Best practices for data management and sharing in experimental biomedical research.

Effective data management is crucial for scientific integrity and reproducibility, a cornerstone of scientific progress. Well-organized and well-documented data enable validation and building on results. Data management encompasses activities including organization, documentation, storage, sharing, and preservation. Robust data management establishes credibility, fostering trust within the scientific community and benefiting researchers' careers. In experimental biomedicine, comprehensive data management is vital due to the typically intricate protocols, extensive metadata, and large datasets. Low-throughput experiments, in particular, require careful management to address variations and errors in protocols and raw data quality. Transparent and accountable research practices rely on accurate documentation of procedures, data collection, and analysis methods. Proper data management ensures long-term preservation and accessibility of valuable datasets. Well-managed data can be revisited, contributing to cumulative knowledge and potential new discoveries. Publicly funded research has an added responsibility for transparency, resource allocation, and avoiding redundancy. Meeting funding agency expectations increasingly requires rigorous methodologies, adherence to standards, comprehensive documentation, and widespread sharing of data, code, and other auxiliary resources. This review provides critical insights into raw and processed data, metadata, high-throughput versus low-throughput datasets, a common language for documentation, experimental and reporting guidelines, efficient data management systems, sharing practices, and relevant repositories. We systematically present available resources and optimal practices for wide use by experimental biomedical researchers.

Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Comparative analysis of the minimal information for studies of extracellular vesicles guidelines: Advancements and implications for extracellular vesicle research.

In 2014, the International Society for Extracellular Vesicles (ISEV) introduced the Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines to establish standards for extracellular vesicle (EV) research. These guidelines aimed to enhance reliability and reproducibility, addressing the expanding field of EV science. EVs, membrane-bound particles released by cells, play crucial roles in intercellular communication and are potential biomarkers for various conditions. Over the years, the EV landscape witnessed a surge in publications, emphasizing their roles in cancer and immune modulation. In response, the MISEV guidelines underwent evolution, leading to the MISEV2018 update. This version, generated through community outreach, provided a comprehensive framework for EV research methodologies, emphasizing separation, characterization, reporting standards, and community engagement. The MISEV2018 guidelines reflected responsiveness to feedback, acknowledging the evolving EV research landscape. The guidelines served as a testament to the commitment of the scientific community to rigorous standards and the collective discernment of experts. The present article compares previous MISEV guidelines with its 2023 counterpart, highlighting advancements, changes, and impacts on EV research standardization. The 2023 guidelines build upon the 2018 principles, offering new recommendations for emerging areas. This comparative exploration contributes to understanding the transformative journey in EV research, emphasizing MISEV's pivotal role and the scientific community's adaptability to challenges.

Update in Adult Transgender Medicine.

Transgender people often face barriers in health care due to lack of access to care, lack of knowledgeable healthcare professionals, discrimination, and gaps in medical and mental health research. Existing research on transgender health has focused heavily on mental health, HIV/AIDS, sexually transmitted diseases/infections, and substance abuse. Gender-affirming hormone therapy and/or surgery allows for some alignment of biology and gender identity. Gender-affirming care may offer quality-of-life benefits, which may outweigh modest concerns related to exogenous hormone therapy. The Endocrine Society treatment guidelines were revised in 2017, and this article reviews recent data that might inform a future guideline revision. Future longitudinal research is needed to close the gap in knowledge in the field of transgender medicine.

Using the PharmCAT tool for Pharmacogenetic clinical decision support.

Here, we will provide our insights into the usage of PharmCAT as part of a pharmacogenetic clinical decision support pipeline, which addresses the challenges in mapping clinical dosing guidelines to variants to be extracted from genetic datasets. After a general outline of pharmacogenetics, we describe some features of PharmCAT and how we integrated it into a pharmacogenetic clinical decision support system within a clinical information system. We conclude with promising developments regarding future PharmCAT releases.

Integration of a polygenic score into guideline-recommended prediction of cardiovascular disease.

