bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarker identification by interpretable maximum mean discrepancy
Authors: Adamer Michael F , Brüningk Sarah C , Chen Dexiong , Borgwardt Karsten 
Published: June 2024

Abstract

Motivation
In many biomedical applications, we are confronted with paired groups of samples, such as treated versus control. The aim is to detect discriminating features, i.e. biomarkers, based on high-dimensional (omics-) data. This problem can be phrased more generally as a two-sample problem requiring statistical significance testing to establish differences, and interpretations to identify distinguishing features. The multivariate maximum mean discrepancy (MMD) test quantifies group-level differences, whereas statistically significantly associated features are usually found by univariate feature selection. Currently, few general-purpose methods simultaneously perform multivariate feature selection and two-sample testing.

Results
We introduce a sparse, interpretable, and optimized MMD test (SpInOpt-MMD) that enables two-sample testing and feature selection in the same experiment. SpInOpt-MMD is a versatile method and we demonstrate its application to a variety of synthetic and real-world data types including images, gene expression measurements, and text data. SpInOpt-MMD is effective in identifying relevant features in small sample sizes and outperforms other feature selection methods such as SHapley Additive exPlanations and univariate association analysis in several experiments.

Availability and implementation
The code and links to our public data are available at https://github.com/BorgwardtLab/spinoptmmd.
Identifying new cancer genes based on the integration of annotated gene sets via hypergraph neural networks
Authors: Deng Chao , Li Hong-Dong , Zhang Li-Shen , Liu Yiwei , Li Yaohang , Wang Jianxin 
Published: June 2024

Abstract

Motivation
Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited.

Results
Here, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of employing hypergraphs for representing annotated gene sets. Second, we validate the accuracy of DISHyper-predicted cancer genes using functional validation results and multiple independent functional genomics data. Third, our model predicts 44 novel cancer genes, and subsequent analysis shows their significant associations with multiple types of cancers. Overall, our study provides a new perspective for discovering cancer genes and reveals previously undiscovered cancer genes.

Availability and implementation
DISHyper is freely available for download at https://github.com/genemine/DISHyper.
RiboDiffusion: tertiary structure-based RNA inverse folding with generative diffusion models
Authors: Huang Han , Lin Ziqian , He Dongchen , Hong Liang , Li Yu 
Published: June 2024

Abstract

Motivation
RNA design shows growing applications in synthetic biology and therapeutics, driven by the crucial role of RNA in various biological processes. A fundamental challenge is to find functional RNA sequences that satisfy given structural constraints, known as the inverse folding problem. Computational approaches have emerged to address this problem based on secondary structures. However, designing RNA sequences directly from 3D structures is still challenging, due to the scarcity of data, the nonunique structure-sequence mapping, and the flexibility of RNA conformation.

Results
In this study, we propose RiboDiffusion, a generative diffusion model for RNA inverse folding that can learn the conditional distribution of RNA sequences given 3D backbone structures. Our model consists of a graph neural network-based structure module and a Transformer-based sequence module, which iteratively transforms random sequences into desired sequences. By tuning the sampling weight, our model allows for a trade-off between sequence recovery and diversity to explore more candidates. We split test sets based on RNA clustering with different cut-offs for sequence or structure similarity. Our model outperforms baselines in sequence recovery, with an average relative improvement of 11% for sequence similarity splits and 16% for structure similarity splits. Moreover, RiboDiffusion performs consistently well across various RNA length categories and RNA types. We also apply in silico folding to validate whether the generated sequences can fold into the given 3D RNA backbones. Our method could be a powerful tool for RNA design that explores the vast sequence space and finds novel solutions to 3D structural constraints.

Availability and implementation
The source code is available at https://github.com/ml4bio/RiboDiffusion.
Unveil cis-acting combinatorial mRNA motifs by interpreting deep neural network
Authors: Zeng Xiaocheng , Wei Zheng , Du Qixiu , Li Jiaqi , Xie Zhen , Wang Xiaowo 
Published: June 2024

Abstract

Summary
Cis-acting mRNA elements play a key role in the regulation of mRNA stability and translation efficiency. Revealing the interactions of these elements and their impact plays a crucial role in understanding the regulation of the mRNA translation process, which supports the development of mRNA-based medicine or vaccines. Deep neural networks (DNN) can learn complex cis-regulatory codes from RNA sequences. However, extracting these cis-regulatory codes efficiently from DNN remains a significant challenge. Here, we propose a method based on our toolkit NeuronMotif and motif mutagenesis, which not only enables the discovery of diverse and high-quality motifs but also efficiently reveals motif interactions. By interpreting deep-learning models, we have discovered several crucial motifs that impact mRNA translation efficiency and stability, as well as some unknown motifs or motif syntax, offering novel insights for biologists. Furthermore, we note that it is challenging to enrich motif syntax in datasets composed of randomly generated sequences, and they may not contain sufficient biological signals.

