Advances and challenges in Bioinformatics and Biomedical Engineering: IWBBIO 2020.

This Supplement issue, presents five research articles which are distributed, mainly due to the subject they address, from the 8th International Work-Conference on Bioinformatics and Biomedical Engineering (IWBBIO 2020), which was held on line, during September, 30th-2nd October, 2020. These contributions have been chosen because of their quality and the importance of their findings. Those contributions were then invited to participate in this supplement for the following journals of BMC: BMC Bioinformatics and BMC Genomics. In the present Editorial in BMC journal, we summarize the contributions that provide a clear overview of the thematic areas covered by the IWBBIO conference, ranging from theoretical/review aspects to real-world applications of bioinformatic and biomedical engineering.

Non-small-cell lung cancer classification via RNA-Seq and histology imaging probability fusion.

BACKGROUND: Adenocarcinoma and squamous cell carcinoma are the two most prevalent lung cancer types, and their distinction requires different screenings, such as the visual inspection of histology slides by an expert pathologist, the analysis of gene expression or computer tomography scans, among others. In recent years, there has been an increasing gathering of biological data for decision support systems in the diagnosis (e.g. histology imaging, next-generation sequencing technologies data, clinical information, etc.). Using all these sources to design integrative classification approaches may improve the final diagnosis of a patient, in the same way that doctors can use multiple types of screenings to reach a final decision on the diagnosis. In this work, we present a late fusion classification model using histology and RNA-Seq data for adenocarcinoma, squamous-cell carcinoma and healthy lung tissue. RESULTS: The classification model improves results over using each source of information separately, being able to reduce the diagnosis error rate up to a 64% over the isolate histology classifier and a 24% over the isolate gene expression classifier, reaching a mean F1-Score of 95.19% and a mean AUC of 0.991. CONCLUSIONS: These findings suggest that a classification model using a late fusion methodology can considerably help clinicians in the diagnosis between the aforementioned lung cancer cancer subtypes over using each source of information separately. This approach can also be applied to any cancer type or disease with heterogeneous sources of information.

Main findings and advances in bioinformatics and biomedical engineering- IWBBIO 2018.

In the current supplement, we are proud to present seventeen relevant contributions from the 6th International Work-Conference on Bioinformatics and Biomedical Engineering (IWBBIO 2018), which was held during April 25-27, 2018 in Granada (Spain). These contributions have been chosen because of their quality and the importance of their findings.

Integration of RNA-Seq data with heterogeneous microarray data for breast cancer profiling.

BACKGROUND: Nowadays, many public repositories containing large microarray gene expression datasets are available. However, the problem lies in the fact that microarray technology are less powerful and accurate than more recent Next Generation Sequencing technologies, such as RNA-Seq. In any case, information from microarrays is truthful and robust, thus it can be exploited through the integration of microarray data with RNA-Seq data. Additionally, information extraction and acquisition of large number of samples in RNA-Seq still entails very high costs in terms of time and computational resources.This paper proposes a new model to find the gene signature of breast cancer cell lines through the integration of heterogeneous data from different breast cancer datasets, obtained from microarray and RNA-Seq technologies. Consequently, data integration is expected to provide a more robust statistical significance to the results obtained. Finally, a classification method is proposed in order to test the robustness of the Differentially Expressed Genes when unseen data is presented for diagnosis. RESULTS: The proposed data integration allows analyzing gene expression samples coming from different technologies. The most significant genes of the whole integrated data were obtained through the intersection of the three gene sets, corresponding to the identified expressed genes within the microarray data itself, within the RNA-Seq data itself, and within the integrated data from both technologies. This intersection reveals 98 possible technology-independent biomarkers. Two different heterogeneous datasets were distinguished for the classification tasks: a training dataset for gene expression identification and classifier validation, and a test dataset with unseen data for testing the classifier. Both of them achieved great classification accuracies, therefore confirming the validity of the obtained set of genes as possible biomarkers for breast cancer. Through a feature selection process, a final small subset made up by six genes was considered for breast cancer diagnosis. CONCLUSIONS: This work proposes a novel data integration stage in the traditional gene expression analysis pipeline through the combination of heterogeneous data from microarrays and RNA-Seq technologies. Available samples have been successfully classified using a subset of six genes obtained by a feature selection method. Consequently, a new classification and diagnosis tool was built and its performance was validated using previously unseen samples.

