Search

Biomechanical and clinical gait research observes muscles and tendons in limbs to study their functions and behaviour. Therefore, movements of distinct anatomical landmarks, such as muscle-tendon junctions, are frequently measured. We propose a reliable and time efficient machine-learning approach to track these junctions in ultrasound videos and support clinical biomechanists in gait analysis. In order to facilitate this process, a method based on deep-learning was introduced. We gathered an extensive dataset, covering 3 functional movements, 2 muscles, collected on 123 healthy and 38 impaired subjects with 3 different ultrasound systems, and providing a total of 66864 annotated ultrasound images in our network training. Furthermore, we used data collected across independent laboratories and curated by researchers with varying levels of experience. For the evaluation of our method a diverse test-set was selected that is independently verified by four specialists. We show that our model achieves similar performance scores to the four human specialists in identifying the muscle-tendon junction position. Our method provides time-efficient tracking of muscle-tendon junctions, with prediction times of up to 0.078 seconds per frame (approx. 100 times faster than manual labeling). All our codes, trained models and test-set were made publicly available and our model is provided as a free-to-use online service on https://deepmtj.org/., Comment: in IEEE Transactions on Biomedical Engineering

Summary Objective: To identify and highlight research papers representing noteworthy developments in signals, sensors, and imaging informatics in 2020. Method: A broad literature search was conducted on PubMed and Scopus databases. We combined Medical Subject Heading (MeSH) terms and keywords to construct particular queries for sensors, signals, and image informatics. We only considered papers that have been published in journals providing at least three articles in the query response. Section editors then independently reviewed the titles and abstracts of preselected papers assessed on a three-point Likert scale. Papers were rated from 1 (do not include) to 3 (should be included) for each topical area (sensors, signals, and imaging informatics) and those with an average score of 2 or above were subsequently read and assessed again by two of the three co-editors. Finally, the top 14 papers with the highest combined scores were considered based on consensus. Results: The search for papers was executed in January 2021. After removing duplicates and conference proceedings, the query returned a set of 101, 193, and 529 papers for sensors, signals, and imaging informatics, respectively. We filtered out journals that had less than three papers in the query results, reducing the number of papers to 41, 117, and 333, respectively. From these, the co-editors identified 22 candidate papers with more than 2 Likert points on average, from which 14 candidate best papers were nominated after intensive discussion. At least five external reviewers then rated the remaining papers. The four finalist papers were found using the composite rating of all external reviewers. These best papers were approved by consensus of the International Medical Informatics Association (IMIA) Yearbook editorial board. Conclusions. Sensors, signals, and imaging informatics is a dynamic field of intense research. The four best papers represent advanced approaches for combining, processing, modeling, and analyzing heterogeneous sensor and imaging data. The selected papers demonstrate the combination and fusion of multiple sensors and sensor networks using electrocardiogram (ECG), electroencephalogram (EEG), or photoplethysmogram (PPG) with advanced data processing, deep and machine learning techniques, and present image processing modalities beyond state-of-the-art that significantly support and further improve medical decision making.

Author(s): Hsu, William; Baumgartner, Christian; Deserno, Thomas M; Section Editors for the IMIA Yearbook Section on Sensors, Signals, and Imaging Informatics | Abstract: ObjectiveTo highlight noteworthy papers that are representative of 2019 developments in the fields of sensors, signals, and imaging informatics.MethodA broad literature search was conducted in January 2020 using PubMed. Separate predefined queries were created for sensors/signals and imaging informatics using a combination of Medical Subject Heading (MeSH) terms and keywords. Section editors reviewed the titles and abstracts of both sets of results. Papers were assessed on a three-point Likert scale by two co-editors, rated from 3 (do not include) to 1 (should be included). Papers with an average score of 2 or less were then read by all three section editors, and the group nominated top papers based on consensus. These candidate best papers were then rated by at least six external reviewers.ResultsThe query related to signals and sensors returned a set of 255 papers from 140 unique journals. The imaging informatics query returned a set of 3,262 papers from 870 unique journals. Based on titles and abstracts, the section co-editors jointly filtered the list down to 50 papers from which 15 candidate best papers were nominated after discussion. A composite rating after review determined four papers which were then approved by consensus of the International Medical Informatics Association (IMIA) Yearbook editorial board. These best papers represent different international groups and journals.ConclusionsThe four best papers represent state-of-the-art approaches for processing, combining, and analyzing heterogeneous sensor and imaging data. These papers demonstrate the use of advanced machine learning techniques to improve comparisons between images acquired at different time points, fuse information from multiple sensors, and translate images from one modality to another.