BACKGROUND AND AIMS: It is not clear how a polygenic risk score (PRS) can be best combined with guideline-recommended tools for cardiovascular disease (CVD) risk prediction, e.g. SCORE2. METHODS: A PRS for coronary artery disease (CAD) was calculated in participants of UK Biobank (n = 432 981). Within each tenth of the PRS distribution, the odds ratios (ORs)-referred to as PRS-factor-for CVD (i.e. CAD or stroke) were compared between the entire population and subgroups representing the spectrum of clinical risk. Replication was performed in the combined Framingham/Atherosclerosis Risk in Communities (ARIC) populations (n = 10 757). The clinical suitability of a multiplicative model 'SCORE2 × PRS-factor' was tested by risk reclassification. RESULTS: In subgroups with highly different clinical risks, CVD ORs were stable within each PRS tenth. SCORE2 and PRS showed no significant interactive effects on CVD risk, which qualified them as multiplicative factors: SCORE2 × PRS-factor = total risk. In UK Biobank, the multiplicative model moved 9.55% of the intermediate (n = 145 337) to high-risk group increasing the individuals in this category by 56.6%. Incident CVD occurred in 8.08% of individuals reclassified by the PRS-factor from intermediate to high risk, which was about two-fold of those remained at intermediate risk (4.08%). Likewise, the PRS-factor shifted 8.29% of individuals from moderate to high risk in Framingham/ARIC. CONCLUSIONS: This study demonstrates that absolute CVD risk, determined by a clinical risk score, and relative genetic risk, determined by a PRS, provide independent information. The two components may form a simple multiplicative model improving precision of guideline-recommended tools in predicting incident CVD.

Revised Swedish infant feeding guidelines are associated with earlier introduction of allergenic foods.

BACKGROUND: Randomized controlled trials have demonstrated that early introduction of allergenic foods, such as peanut and egg, can reduce food allergy in high-risk children. Many international guidelines recommend introduction of allergenic foods in the first year of life, and accordingly, the Swedish National Food agency released updated guidelines in June 2019. OBJECTIVE: Our aim was to examine whether the age at introduction and consumption frequency of allergenic foods have changed since release of the revised national guidelines on the introduction of solid foods in Sweden. METHODS: Children born between June 2016 and December 2018 (n = 1925) were compared with children born between June 2019 and April 2021 (n = 1761) by using data from the NorthPop Birth Cohort study. Data on food introduction, eczema, and food allergy were prospectively collected until age 18 months by using web-based questionnaires. IgE sensitization was assessed at 18 age months. RESULTS: The proportion of participants who had been introduced to egg, legume, soy products, peanut, almond, and cashew nut during the first year of life increased after implementation of the revised national guidelines. The most significant changes were seen for legume (from 55.2% to 69.8% [adjusted odds ratio = 1.90 (95% CI = 1.62-2.24)]) and peanut (from 29.2% to 43.2% adjusted odds ratio = 1.87 (95% CI = 1.55-2.24)]); consumption frequency had also increased. No differences in the prevalence of eczema, food allergy, or sensitization to the foods of interest were found. CONCLUSION: Since release of the revised guidelines, infants in the general population are introduced to and consume a variety of allergenic foods earlier and more frequently; however, early manifestations of allergic disease have remained unchanged.

Is the assessment of asthma treatment efficacy sufficiently comprehensive?

The goal of asthma guideline therapy is to achieve disease control, by minimizing impairment and decreasing the risk of exacerbations and adverse effects of the disease and its treatment. The primary objective of most clinical trials of biologics for severe asthma is a reduction in exacerbation rate. Recently, studies with patients at the lower guideline steps have also selected exacerbation reduction as a primary objective. These trials in patients with milder disease frequently demonstrate statistically significantly fewer exacerbations, but their power calculations reflect larger sample size and smaller effect size. Exacerbations have a precise consensus definition, although a minimal clinically important difference has not been established. Reduction of exacerbations in severe asthma is commonly 10-fold greater than in mild disease. Further, reduction in exacerbations is not always associated with reduced impairment. If superior control is the objective, both domains should demonstrate consistent and parallel improvement. The disconnect may reflect the need for alternative tools for measurement of impairment or, possibly, different therapeutic mechanisms of action. Determining response to biologics or discussion of disease remission requires assessing symptoms that may occur daily rather than focusing on exacerbations that occur once or twice a year for patients at the highest steps of care according to the guidelines.

Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. METHODS: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. RESULTS: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. CONCLUSIONS: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.

In Support of Breast-/Chestfeeding by People With HIV in High-Income Settings.

Given that HIV can be transmitted through breastfeeding, historically, breastfeeding among women with HIV in the US and other resource-rich settings was discouraged. Formula feeding was the mandated feeding option out of concern for breast-milk transmission of HIV, which occurred in 16-24% of cases pre-antiretroviral therapy (pre-ART) use. In January 2023, the US Department of Health and Human Services' Perinatal Guidelines were revised to support shared decision-making for infant feeding choices. Updated clinical trials' data from resource-limited settings suggest the actual breastmilk HIV transmission rate in the context of maternal ART or neonatal postexposure prophylaxis is 0.3-1%. High-income countries are reporting more people with HIV breastfeeding their infants without cases of HIV transmission. We present the reasons for fully embracing breast-/chestfeeding as a viable, safe infant feeding option for HIV-exposed infants in high-income settings, while acknowledging unanswered questions and the need to continually craft more nuanced clinical guidance.