Statistical Analysis of the Main Configuration Parameters of the Network Dynamic and Adaptive Radio Protocol (DARP).

The present work analyses the wireless sensor network protocol (DARP) and the impact of different configuration parameter sets on its performance. Different scenarios have been considered, in order to gain a better understanding of the influence of the configuration on network protocols. The developed statistical analysis is based on the method known as Analysis of Variance (ANOVA), which focuses on the effect of the configuration on the performance of DARP. Three main dependent variables were considered: number of control messages sent during the set-up time, energy consumption and convergence time. A total of 20,413 simulations were carried out to ensure greater robustness in the statistical conclusions. The main goal of this work is to discover the most critical configuration parameters for the protocol, with a view to potential applications in Smart City type scenarios.

Identification of gene expression profiling associated with erlotinib-related skin toxicity in pancreatic adenocarcinoma patients.

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that showed activity against pancreatic ductal adenocarcinoma (PDAC). The drug's most frequently reported side effect as a result of EGFR inhibition is skin rash (SR), a symptom which has been associated with a better therapeutic response to the drug. Gene expression profiling can be used as a tool to predict which patients will develop this important cutaneous manifestation. The aim of the present study was to identify which genes may influence the appearance of SR in PDAC patients. The study included 34 PDAC patients treated with erlotinib: 21 patients developed any grade of SR, while 13 patients did not (controls). Before administering any chemotherapy regimen and the development of SR, we collected RNA from peripheral blood samples of all patients and studied the differential gene expression pattern using the Illumina microarray platform HumanHT-12 v4 Expression BeadChip. Seven genes (FAM46C, IFITM3, GMPR, DENND6B, SELENBP1, NOL10, and SIAH2), involved in different pathways including regulatory, migratory, and signalling processes, were downregulated in PDAC patients with SR. Our results suggest the existence of a gene expression profiling significantly correlated with erlotinib-induced SR in PDAC that could be used as prognostic indicator in this patients.

Ontology-Based High-Level Context Inference for Human Behavior Identification.

Recent years have witnessed a huge progress in the automatic identification of individual primitives of human behavior, such as activities or locations. However, the complex nature of human behavior demands more abstract contextual information for its analysis. This work presents an ontology-based method that combines low-level primitives of behavior, namely activity, locations and emotions, unprecedented to date, to intelligently derive more meaningful high-level context information. The paper contributes with a new open ontology describing both low-level and high-level context information, as well as their relationships. Furthermore, a framework building on the developed ontology and reasoning models is presented and evaluated. The proposed method proves to be robust while identifying high-level contexts even in the event of erroneously-detected low-level contexts. Despite reasonable inference times being obtained for a relevant set of users and instances, additional work is required to scale to long-term scenarios with a large number of users.

Design, implementation and validation of a novel open framework for agile development of mobile health applications.

The delivery of healthcare services has experienced tremendous changes during the last years. Mobile health or mHealth is a key engine of advance in the forefront of this revolution. Although there exists a growing development of mobile health applications, there is a lack of tools specifically devised for their implementation. This work presents mHealthDroid, an open source Android implementation of a mHealth Framework designed to facilitate the rapid and easy development of mHealth and biomedical apps. The framework is particularly planned to leverage the potential of mobile devices such as smartphones or tablets, wearable sensors and portable biomedical systems. These devices are increasingly used for the monitoring and delivery of personal health care and wellbeing. The framework implements several functionalities to support resource and communication abstraction, biomedical data acquisition, health knowledge extraction, persistent data storage, adaptive visualization, system management and value-added services such as intelligent alerts, recommendations and guidelines. An exemplary application is also presented along this work to demonstrate the potential of mHealthDroid. This app is used to investigate on the analysis of human behavior, which is considered to be one of the most prominent areas in mHealth. An accurate activity recognition model is developed and successfully validated in both offline and online conditions.