The use of different cardiac imaging modalities such as MRI, CT or ultrasound enables the visualization and interpretation of altered morphological structures and function of the heart. In recent years, there has been an increasing interest in AI and deep learning that take into account spatial and temporal information in medical image analysis. In particular, deep learning tools using temporal information in image processing have not yet found their way into daily clinical practice, despite its presumed high diagnostic and prognostic value. This review aims to synthesize the most relevant deep learning methods and discuss their clinical usability in dynamic cardiac imaging using for example the complete spatiotemporal image information of the heart cycle. Selected articles were categorized according to the following indicators: clinical applications, quality of datasets, preprocessing and annotation, learning methods and training strategy, and test performance. Clinical usability was evaluated based on these criteria by classifying the selected papers into (i) clinical level, (ii) robust candidate and (iii) proof of concept applications. Interestingly, not a single one of the reviewed papers was classified as a "clinical level" study. Almost 39% of the articles achieved a "robust candidate" and as many as 61% a "proof of concept" status. In summary, deep learning in spatiotemporal cardiac imaging is still strongly research-oriented and its implementation in clinical application still requires considerable efforts. Challenges that need to be addressed are the quality of datasets together with clinical verification and validation of the performance achieved by the used method.

Objective: To identify research works that exemplify recent developments in the field of sensors, signals, and imaging informatics. Method: A broad literature search was conducted using PubMed and Web of Science, supplemented with individual papers that were nominated by section editors. A predefined query made from a combination of Medical Subject Heading (MeSH) terms and keywords were used to search both sources. Section editors then filtered the entire set of retrieved papers with each paper having been reviewed by two section editors. Papers were assessed on a three-point Likert scale by two section editors, rated from 0 (do not include) to 2 (should be included). Only papers with a combined score of 2 or above were considered. Results: A search for papers was executed at the start of January 2019, resulting in a combined set of 1,459 records published in 2018 in 119 unique journals. Section editors jointly filtered the list of candidates down to 14 nominations. The 14 candidate best papers were then ranked by a group of eight external reviewers. Four papers, representing different international groups and journals, were selected as the best papers by consensus of the International Medical Informatics Association (IMIA) Yearbook editorial board. Conclusions: The fields of sensors, signals, and imaging informatics have rapidly evolved with the application of novel artificial intelligence/machine learning techniques. Studies have been able to discover hidden patterns and integrate different types of data towards improving diagnostic accuracy and patient outcomes. However, the quality of papers varied widely without clear reporting standards for these types of models. Nevertheless, a number of papers have demonstrated useful techniques to improve the generalizability, interpretability, and reproducibility of increasingly sophisticated models.

