site visits and key informant interviews (n=33) were conducted with project leaders and staff in five health systems funded by an American Cancer Society grants program. Within- and cross-site analyses identified CFIR constructs that influenced implementation of provider and client-oriented strategies to promote CRC screening through colonoscopies and fecal immunochemical tests. Of the five CFIR domains, constructs within four CFIR domains (inner setting, outer setting, individual characteristics and process domains) were particularly salient in discussions of implementation while constructs within one CFIR domain (characteristics of the intervention) were not. This study provides a detailed description of how facilitating and inhibiting factors influenced the implementation of evidence-based practices related to CRC screening within safety net health systems. These findings can inform future efforts to promote evidence-based strategies to increase CRC screening rates in safety net health systems.

Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening.

PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (χ2=16.98, P<0.001). Overall, informed choice was high in both nonpregnant (77.4%) and pregnant (72.9%) women (χ2=0.21, P=0.644), and more tested (76.0%) than not-tested (66.7%) women (χ2=6.35, P=0.012) made an informed choice. Measures of depression, stress, and anxiety were similar to population norms for ~85% of women. Decisional conflict and regret were generally low; however, decisional uncertainty and regret were greater in pregnant than nonpregnant women, and not-tested than tested women (uncertainty: χ2=18.51, P<0.001 and χ2=43.11, P<0.001, respectively; regret: χ2=6.61, P<0.037 and χ2=35.54, P<0.001, respectively).ConclusionWe provide evidence to inform guidelines that population FXS carrier screening can be implemented with minimal psychosocial harms following appropriate information and prescreening genetic counseling.

Clinical audit of genetic testing and referral patterns for fragile X and associated conditions.

An audit was conducted of laboratory/clinical databases of genetic tests performed between January 2003 and December 2009, and for 2014, as well as referrals to the clinical service and a specialist multidisciplinary clinic, to determine genetic testing request patterns for fragile X syndrome and associated conditions and referrals for genetic counseling/multidisciplinary management in Victoria, Australia. An expanded allele (full mutation, premutation or intermediate) was found in 3.7% of tests. Pediatricians requested ∼70% of test samples, although fewer general practitioners and more obstetricians/gynecologists ordered tests in 2014. Median age at testing for individuals with a full mutation seeking a diagnosis without a fragile X family history was 4.3 years (males) and 9.4 years (females); these ages were lower when pediatricians ordered the tests (2.1 years and 6.1 years, respectively). Individuals with a premutation were generally tested at a later age (median age: males, 33.2 years; females, 36.4 years). Logistic regression showed that a family history of ID (OR 3.28 P = 0.005, CI 1.77-5.98) was the only indication to independently increase the likelihood of a test-positive (FM or PM) result. Following testing, ∼25% of full mutation or premutation individuals may not have attended clinical services providing genetic counseling or multidisciplinary management for these families. The apparent delay in fragile X syndrome diagnosis and lack of appropriate referrals for some may result in less than optimal management for these families. These findings suggest continued need for awareness and education of health professionals around diagnosis and familial implications of fragile X syndrome and associated conditions. © 2016 Wiley Periodicals, Inc.

Self-reported awareness of genetic testing, the impact of family history, and access to clinical trials for people diagnosed with ovarian cancer in Australia.

Objectives: To assess the understanding of people diagnosed with ovarian cancer regarding genetic testing; to understand knowledge gaps among people diagnosed with ovarian cancer that may impact best practice care; and to monitor overall changes in understanding from 2015 to 2022. Design: Longitudinal 'opt-in' study using an online survey tool at three timepoints: 2015, 2018 and 2022. Participants: People in Australia (or their families / caregivers) diagnosed with ovarian cancer between 2010 and 2022). Main outcome measures: Self-reported awareness of heritable risk factors for ovarian cancer, genetic testing approaches and participation in clinical trials. Results: The study indicated that there have been improvements in the understanding and awareness of people diagnosed with ovarian cancer regarding familial risk (an increase from 43.6% (45 of 149) in 2015 to 62.9% (166 of 264) in 2022); but people were less likely to be aware of the difference between somatic (tumour) and germline testing (120 of 266, 45.1%). However, there were self-reported improvements to clinical trial access in non-metropolitan areas (12 of 64, 18.8% in 2022 compared to 22 of 145, 15.2% in 2018), bringing it on par with metropolitan areas (32 of 169, 18.9% in 2022). Conclusions: Despite improved awareness about genetic testing among people diagnosed with ovarian cancer, there remain knowledge gaps in understanding of genetic testing types (germline and somatic) and gene variant targeted therapies; and further work to improve clinical trial awareness and access is required.

Successes and challenges of implementing a lung cancer screening program in federally qualified health centers: a qualitative analysis using the Consolidated Framework for Implementation Research.

