Feasibility and ethics of using data from the Scottish newborn blood spot archive for research

Background: Newborn heel prick blood spots are routinely used to screen for inborn errors of metabolism and life-limiting inherited disorders. The potential value of secondary data from newborn blood spot archives merits ethical consideration and assessment of feasibility for public benefit. Early life exposures and behaviours set health trajectories in childhood and later life. The newborn blood spot is potentially well placed to create an unbiased and cost-effective population-level retrospective birth cohort study. Scotland has retained newborn blood spots for all children born since 1965, around 3 million in total. However, a moratorium on research access is currently in place, pending public consultation. Methods: We conducted a Citizens’ Jury as a first step to explore whether research use of newborn blood spots was in the public interest. We also assessed the feasibility and value of extracting research data from dried blood spots for predictive medicine. Results: Jurors delivered an agreed verdict that conditional research access to the newborn blood spots was in the public interest. The Chief Medical Officer for Scotland authorised restricted lifting of the current research moratorium to allow a feasibility study. Newborn blood spots from consented Generation Scotland volunteers were retrieved and their potential for both epidemiological and biological research demonstrated. Conclusions: Through the Citizens’ Jury, we have begun to identify under what conditions, if any, should researchers in Scotland be granted access to the archive. Through the feasibility study, we have demonstrated the potential value of research access for health data science and predictive medicine

The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

Wedge versus core biopsy at time zero: which provides better predictive value for delayed graft function with the Remuzzi histological scoring system?

Background: Histopathological features on time-zero renal biopsies correlate with graft outcome after renal transplantation. With increasing numbers of marginal donors, assessment of pre-implantation graft quality is essential. The clinician's choice of wedge or core biopsy is performed without evidence of efficacy or safety. This study aims to compare the information derived from wedge biopsy versus core biopsy. Methods: Prospective evaluation of 37 wedge biopsies and 30 core biopsies was performed. Histopathological data were collected on number of glomeruli and arterioles observed, and Remuzzi scoring for glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriolar narrowing was performed. Clinical data on delayed graft function (DGF) were also collated. Sensitivity, specificity, and positive and negative predictive values for DGF were compared. Results: Patient demographics between the two cohorts were comparable. No complications of biopsies occurred; 81% of wedge biopsies versus 50% of core biopsies had >10 glomeruli (P = .01), whereas 32% of wedge biopsies and 57% of core biopsies had >2 arterioles (P = .02). Wedge biopsies were more likely to identify pathology with more glomerulosclerosis, tubular atrophy (P < .01), and interstitial fibrosis (P < .01). There was a non-significant trend toward high Remuzzi scores in wedge biopsy (22% versus 7% with Remuzzi ≥4; P = .12). The sensitivity and positive predictive value of Remuzzi ≥4 for predicting DGF was better on wedge biopsy (45.5% versus 0%; P < .01 and 62.5% versus 0%; P < .01, respectively). Conclusions: Wedge biopsies were safe and superior to core biopsies for identifying clinically significant histopathological findings on pre-implantation renal biopsy. We believe that the wedge biopsy is the method of choice for time-zero biopsies

Shift in harms and benefits of cervical cancer screening in the era of HPV screening and vaccination: a modelling study

Objective: To calculate the changes in harms and benefits of cervical cancer screening over the first three screening rounds of the Dutch high-risk human papillomavirus (hrHPV) screening programme. Design: Microsimulation study. Setting: Dutch hrHPV screening programme; women are invited for screening every 5 or 10 years (depending on age and screening history) from age 30 to 65. Population: Partly vaccinated population of 100 million Dutch women. Methods: Microsimulation model MISCAN was used to estimate screening effects. Sensitivity analyses were performed on test characteristics and attendance. Main outcome measures: Harms (screening tests, unnecessary referrals, treatment-related health problems), benefits (CIN2 + diagnoses) and programme efficiency (number needed to screen [NNS]) over the first (period 2017–2021), second (period 2022–2026) and third (period 2027–2031) rounds of hrHPV-based screening. Results: The number of screening tests and CIN2 + diagnoses decreased from the first to the second round (−25.8% and −23.6%, respectively). In the third screening round, these numbers decreased further, albeit only slightly (−2.7% and −5.3%, respectively). NNS to detect a CIN2 + remained constant over the rounds; however, it increased in younger age groups while decreasing in older age groups. Conclusion: Both harms and benefits of hrHPV screening decreased over the first screening rounds. For younger women, the efficiency would decrease, whereas longer screening intervals would lead to increased efficiency in older women. Programme efficiency overall remained stable, showing the importance of longer intervals for low-risk women. Tweetable abstract:: Cervical cancer screening: both harms and benefits of hrHPV screening will decrease in the future