Recording muscle tendon junction displacements during movement, allows separate investigation of the muscle and tendon behaviour, respectively. In order to provide a fully-automatic tracking method, we employ a novel deep learning approach to detect the position of the muscle tendon junction in ultrasound images. We utilize the attention mechanism to enable the network to focus on relevant regions and to obtain a better interpretation of the results. Our data set consists of a large cohort of 79 healthy subjects and 28 subjects with movement limitations performing passive full range of motion and maximum contraction movements. Our trained network shows robust detection of the muscle tendon junction on a diverse data set of varying quality with a mean absolute error of 2.55$\pm$1 mm. We show that our approach can be applied for various subjects and can be operated in real-time. The complete software package is available for open-source use via: https://github.com/luuleitner/deepMTJ, Comment: Accepted version to be published in 2020, 42nd Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Montreal, Canada

Our sense of balance and spatial orientation strongly depends on the correct functionality of our vestibular system. Vestibular dysfunction can lead to blurred vision and impaired balance and spatial orientation, causing a significant decrease in quality of life. Recent studies have shown that vestibular implants offer a possible treatment for patients with vestibular dysfunction. The close proximity of the vestibular nerve bundles, the facial nerve and the cochlear nerve poses a major challenge to targeted stimulation of the vestibular system. Modeling the electrical stimulation of the vestibular system allows for an efficient analysis of stimulation scenarios previous to time and cost intensive in vivo experiments. Current models are based on animal data or CAD models of human anatomy. In this work, a (semi-)automatic modular workflow is presented for the stepwise transformation of segmented vestibular anatomy data of human vestibular specimens to an electrical model and subsequently analyzed. The steps of this workflow include (i) the transformation of labeled datasets to a tetrahedra mesh, (ii) nerve fiber anisotropy and fiber computation as a basis for neuron models, (iii) inclusion of arbitrary electrode designs, (iv) simulation of quasistationary potential distributions, and (v) analysis of stimulus waveforms on the stimulation outcome. Results obtained by the workflow based on human datasets and the average shape of a statistical model revealed a high qualitative agreement and a quantitatively comparable range compared to data from literature, respectively. Based on our workflow, a detailed analysis of intra- and extra-labyrinthine electrode configurations with various stimulation waveforms and electrode designs can be performed on patient specific anatomy, making this framework a valuable tool for current optimization questions concerning vestibular implants in humans.

This article presents a new input device for spastic patients and others with similar symptoms. The sensor consists of a disc used to determine positions and can replace standard joysticks in medical devices such as electric-powered wheelchairs. Using a standard joystick while operating a powered wheelchair can result in dangerous situations when spastic movements occur and extremities cramp making them uncontrollable. To avoid this, a disc was developed that can be controlled with any body part. By shifting weight (x- and y-axis) the disc can tilt in any direction creating a proportional output signal and can also be pushed down in the center (z-axis) to open a menu on a screen for example. When spasms occur it is impossible for users to get stuck on the input device because the disc is flat and can be mounted within a control panel. Body parts coming into contact with the disc would merely slide across the disc without triggering unintentional actions. The sensor presented here is also adaptive and can be adjusted to fit a user’s strength and range of motion. This proposal aims to develop an input device that enables spastic patients to operate sensitive systems safely.

Movement science investigating muscle and tendon functions during locomotion utilizes commercial ultrasound imagers built for medical applications. These limit biomechanics research due to their form factor, range of view, and spatio-temporal resolution. This review systematically investigates the technical aspects of applying ultrasound as a research tool to investigate human and animal locomotion. It provides an overview on the ultrasound systems used and of their operating parameters. We present measured fascicle velocities and discuss the results with respect to operating frame rates during recording. Furthermore, we derive why muscle and tendon functions should be recorded with a frame rate of at least 150 Hz and a range of view of 250 mm. Moreover, we analyze why and how the development of better ultrasound observation devices at the hierarchical level of muscles and tendons can support biomechanics research. Additionally, we present recent technological advances and their possible application. We provide a list of recommendations for the development of a more advanced ultrasound sensor system class targeting biomechanical applications. Looking to the future, mobile, ultrafast ultrasound hardware technologies create immense opportunities to expand the existing knowledge of human and animal movement., Sensors, 19 (19), ISSN:1424-8220