Availability and implementation
The source code and data used to produce the results and analyses presented in this manuscript are available from GitHub (https://github.com/WangLabTHU/combmotif)
O01 Survey of Scottish Dermatology Society members on the new Medicines and Healthcare products Regulatory Agency isotretinoin recommendations
Authors: Dubash Faisal , Dawe Robert , Affleck Andrew 
Published: June 2024

Abstract
Recent Medicines and Healthcare products Regulatory Agency (MHRA) isotretinoin legislation includes significant changes that will affect clinical practice (Medicines and Healthcare products Regulatory Agency. Drug Safety Update volume 16, issue 9: April 2023: 4). We obtained opinions from members of the Scottish Dermatological Society (SDS) on these recommendations. Five questions were circulated to members using a Microsoft Forms e-survey, and responders were anonymous. In total, 77 of 180 members responded in a 1-week period, with a 43% response rate. Open comments were also captured in a free-text box. The results included the following. Question 1: 95% (73 of 77) of responders stated that the new MHRA legislation is more likely to harm people with severe acne, while 3% (2 of 77) believed the recommendations would help patients with acne. Another 3% (2 of 77) answered ‘other’, with one stating ‘there are some improvements and some issues with this guidance’ and ‘people with severe acne will have to wait longer to start isotretinoin and suffer harm’. Question 2: 92% (71 of 77) felt that the views of people with severe acne were not considered. Question 3: 99% (76 of 77) of SDS members agreed that the new recommendations were not based on good evidence. Question 4: 90% (69 of 77) were against the requirement for two separate healthcare practitioners to approve isotretinoin prescribing in patients aged &lt; 18 years. Question 5: 87% (67 of 77) agreed that clinicians should not need to ask about sexual dysfunction at every consultation, while 13% (10 of 77) believe we should. Open comments highlighted common themes such as ‘significant delays in patient access to isotretinoin, additional staff required for decisions, legislation being a barrier to prescribing effective treatment, additional patient harm such as scarring, effect on quality of life and concerns of worsening mental health due to the guidance’. ‘Further damage to the doctor–patient relationship’ was raised as ‘patients would be victim to a nocebo effect’. There was frustration expressed about the creation of more meaningless tick-box exercises and it was widely perceived that the legislation was authoritarian and disproportionately represented a minority opinion over an ‘unheard’ patient majority. There was also a feeling that there had been a ‘lack of expert dermatological opinion involved in the process of developing the guidance’. Overall, an overwhelming response from SDS members highlighted many concerns with the MHRA guidance and its impact on patient care. Isotretinoin appears to have been demonized without any scientific basis. The results of this survey question the credibility of the MHRA and their recommendations. We propose the creation of an objective working group, with no conflicts of interest, to re-evaluate the MHRA recommend­ations and accurately reflect the current evidence base.
P008 In over our heads?
Authors: Long Amy , Murphy Lisa , Quigley Claire , Leonard Niamh , Wynne Bairbre 
Published: June 2024