Reducing unnecessary referrals for colposcopy in hrHPV-positive women within the Dutch cervical cancer screening programme: A modelling study

Background: With the implementation of primary high-risk human papillomavirus (hrHPV) screening in the Netherlands, an increase was observed in the number of unnecessary referrals (≤Cervical Intraepithelial Neoplasia (CIN) 1) to colposcopy. We aimed to investigate which alternative triage strategies safely reduce unnecessary referrals in HPV-based cervical cancer screening programmes. Methods: Microsimulation model MISCAN was used to simulate an unvaccinated cohort of ten million 30-year old Dutch women. We calculated unnecessary referrals, cervical cancer incidence, mortality, costs and QALYs for 24 triage strategies. Condition for direct referral (atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), conditional on HPV-genotype 16/18/other high risk (OHR)), type of triage test (cytology alone or combined with hrHPV) and time to triage test (6 or 12 months) was varied. Results: The 24 triage strategies had varying effects on the number of unnecessary referrals ranging from −72% to +35%. Adjusting conditions for referral to ‘HPV16/18+ and ASC-US+’ and ‘HPVOHR+ and HSIL+’ and extending the interval between tests to 12 months resulted in a reduction in unnecessary referrals of 40% (incidence +0%, mortality −1%). Reduction in unnecessary referrals without genotyping was achieved by adjusting conditions for direct referral to LSIL (12 months to repeat test) (unnecessary referrals −37%, incidence +2%, mortality +0%). Conclusions: To reduce the number of unnecessary referrals without increasing incidence and mortality by more than 2% in the Dutch cervical cancer screening programme, genotyping for HPV16 or HPV16/18 should be implemented with 12 months to repeat testing

Cost-effectiveness of HPV-based cervical screening based on first year results in the Netherlands: a modelling study

Objective: We aim to compare the cost-effectiveness of the old cytology programme with the new high-risk human papillomavirus (hrHPV) screening programme, using performance indicators from the new Dutch hrHPV screening programme. Design: Model-based cost-effectiveness analysis. Setting: The Neth

Risk of gynecologic cancer after atypical glandular cells found on cervical cytology: A population-based cohort study

Background: Atypical glandular cells (AGC) are rare abnormalities found on cervical cytology associated with a range of lesions of the female reproductive system. We compared the risk of cervical and other gynecologic cancers following AGC on cervical cytology with the risk following squamous cell abnormalities of comparable severity. Methods: We used data from the Dutch Pathology Archive (PALGA) from 2000 to 2015 to categorize cervical cytology tests into groups based on most severe cytologic abnormality and correlated follow-up advice (normal cytology and "no follow-up"advice, squamous-cell-based, AGC-based, and combined AGC/squamouscell based each with either repeat testing or referral advice). Cancer data were linked from the Netherlands Cancer Registry. Cox proportional hazard models were calculated stratified by age [younger (<50 years) and older (50+ years)], adjusted for number of previous primary cytology tests. Results: 8,537,385 cytology smears and 9,061 cancers were included. When repeat cytology testing was advised, HRs of cervical cancer (younger women: HR, 6.91; 95% CI, 5.48-8.71; older women: HR, 3.98; 95% CI, 2.38-6.66) or other gynecologic cancer diagnosis in younger women (HR, 2.82; 95% CI, 1.39- 5.74) were significantly higher after an AGC-based abnormality compared with squamous-based abnormalities. Hazards were also significantly higher for "referral"advice cytology, except for cervical cancer among older women (HR, 0.88; 95% CI, 0.63-1.21). Conclusions: AGC indicates an increased risk of gynecologic cancer compared with squamous-based abnormalities of comparable severity. Impact: Gynecologists should be alert for cervical and endometrial cancers when examining women referred following AGC