This article presents a new optical, multi-functional, high-resolution 3-axis sensor which serves to navigate and can, for example, replace standard joysticks in medical devices such as electric wheelchairs, surgical robots or medical diagnosis devices. A light source, e.g., a laser diode, is affixed to a movable axis and projects a random geometric shape on an image sensor (CMOS or CCD). The downstream microcontroller’s software identifies the geometric shape’s center, distortion and size, and then calculates x, y, and z coordinates, which can be processed in attached devices. Depending on the image sensor in use (e.g., 6.41 megapixels), the 3-axis sensor features a resolution of 1544 digits from right to left and 1038 digits up and down. Through interpolation, these values rise by a factor of 100. A unique feature is the exact reproducibility (deflection to coordinates) and its precise ability to return to its neutral position. Moreover, optical signal processing provides a high level of protection against electromagnetic and radio frequency interference. The sensor is adaptive and adjustable to fit a user’s range of motion (stroke and force). This recommendation aims to optimize sensor systems such as joysticks in medical devices in terms of safety, ease of use, and adaptability.

Background This work presents a machine learning strategy to increase sensitivity in tandem mass spectrometry (MS/MS) data analysis for peptide/protein identification. MS/MS yields thousands of spectra in a single run which are then interpreted by software. Most of these computer programs use a protein database to match peptide sequences to the observed spectra. The peptide-spectrum matches (PSMs) must also be assessed by computational tools since manual evaluation is not practicable. The target-decoy database strategy is largely used for error estimation in PSM assessment. However, in general, that strategy does not account for sensitivity. Results In a previous study, we proposed the method MUMAL that applies an artificial neural network to effectively generate a model to classify PSMs using decoy hits with increased sensitivity. Nevertheless, the present approach shows that the sensitivity can be further improved with the use of a cost matrix associated with the learning algorithm. We also demonstrate that using a threshold selector algorithm for probability adjustment leads to more coherent probability values assigned to the PSMs. Our new approach, termed MUMAL2, provides a two-fold contribution to shotgun proteomics. First, the increase in the number of correctly interpreted spectra in the peptide level augments the chance of identifying more proteins. Second, the more appropriate PSM probability values that are produced by the threshold selector algorithm impact the protein inference stage performed by programs that take probabilities into account, such as ProteinProphet. Our experiments demonstrate that MUMAL2 reached around 15% of improvement in sensitivity compared to the best current method. Furthermore, the area under the ROC curve obtained was 0.93, demonstrating that the probabilities generated by our model are in fact appropriate. Finally, Venn diagrams comparing MUMAL2 with the best current method show that the number of exclusive peptides found by our method was nearly 4-fold higher, which directly impacts the proteome coverage. Conclusions The inclusion of a cost matrix and a probability threshold selector algorithm to the learning task further improves the target-decoy database analysis for identifying peptides, which optimally contributes to the challenging task of protein level identification, resulting in a powerful computational tool for shotgun proteomics.

We investigated different mathematical models concerning signaling pathways and built a new pathway model for TNF� -NF B signaling using an integrative analytical approach. This integrative approach consists of a knowledgebase, model designing/visualization and simulation environments. In particular, our new TNF� -NF B signaling pathway model was developed based on literature studies and the use of ordinary differential equations and a detailed protein-protein interaction connectivity map within this approach. Using the most detailed mathematical model as a base model, three new proteins -- TRAF1, FLIP, and MEKK3 -- were identified and included in our new model. Our results show that this integrative approach offers the most detailed and consistent mathematical description for TNF� - NF B signaling and further increases the understanding of TNF� -NF B signaling pathway. This tool can be downloaded through the following link (http://sourceforge.net/projects/dmsp11/).