Abstract
We present the case of severe circumferential folliculitis decalvans in a 42-year-old White man. He presented to dermatology age 38 years with a 5-year history of a nonpainful, occasionally itchy pustulating process from crown to occipital scalp, resulting in hair loss. A progressive process, it began on the nape of the neck as rough, red skin and slowly spread outwards. Past medical history included teenage acne. He did not smoke. He was on lymecycline at the time of presentation, prescribed by his general practitioner, and no other medications. On examination he had an extensive (25 × 18 cm) area with crud, pustulation with yellow discharge and cicatricial alopecia. There was an indurated red rim. Removal of the crust revealed friable granulation-like tissue. There were no other significant findings on full-skin exam. He had punch biopsies for histopathology and bacterial and fungal culture. Histopathology showed hair-bearing skin with extensive inflammation around hair follicles. There was focal acute folliculitis. The inflammatory infiltrate contained lymphocytes and prominent plasma cells. Fungal and bacterial cultures were negative. His condition had a profound impact on his quality of life. He suffered mentally from the stigma associated with folliculitis decalvans, and the severity of his condition compounded this. Over the proceeding 4 years his engagement with the service diminished and compliance wavered. He was treated with rifampicin and clindamycin, in multiple short courses and once consecutively for 6 months, which yielded some improvement. He declined nurse treatment for debridement and dressings, opting to do so himself at home with his wife’s assistance. He was highly qualified in business, yet remained unemployed. In 2023 he contacted dermatology requesting to be seen. He was off treatment for over 2 years. His scalp disease was extensive with circumferential involvement of his head, including matting of his facial hair with pus. Bacterial swabs grew Staphylococcal aureus. He attended twice-weekly nursing appointments for debridement. Clobetasol propionate was used on overgranulated tissue. He was treated with flucloxacillin (500 mg, four times daily for 2 weeks), followed by doxycycline (100 mg daily for 6 weeks), followed by azithromycin (500 mg, three times weekly for 4 weeks). He has achieved considerable improvement and is being considered for oral dapsone. Folliculitis decalvans is a debilitating disease with far-reaching personal consequence. This case depicts the severe end of the disease spectrum, and the issues that can arise in that context. Challenges faced by his team were not only medical, but also psychological by way of gaining the patient’s trust and managing vulnerabilities.
P014 Eosinophilic dermatosis of haematological malignancy: a chronic relapsing pruritic condition
Authors: Diong Sophie , Vandenberghe Elisabeth , Mellerick Lisa , Wynne Bairbre 
Published: June 2024

Abstract
Eosinophilic dermatosis of haematological malignancy (EDHM) is a rare condition first reported in 1965. Although associated with a myriad of haematoproliferative conditions, it is most commonly linked with chronic lymphocytic leukaemia (CLL). With its typical lesions being intensely pruritic erythematous papules, nodules and bullae, it was initially thought to be a hypersensitivity reaction to insect bites. A 70-year-old man was referred for an 11-year history of an overexuberant response to insect bites. He gave a history of an intermittent blistering rash associated with intense generalized pruritus. He noted lesions occurring on both exposed and nonexposed body sites, and throughout the year. His background was significant for CLL, under surveillance, which was diagnosed a decade ago. Physical examination revealed erythematous papules and nodules on the neck, forehead and limbs, with an intact tense bulla at the left ankle. The morphology observed raised suspicion for Sweet syndrome, bullous pemphigoid, cutaneous T-cell lymphoma and EDHM. Laboratory investigations revealed an elevated lymphocyte count in keeping with his known diagnosis of CLL. Other results were within normal limits. Culture biopsy, and direct and indirect immunofluorescence studies were negative. Biopsies illustrated a dense pandermal perivascular lymphocytic inflammation, with an associated lymphocytic vasculitis. Numerous eosinophils were seen. Immunohistochemistry highlighted no convincing involvement by CLL. No clonal T-cell receptor gene rearrangements were identified. Given both the clinical and pathological features, a diagnosis of EDHM was made. Our patient responded to a course of weaning oral steroids commenced synchronously for a respiratory tract infection, alongside moderate-potency topical steroids. In the event of a future flare, steroid-sparing agents to be considered include dapsone and doxycycline, which have shown efficacy in the literature. EDHM can precede, antedate or occur concurrently with a CLL diagnosis. Although exaggerated arthropod responses are associated with CLL, EDHM is believed to be a separate process. Its pathogenesis remains unknown, but hypotheses include underlying malignancy-­related immune dysregulation, with a shift towards a T helper type 2 response and excess interleukin-4 and interleukin-5 production, which drive eosinophil recruitment and stimulation. This chronic relapsing dermatosis is characterized by clinical polymorphism and suggestive, but nonspecific, histopathological traits. Careful clinicopathological correlation is essential for diagnosis. Management options depend on the severity and frequency of flares. Varying responses to treatment are reported, but there is no gold-standard treatment. It is important that dermatologists are aware of EDHM as its diagnosis carries a potential negative prognostic outlook on the underlying haematological malignancy.
P023 Real-world melanoma miss rate in an NHS hospital dermatology service
Authors: Shirwac Hafsa Faarax , Morgan Hannah , Greenish Huw , Carswell Sarah , Heath Harry , Koutsis James , Guitera Pascale , Anderson Alexander D G 
Published: June 2024