Predicting the accuracy of multiple sequence alignment algorithms by using computational intelligent techniques.

Multiple sequence alignments (MSAs) have become one of the most studied approaches in bioinformatics to perform other outstanding tasks such as structure prediction, biological function analysis or next-generation sequencing. However, current MSA algorithms do not always provide consistent solutions, since alignments become increasingly difficult when dealing with low similarity sequences. As widely known, these algorithms directly depend on specific features of the sequences, causing relevant influence on the alignment accuracy. Many MSA tools have been recently designed but it is not possible to know in advance which one is the most suitable for a particular set of sequences. In this work, we analyze some of the most used algorithms presented in the bibliography and their dependences on several features. A novel intelligent algorithm based on least square support vector machine is then developed to predict how accurate each alignment could be, depending on its analyzed features. This algorithm is performed with a dataset of 2180 MSAs. The proposed system first estimates the accuracy of possible alignments. The most promising methodologies are then selected in order to align each set of sequences. Since only one selected algorithm is run, the computational time is not excessively increased.

mDurance: A Novel Mobile Health System to Support Trunk Endurance Assessment.

Low back pain is the most prevalent musculoskeletal condition. This disorder constitutes one of the most common causes of disability worldwide, and as a result, it has a severe socioeconomic impact. Endurance tests are normally considered in low back pain rehabilitation practice to assess the muscle status. However, traditional procedures to evaluate these tests suffer from practical limitations, which potentially lead to inaccurate diagnoses. The use of digital technologies is considered here to facilitate the task of the expert and to increase the reliability and interpretability of the endurance tests. This work presents mDurance, a novel mobile health system aimed at supporting specialists in the functional assessment of trunk endurance by using wearable and mobile devices. The system employs a wearable inertial sensor to track the patient trunk posture, while portable electromyography sensors are used to seamlessly measure the electrical activity produced by the trunk muscles. The information registered by the sensors is processed and managed by a mobile application that facilitates the expert's normal routine, while reducing the impact of human errors and expediting the analysis of the test results. In order to show the potential of the mDurance system, a case study has been conducted. The results of this study prove the reliability of mDurance and further demonstrate that practitioners are certainly interested in the regular use of a system of this nature.

Optimizing multiple sequence alignments using a genetic algorithm based on three objectives: structural information, non-gaps percentage and totally conserved columns.

MOTIVATION: Multiple sequence alignments (MSAs) are widely used approaches in bioinformatics to carry out other tasks such as structure predictions, biological function analyses or phylogenetic modeling. However, current tools usually provide partially optimal alignments, as each one is focused on specific biological features. Thus, the same set of sequences can produce different alignments, above all when sequences are less similar. Consequently, researchers and biologists do not agree about which is the most suitable way to evaluate MSAs. Recent evaluations tend to use more complex scores including further biological features. Among them, 3D structures are increasingly being used to evaluate alignments. Because structures are more conserved in proteins than sequences, scores with structural information are better suited to evaluate more distant relationships between sequences. RESULTS: The proposed multiobjective algorithm, based on the non-dominated sorting genetic algorithm, aims to jointly optimize three objectives: STRIKE score, non-gaps percentage and totally conserved columns. It was significantly assessed on the BAliBASE benchmark according to the Kruskal-Wallis test (P < 0.01). This algorithm also outperforms other aligners, such as ClustalW, Multiple Sequence Alignment Genetic Algorithm (MSA-GA), PRRP, DIALIGN, Hidden Markov Model Training (HMMT), Pattern-Induced Multi-sequence Alignment (PIMA), MULTIALIGN, Sequence Alignment Genetic Algorithm (SAGA), PILEUP, Rubber Band Technique Genetic Algorithm (RBT-GA) and Vertical Decomposition Genetic Algorithm (VDGA), according to the Wilcoxon signed-rank test (P < 0.05), whereas it shows results not significantly different to 3D-COFFEE (P > 0.05) with the advantage of being able to use less structures. Structural information is included within the objective function to evaluate more accurately the obtained alignments. AVAILABILITY: The source code is available at http://www.ugr.es/~fortuno/MOSAStrE/MO-SAStrE.zip.