Make Modern Microbiology Matter More in the 2023 European Society of Cardiology Guidelines for the Management of Infective Endocarditis.

The European Society of Cardiology (ESC) 2023 guidelines for the management of infective endocarditis (IE) stress that a multidisciplinary approach is needed to manage patients with IE. In our view, the guidelines do not include the relevant perspectives from modern microbiology. The diagnostic criteria for IE were changed in the ESC 2023 guidelines, and many IE-causing pathogens are either not clearly defined. Moreover, an improved understanding of the relationship between bacterial species and the risk for IE has not been implemented. The guidelines give detailed and, in our view, incorrect instructions about diagnostic testing in blood culture-negative IE without presenting proper evidence. Other important diagnostic aspects, such as the value of repeated blood cultures and incubation time for blood cultures, are not discussed. We believe that a multidisciplinary collaboration that include microbiologists would have improved these guidelines, and we hope for a future harmonization of diagnostic criteria for IE.

The European Organisation of External Quality Assurance Providers in Laboratory Medicine (EQALM) Statement: guidelines for publishing about interlaboratory comparison studies (PubILC).

Data and results from interlaboratory comparison (ILC) studies, external quality assessment (EQA) and proficiency testing (PT) activities are important and valuable contributions both to the further development of all disciplines of medical laboratory diagnostics, and to the evaluation and comparison of in vitro diagnostic assays. So far, however, there are no recommendations as to which essential items should be addressed in publications on interlaboratory comparisons. The European Organization of External Quality Assurance Providers in Laboratory Medicine (EQALM) recognized the need for such recommendations, and these were developed by a group of experts. The result of this endeavor is the EQALM Statement on items recommended to be addressed in publications on interlaboratory comparison activities (PubILC), in conjunction with a user-friendly checklist. Once adopted by authors and journals, the EQALM Statement will ensure essential information and/or study-related facts are included within publications on EQA/PT activities.

Pretransplant screening for coronary artery disease: data are required before practice change.

Declining rates of peritransplant cardiovascular death, an increasing burden of pretransplant tests, and concerns about the effectiveness of screening candidates for coronary artery disease have led many transplant programs to de-escalate screening protocols. Recent Kidney Disease: Improving Global Outcomes and American Heart Association scientific statements and guidelines neatly summarize current evidence, but also identify areas of need. Here, we argue that key questions should be addressed by adequately powered clinical trials before our long-held screening paradigms are completely rewritten.

Real-world utilization, patient characteristics, and treatment patterns among men with localized prostate cancer tested with the 17-gene genomic prostate score® (GPSTM) assay.

OBJECTIVES: Descriptive study focusing on real-world utilization and characteristics of men with prostate cancer tested with the 17-gene Genomic Prostate Score® (GPS™) assay by linking administrative claims and electronic health record (EHR) data with GPS results. METHODS: This retrospective, observational cohort study (January 1, 2013 to December 31, 2020) included men aged 40-80 years with localized prostate cancer claims, continuous enrollment in Optum's Integrated Claims data set, ≥1 day of EHR clinical activity, and a GPS result. Men were classified as undergoing definitive therapy (DT) (prostatectomy, radiation, or focal therapy) or active surveillance (AS). AS and DT distribution were analyzed across GPS results, National Comprehensive Cancer Network® (NCCN®) risk, and race. Costs were assessed 6 months after the first GPS result (index); clinical outcomes and AS persistence were assessed during the variable follow-up. All variables were analyzed descriptively. RESULTS: Of 834 men, 650 (77.9%) underwent AS and 184 (22.1%) DT. Most men had Quan-Charlson comorbidity scores of 1-2 and a tumor stage of T1c (index). The most common Gleason patterns were 3 + 3 (79.6%) (AS cohort) and 3 + 4 (55.9%) (DT cohort). The mean (standard deviation) GPS results at index were 23.2 (11.3) (AS) and 30.9 (12.9) (DT). AS decreased with increasing GPS result and NCCN risk. Differences between races were minimal. Total costs were substantially higher in the DT cohort. CONCLUSIONS: Most men with GPS-tested localized prostate cancer underwent AS, indicating the GPS result can inform clinical management. Decreasing AS with increasing GPS result and NCCN risk suggests the GPS complements NCCN risk stratification.