In recent years, studies have shown that low-dose computed tomography (LDCT) is a safe and effective way to screen high-risk adults for lung cancer. Despite this, uptake remains low, especially in limited-resource settings. The American Cancer Society (ACS) partnered with two federally qualified health centers and accredited screening facilities on a 2 year pilot project to implement an LDCT screening program. Both sites attempted to develop a referral program and care coordination practices to move patients through the screening continuum and identify critical facilitators and barriers to implementation. Evaluators conducted key informant interviews (N = 46) with clinical and administrative staff, as well as regional ACS staff during annual site visits. The Consolidated Framework for Implementation Research guided our analysis of factors associated with effective implementation and improved screening outcomes. One study site established a sustainable lung screening program, while the other struggled to overcome significant implementation barriers. Increased time spent with patients, disruption to normal workflows, and Medicaid reimbursement policies presented challenges at both sites. Supportive, engaged leaders and knowledgeable champions who provided clear implementation guidance improved staff engagement and were able to train, guide, and motivate staff throughout the intervention. A slow, stepwise implementation process allowed one site's project champions to pilot test new processes and resolve issues before scaling up. This pilot study provides critical insights into the necessary resources and steps for successful lung cancer screening program implementation in underserved settings. Future efforts can build upon these findings and identify and address possible facilitators and barriers to screening program implementation.

Implementation of a Lung Cancer Screening Program in Two Federally Qualified Health Centers.

Using low-dose computed tomography (LDCT) to screen for lung cancer is associated with improved outcomes among eligible current and former smokers (ie, aged 55-77, at least 30-pack-year smoking history, current smoker or former smoker who quit within the past 15 years). However, the overall uptake of LDCT is low, especially in health care settings with limited personnel and financial resources. To increase access to lung cancer screening services, the American Cancer Society partnered with 2 federally qualified health centers (FQHCs) in Tennessee and West Virginia to conduct a pilot project focused on developing and refining the LDCT screening referral processes and practices. Each FQHC was required to partner with an American College of Radiology-designated lung cancer screening center in its area to ensure high-quality patient care. The pilot project was conducted in 2 phases: 6 months of capacity building (January-June 2016) followed by 2 years of implementation (July 2016-June 2018). One site created a sustainable LDCT referral program, and the other site encountered numerous barriers and failed to overcome them. This case study highlights implementation barriers and factors associated with success and improved outcomes in LDCT screening.

State Variation in Low-Dose Computed Tomography Scanning for Lung Cancer Screening in the United States.

BACKGROUND: Annual lung cancer screening (LCS) with low-dose chest computed tomography in older current and former smokers (ie, eligible adults) has been recommended since 2013. Uptake has been slow and variable across the United States. We estimated the LCS rate and growth at the national and state level between 2016 and 2018. METHODS: The American College of Radiology's Lung Cancer Screening Registry was used to capture screening events. Population-based surveys, the US Census, and cancer registry data were used to estimate the number of eligible adults and lung cancer mortality (ie, burden). Lung cancer screening rates (SRs) in eligible adults and screening rate ratios with 95% confidence intervals (CI) were used to measure changes by state and year. RESULTS: Nationally, the SR was steady between 2016 (3.3%, 95% CI = 3.3% to 3.7%) and 2017 (3.4%, 95% CI = 3.4% to 3.9%), increasing to 5.0% (95% CI = 5.0% to 5.7%) in 2018 (2018 vs 2016 SR ratio = 1.52, 95% CI = 1.51 to 1.62). In 2018, several southern states with a high lung-cancer burden (eg, Mississippi, West Virginia, and Arkansas) had relatively low SRs (<4%) among eligible adults, whereas several northeastern states with lower lung cancer burden (eg, Massachusetts, Vermont, and New Hampshire) had the highest SRs (12.8%-15.2%). The exception was Kentucky, which had the nation's highest lung cancer mortality rate and one of the highest SRs (13.7%). CONCLUSIONS: Fewer than 1 in 20 eligible adults received LCS nationally, and uptake varied widely across states. LCS rates were not aligned with lung cancer burden across states, except for Kentucky, which has supported comprehensive efforts to implement LCS.

Integrating evidence-based practices for increasing cancer screenings in safety net health systems: a multiple case study using the Consolidated Framework for Implementation Research.

BACKGROUND: Implementing evidence-based practices (EBPs) to increase cancer screenings in safety net primary care systems has great potential for reducing cancer disparities. Yet there is a gap in understanding the factors and mechanisms that influence EBP implementation within these high-priority systems. Guided by the Consolidated Framework for Implementation Research (CFIR), our study aims to fill this gap with a multiple case study of health care safety net systems that were funded by an American Cancer Society (ACS) grants program to increase breast and colorectal cancer screening rates. The initiative funded 68 safety net systems to increase cancer screening through implementation of evidence-based provider and client-oriented strategies. METHODS: Data are from a mixed-methods evaluation with nine purposively selected safety net systems. Fifty-two interviews were conducted with project leaders, implementers, and ACS staff. Funded safety net systems were categorized into high-, medium-, and low-performing cases based on the level of EBP implementation. Within- and cross-case analyses were performed to identify CFIR constructs that influenced level of EBP implementation. RESULTS: Of 39 CFIR constructs examined, six distinguished levels of implementation. Two constructs were from the intervention characteristics domain: adaptability and trialability. Three were from the inner setting domain: leadership engagement, tension for change, and access to information and knowledge. Engaging formally appointed internal implementation leaders, from the process domain, also distinguished level of implementation. No constructs from the outer setting or individual characteristics domain differentiated systems by level of implementation. CONCLUSIONS: Our study identified a number of influential CFIR constructs and illustrated how they impacted EBP implementation across a variety of safety net systems. Findings may inform future dissemination efforts of EBPs for increasing cancer screening in similar settings. Moreover, our analytic approach is similar to previous case studies using CFIR and hence could facilitate comparisons across studies.