Transcriptional profiling of peripheral blood in pancreatic adenocarcinoma patients identifies diagnostic biomarkers.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with poor survival rates. Fast detection of PDAC appears to be the most relevant strategy to improve the long-term survival of patients. AIMS: Our objective was to identify new markers in peripheral blood that differentiates between PDAC patients and healthy controls. METHODS: Peripheral blood samples from PDAC patients (n = 18) and controls (n = 18) were analyzed by whole genome cDNA microarray hybridization. The most relevant genes were validated by quantitative real-time PCR (RT-qPCR) in the same set of samples. Finally, our gene prediction set was tested in a blinded set of new peripheral blood samples (n = 30). RESULTS: Microarray studies identified 87 genes differentially expressed in peripheral blood samples from PDAC patients. Four of these genes were selected for analysis by RT-qPCR, which confirmed the previously observed changes. In our blinded validation study, the combination of CLEC4D and IRAK3 predicted the diagnosis of PDAC with 93 % accuracy, with a sensitivity of 86 % and specificity of 100 %. CONCLUSIONS: Peripheral blood gene expression profiling is an useful tool for the diagnosis of PDAC. We present a validated four-gene predictor set (ANKRD22, CLEC4D, VNN1, and IRAK3) that may be useful in PDAC diagnosis.

PhysioDroid: combining wearable health sensors and mobile devices for a ubiquitous, continuous, and personal monitoring.

Technological advances on the development of mobile devices, medical sensors, and wireless communication systems support a new generation of unobtrusive, portable, and ubiquitous health monitoring systems for continuous patient assessment and more personalized health care. There exist a growing number of mobile apps in the health domain; however, little contribution has been specifically provided, so far, to operate this kind of apps with wearable physiological sensors. The PhysioDroid, presented in this paper, provides a personalized means to remotely monitor and evaluate users' conditions. The PhysioDroid system provides ubiquitous and continuous vital signs analysis, such as electrocardiogram, heart rate, respiration rate, skin temperature, and body motion, intended to help empower patients and improve clinical understanding. The PhysioDroid is composed of a wearable monitoring device and an Android app providing gathering, storage, and processing features for the physiological sensor data. The versatility of the developed app allows its use for both average users and specialists, and the reduced cost of the PhysioDroid puts it at the reach of most people. Two exemplary use cases for health assessment and sports training are presented to illustrate the capabilities of the PhysioDroid. Next technical steps include generalization to other mobile platforms and health monitoring devices.

Dealing with the effects of sensor displacement in wearable activity recognition.

Most wearable activity recognition systems assume a predefined sensor deployment that remains unchanged during runtime. However, this assumption does not reflect real-life conditions. During the normal use of such systems, users may place the sensors in a position different from the predefined sensor placement. Also, sensors may move from their original location to a different one, due to a loose attachment. Activity recognition systems trained on activity patterns characteristic of a given sensor deployment may likely fail due to sensor displacements. In this work, we innovatively explore the effects of sensor displacement induced by both the intentional misplacement of sensors and self-placement by the user. The effects of sensor displacement are analyzed for standard activity recognition techniques, as well as for an alternate robust sensor fusion method proposed in a previous work. While classical recognition models show little tolerance to sensor displacement, the proposed method is proven to have notable capabilities to assimilate the changes introduced in the sensor position due to self-placement and provides considerable improvements for large misplacements.

Window size impact in human activity recognition.