Attitudes toward the American Cancer Society's 2020 cervical cancer screening guidelines: A qualitative study of a national sample of US clinicians.

BACKGROUND: The 2020 American Cancer Society (ACS) guidelines are the most recent national guidelines for cervical cancer screening. These guidelines propose two major changes from current practice: initiating screening at age 25 years and using primary human papillomavirus (HPV) testing. Adoption of guidelines often occurs slowly, and therefore understanding clinician attitudes is important to facilitate practice change. METHODS: Interviews with a national sample of clinicians who perform cervical cancer screening in a variety of settings explored attitudes toward the two major changes from the 2020 ACS cervical cancer screening guidelines. Clinicians participated in 30- to 60-min interviews exploring their attitudes toward various aspects of cervical cancer screening. Qualitative analysis was performed. RESULTS: Seventy clinicians participated from across the United States. Few respondents were initiating screening at age 25 years, and none were using primary HPV testing. However, over half would be willing to adopt these practices if supported by scientific evidence and recommended by professional medical organizations. Barriers to adoption included the lack of endorsement by professional societies, lack of laboratory availability and insurance coverage, limited autonomy within large health care systems, and concerns related to missed disease. CONCLUSIONS: Few clinicians have adopted screening initiation or primary HPV testing, as recommended by the 2020 ACS guidelines, but over half were open to adopting these changes. Implementation may be facilitated via professional organization endorsement, clinician education, and laboratory, health care system, and insurance support. PLAIN LANGUAGE SUMMARY: In 2020, the American Cancer Society (ACS) released updated guidelines for cervical cancer screening. The main changes to current practices were to initiate screening at age 25 years instead of age 21 years and to screen using primary human papillomavirus (HPV) testing rather than cytology alone or in combination with HPV testing. We performed in-depth interviews with 70 obstetrics and gynecology, family medicine, and internal medicine physicians and advanced practice providers about their attitudes toward these guidelines. Few clinicians are following the 2020 ACS guidelines, but over half were open to changing practice if the changes were supported by evidence and recommended by professional medical organizations. Barriers to adoption included the lack of endorsement by professional medical organizations, logistical issues, and concerns about missed disease.

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world.

BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Diagnosis and Treatment of Helicobacter pylori Infection.

The last 5 years have seen major shifts in defining whom to test and how to treat Helicobacter pylori infection. Peptic ulcer has changed from a chronic disease to a one-off condition, and countries with a high incidence of gastric cancer have begun implementing population-wide screening and treatment. A proactive approach to testing and treatment of H. pylori is now recommended, including outreach to family members of individuals diagnosed with active infection as well as high-risk local populations such as immigrants from high-risk countries. Increasing antimicrobial resistance has resulted in an overall decline in treatment success, causing a rethinking of the approach to development of treatment guidelines as well as the need to adopt the principles of antibiotic usage and antimicrobial stewardship. Required changes include abandoning empiric use of clarithromycin, metronidazole, and levofloxacin triple therapies. Here, we discuss these transformations and give guidance regarding testing and use of therapies that are effective when given empirically.

Letting the mantle out of the bag.

Mantle cell lymphoma is a rare disease that attracts the curiosity of clinicians and scientists due to its heterogeneous clinical behaviour, that can vary from indolent forms to the most aggressive presentations among non-Hodgkin lymphomas. The report by Eyre and colleagues describes the current treatment strategies available in most countries, and offers insights to clinicians for several intriguing difficult-to-treat scenarios. Commentary on: Eyre et al. Diagnosis and management of mantle cell lymphoma: a British Society for Haematology Guideline. Br J Haematol 2024;204:108-126.

Clinical implications of airway obstruction with normal or low FEV1 in childhood and adolescence.

BACKGROUND: Airway obstruction is defined by spirometry as a low forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. This impaired ratio may originate from a low FEV1 (classic) or a normal FEV1 in combination with a large FVC (dysanaptic). The clinical implications of dysanaptic obstruction during childhood and adolescence in the general population remain unclear. AIMS: To investigate the association between airway obstruction with a low or normal FEV1 in childhood and adolescence, and asthma, wheezing and bronchial hyperresponsiveness (BHR). METHODS: In the BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology; Sweden) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy; the Netherlands) birth cohorts, obstruction (FEV1:FVC ratio less than the lower limit of normal, LLN) at ages 8, 12 (PIAMA only) or 16 years was classified as classic (FEV1

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.