Abstract
The aim of this retrospective study was to assess the ‘miss rate’ of dermatology clinicians for detecting malignant melanoma among patients referred on the 2-week-wait skin cancer pathway over a 2-year period. We reviewed patient records from the previous 5 years to identify instances where malignant melanoma might have been misdiagnosed. Malignant melanoma can be missed at various stages of the patient’s journey, leading to delayed diagnosis and potentially serious consequences. Our geographically isolated rural county relies exclusively on a single NHS dermatology department for 2-week-wait skin cancer services, providing a unique opportunity to assess the incidence of missed melanoma. We used a regional cancer registry to identify all primary invasive malignant melanomas (ICD-10 C43) diagnosed between August 2020 and July 2022. Records of any patient who had attended the dermatology department within the 5 years preceding diagnosis were reviewed to identify patients where melanoma might have been previously misdiagnosed. In total, 432 primary melanomas were identified. The male-to-female ratio was 202 : 230 and the median age was 71 years (interquartile range 57–79). Stage at presentation was IA (176, 40.7%), IB (98, 22.7%), II (134, 31.0%), III (19, 4.4%) and IV (5, 1.2%). Nine patients (2.1%) had been given an erroneous benign diagnosis for the same lesion and discharged within 13 months of diagnosis (missed melanoma). The stages of the missed melanomas were IA (two patients), IB (four patients) and II (three patients). In a further four cases (0.9%) the melanoma had prompted action, but the diagnosis was delayed; one had an erroneous negative biopsy, one missed an urgent review, one lesion was monitored, leading to a 6-month delay in diagnosis, and one was incorrectly diagnosed as a basal cell carcinoma, leading to a delay in surgery. A final four (0.9%) cases were diagnosed as benign more than 2 years prior to melanoma diagnosis. These were classified as ‘possible’ misses, as they could have evolved into malignant melanomas in the interim period. Our study reveals a low yet quantifiable melanoma miss rate in a high-volume NHS dermatology service. Future multicentre studies with large datasets are required, to identify risk factors for misdiagnosis. Clinicians managing skin lesion clinics may consider melanoma miss rate as a key performance metric. Strategies to improve the accuracy of this important metric might include the use of prospective databases incorporating digital images of lesions suspected to be benign. The utility of this approach should be investigated further.
P024 Skin cancer referrals by nonmedical practitioners: a prospective observational study
Authors: Anderson Alexander D G , Carswell Sarah , Heath Harry , Koutsis James , Guitera Pascale 
Published: June 2024

Abstract
A shortage of general practitioners (GPs) and increasing healthcare burden have led to nonmedical practitioners (NMPs) assuming new roles in many countries. It is now commonplace in the UK for nurses, paramedics and other NMPs to refer patients to secondary care. Despite this, there is little real-world information regarding clinical performance. The aim of this study was to investigate the appropriateness of skin cancer referrals made by NMPs and to compare this with referrals made by local GPs. Data were collected prospectively from patients referred to an NHS hospital dermatology department with a skin lesion of concern on the ‘2-week-wait’ pathway during a 2-month period in 2022. The profession of the referrer was ascertained from review of referral letters, from direct questioning of each patient and by contacting the GP surgery if required. Patient records and subsequent histology reports were reviewed to determine ultimate diagnosis. The proportion of patients diagnosed with skin malignancy (malignant melanoma, malignant melanoma in situ, squamous cell carcinoma, basal cell carcinoma, rare skin cancer) and in whom the dermatology clinician arranged an intervention (biopsy, excision, referral to another specialty for treatment) were recorded. In total, 753 patients were included. The overall malignancy rate was 29.3%. Overall, 668 of 753 patients (88.7%) were referred by a GP vs. 85 of 753 (11.3%) by an NMP. Seventy-two of the NMP referrals were made by 47 named individuals. The remaining 13 were made by unnamed practice nurses. Patients recalled an NMP asking for a second opinion in only 15 of 85 cases (18%) cases. Overall, 73% of NMP referrals were made by nurses, 24% by paramedics and 4% by physicians associates. Following clinic visit, 340 of 668 patients (50.9%) in the GP group and 47 of 85 (55%) in the NMP group were discharged without intervention (P = 0.45). An ultimate diagnosis of skin malignancy was made in 196 of 668 patients (29.3%) in the GP group and 25 of 85 (29%) in the NMP group (P = 0.99). Over 10% of referrals on the suspected skin cancer pathway were made by NMPs. There were no significant differences in diagnostic accuracy (number of malignancies) or referral appropriateness (referrals resulting in intervention) between NMPs and GPs. These early data suggest significant potential for NMPs to become more involved in skin lesion assessment. Further work should focus on understanding successful NMP education and supervision strategies and result in standardization and accreditation of training pathways for this increasingly important cohort of referrers.