Signal segmentation is a crucial stage in the activity recognition process; however, this has been rarely and vaguely characterized so far. Windowing approaches are normally used for segmentation, but no clear consensus exists on which window size should be preferably employed. In fact, most designs normally rely on figures used in previous works, but with no strict studies that support them. Intuitively, decreasing the window size allows for a faster activity detection, as well as reduced resources and energy needs. On the contrary, large data windows are normally considered for the recognition of complex activities. In this work, we present an extensive study to fairly characterize the windowing procedure, to determine its impact within the activity recognition process and to help clarify some of the habitual assumptions made during the recognition system design. To that end, some of the most widely used activity recognition procedures are evaluated for a wide range of window sizes and activities. From the evaluation, the interval 1-2 s proves to provide the best trade-off between recognition speed and accuracy. The study, specifically intended for on-body activity recognition systems, further provides designers with a set of guidelines devised to facilitate the system definition and configuration according to the particular application requirements and target activities.

Statistical Analysis of nnU-Net Models for Lung Nodule Segmentation.

This paper aims to conduct a statistical analysis of different components of nnU-Net models to build an optimal pipeline for lung nodule segmentation in computed tomography images (CT scan). This study focuses on semantic segmentation of lung nodules, using the UniToChest dataset. Our approach is based on the nnU-Net framework and is designed to configure a whole segmentation pipeline, thereby avoiding many complex design choices, such as data properties and architecture configuration. Although these framework results provide a good starting point, many configurations in this problem can be optimized. In this study, we tested two U-Net-based architectures, using different preprocessing techniques, and we modified the existing hyperparameters provided by nnU-Net. To study the impact of different settings on model segmentation accuracy, we conducted an analysis of variance (ANOVA) statistical analysis. The factors studied included the datasets according to nodule diameter size, model, preprocessing, polynomial learning rate scheduler, and number of epochs. The results of the ANOVA analysis revealed significant differences in the datasets, models, and preprocessing.

Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization.

The analysis of gene expression quantification data is a powerful and widely used approach in cancer research. This work provides new insights into the transcriptomic changes that occur in healthy uterine tissue compared to those in cancerous tissues and explores the differences associated with uterine cancer localizations and histological subtypes. To achieve this, RNA-Seq data from the TCGA database were preprocessed and analyzed using the KnowSeq package. Firstly, a kNN model was applied to classify uterine cervix cancer, uterine corpus cancer, and healthy uterine samples. Through variable selection, a three-gene signature was identified (VWCE, CLDN15, ADCYAP1R1), achieving consistent 100% test accuracy across 20 repetitions of a 5-fold cross-validation. A supplementary similar analysis using miRNA-Seq data from the same samples identified an optimal two-gene miRNA-coding signature potentially regulating the three-gene signature previously mentioned, which attained optimal classification performance with an 82% F1-macro score. Subsequently, a kNN model was implemented for the classification of cervical cancer samples into their two main histological subtypes (adenocarcinoma and squamous cell carcinoma). A uni-gene signature (ICA1L) was identified, achieving 100% test accuracy through 20 repetitions of a 5-fold cross-validation and externally validated through the CGCI program. Finally, an examination of six cervical adenosquamous carcinoma (mixed) samples revealed a pattern where the gene expression value in the mixed class aligned closer to the histological subtype with lower expression, prompting a reconsideration of the diagnosis for these mixed samples. In summary, this study provides valuable insights into the molecular mechanisms of uterine cervix and corpus cancers. The newly identified gene signatures demonstrate robust predictive capabilities, guiding future research in cancer diagnosis and treatment methodologies.

Novel methodology for detecting and localizing cancer area in histopathological images based on overlapping patches.

Cancer disease is one of the most important pathologies in the world, as it causes the death of millions of people, and the cure of this disease is limited in most cases. Rapid spread is one of the most important features of this disease, so many efforts are focused on its early-stage detection and localization. Medicine has made numerous advances in the recent decades with the help of artificial intelligence (AI), reducing costs and saving time. In this paper, deep learning models (DL) are used to present a novel method for detecting and localizing cancerous zones in WSI images, using tissue patch overlay to improve performance results. A novel overlapping methodology is proposed and discussed, together with different alternatives to evaluate the labels of the patches overlapping in the same zone to improve detection performance. The goal is to strengthen the labeling of different areas of an image with multiple overlapping patch testing. The results show that the proposed method improves the traditional framework and provides a different approach to cancer detection. The proposed method, based on applying 3x3 step 2 average pooling filters on overlapping patch labels, provides a better result with a 12.9% correction percentage for misclassified patches on the HUP dataset and 15.8% on the CINIJ dataset. In addition, a filter is implemented to correct isolated patches that were also misclassified. Finally, a CNN decision threshold study is performed to analyze the impact of the threshold value on the accuracy of the model. The alteration of the threshold decision along with the filter for isolated patches and the proposed method for overlapping patches, corrects about 20% of the patches that are mislabeled in the traditional method. As a whole, the proposed method achieves an accuracy rate of 94.6%. The code is available at https://github.com/sergioortiz26/Cancer_overlapping_filter_WSI_images.

AKI development is an independent predictor of mortality in infective endocarditis.

INTRODUCTION: Infective endocarditis presents a 25% mortality. Acute kidney injury (AKI) develops in up to 70% of the cases. The aim of this study is to evaluate the predictive value of AKI in mortality due to endocarditis and to assess its associated factors. METHODS: Unicentric and retrospective study including all patients with in-hospital diagnosis of endocarditis between 2015 and 2021. Epidemiological data and comorbidities were collected at baseline. During admission, renal function parameters, infection-related variables and mortality were collected. Using adjusted multivariate models, LRA predictive value was determined. RESULTS: One hundred and thirty-four patients (63% males, age 72±15 years) were included. Of them 94 (70%) developed AKI (50% AKIN-1, 29% AKIN-2 and 21% AKIN-3). Factors associated to AKI were age (p=0.03), hypertension (p=0.005), previous chronic kidney disease (p=0.001), heart failure (p=0.006), peripheral vascular disease (p=0.022) and glomerular filtration rate (GFR) at baseline (p<0.001). GFR at baseline was the only factor independently associated to AKI (OR 0.94, p=0.001). In-hospital deaths were registered in 46 (34%) patients. Of them, 45 (98%) patients had developed AKI. AKI was independently associated to mortality through diverse multivariate models. GFR loss (OR 1.054, p<0.001) and GFR at baseline (0.963, p=0.012) also predicted mortality during admission. CONCLUSIONS: AKI development and its severity (GFR loss and AKIN severity) impacts in in-hospital mortality due to infective endocarditis.

Using cited references to improve the retrieval of related biomedical documents.

BACKGROUND: A popular query from scientists reading a biomedical abstract is to search for topic-related documents in bibliographic databases. Such a query is challenging because the amount of information attached to a single abstract is little, whereas classification-based retrieval algorithms are optimally trained with large sets of relevant documents. As a solution to this problem, we propose a query expansion method that extends the information related to a manuscript using its cited references. RESULTS: Data on cited references and text sections in 249,108 full-text biomedical articles was extracted from the Open Access subset of the PubMed Central® database (PMC-OA). Of the five standard sections of a scientific article, the Introduction and Discussion sections contained most of the citations (mean = 10.2 and 9.9 citations, respectively). A large proportion of articles (98.4%) and their cited references (79.5%) were indexed in the PubMed® database. Using the MedlineRanker abstract classification tool, cited references allowed accurate retrieval of the citing document in a test set of 10,000 documents and also of documents related to six biomedical topics defined by particular MeSH® terms from the entire PMC-OA (p-value<0.01). Classification performance was sensitive to the topic and also to the text sections from which the references were selected. Classifiers trained on the baseline (i.e., only text from the query document and not from the references) were outperformed in almost all the cases. Best performance was often obtained when using all cited references, though using the references from Introduction and Discussion sections led to similarly good results. This query expansion method performed significantly better than pseudo relevance feedback in 4 out of 6 topics. CONCLUSIONS: The retrieval of documents related to a single document can be significantly improved by using the references cited by this document (p-value<0.01). Using references from Introduction and Discussion performs almost as well as using all references, which might be useful for methods that require reduced datasets due to computational limitations. Cited references from particular sections might not be appropriate for all topics. Our method could be a better alternative to pseudo relevance feedback though it is limited by full text availability.