Summary Objectives: In this work, a cellular automaton software package for simulating different infectious diseases, storing the simulation results in a data warehouse system and analyzing the obtained results to generate prediction models as well as contingency plans, is proposed. The Brisbane H3N2 flu virus, which has been spreading during the winter season 2009, was used for simulation in the federal state of Tyrol, Austria. Methods: The simulation-modeling framework consists of an underlying cellular automaton. The cellular automaton model is parameterized by known disease parameters and geographical as well as demographical conditions are included for simulating the spreading. The data generated by simulation are stored in the back room of the data warehouse using the Talend Open Studio software package, and subsequent statistical and data mining tasks are performed using the tool, termed Knowledge Discovery in Database Designer (KD3). Results: The obtained simulation results were used for generating prediction models for all nine federal states of Austria. Conclusion: The proposed framework provides a powerful and easy to handle interface for parameterizing and simulating different infectious diseases in order to generate prediction models and improve contingency plans for future events.

In this work we present an application for integrating and analyzing life science data using a biomedical data warehouse system and tools developed in-house enabling knowledge discovery tasks. Knowledge discovery is known as a process where different steps have to be coupled in order to solve a specified question. In order to create such a combination of steps, a data miner using our in-house developed knowledge discovery tool KD3 is able to assemble functional objects to a data mining workflow. The generated workflows can easily be used for ulterior purposes by only adding new data and parameterizing the functional objects in the process. Workflows guide the performance of data integration and aggregation tasks, which were defined and implemented using a public available open source tool. To prove the concept of our application, intelligent query models were designed and tested for the identification of genotype-phenotype correlations in Marfan Syndrome. It could be shown that by using our application, a data miner can easily develop new knowledge discovery algorithms that may later be used to retrieve medical relevant information by clinical researchers.

In this paper, a cellular automaton framework for processing the spatiotemporal spread of infectious diseases is presented. The developed environment simulates and visualizes how infectious diseases might spread, and hence provides a powerful instrument for health care organizations to generate disease prevention and contingency plans. In this study, the outbreak of an avian flu like virus was modeled in the state of Tyrol, and various scenarios such as quarantine, effect of different medications on viral spread and changes of social behavior were simulated. The proposed framework is implemented using the programming language Java. The set up of the simulation environment requires specification of the disease parameters and the geographical information using a population density colored map, enriched with demographic data. The results of the numerical simulations and the analysis of the computed parameters will be used to get a deeper understanding of how the disease spreading mechanisms work, and how to protect the population from contracting the disease. Strategies for optimization of medical treatment and vaccination regimens will also be investigated using our cellular automaton framework. In this study, six different scenarios were simulated. It showed that geographical barriers may help to slow down the spread of an infectious disease, however, when an aggressive and deadly communicable disease spreads, only quarantine and controlled medical treatment are able to stop the outbreak, if at all.

Summary Objectives: Presently, the protein interaction information concerning different signaling pathways is available in a qualitative manner in different online protein interaction databases. The challenge here is to derive a quantitative way of modeling signaling pathways from qualitative way of modeling signaling pathways from a qualitative level. To address this issue we developed a database that includes mathematical modeling knowledge and biological knowledge about different signaling pathways. Methods: The database is part of an integrative environment that includes environments for pathway design, visualization, simulation and a knowledge base that combines biological and modeling information concerning pathways. The system is designed as a client-server architecture. It contains a pathway designing environment and a simulation environment as upper layers with a relational knowledge base as the underlying layer. Results: DMSP – Database for Modeling Signaling Pathways incorporates biological datasets from online databases like BIND, DIP, PIP, and SPiD. The modeling knowledge that has been incorporated is based on a literature study. Pathway models can be designed, visualized and simulated based on the knowledge stored in the DMSP. The user can download the whole dataset and build pathway models using the knowledge stored in our database. As an example, the TNF? pathway model was implemented and tested using this approach. Conclusion: DMSP is an initial step towards the aim of combining modeling and biological knowledge concerning signaling pathways. It helps in understanding pathways in a qualitative manner from a qualitative level. Simulation results enable the interpretation of a biological system from a quantitative and systemtheoretic point of view.

When the era of big data arrived in the early nineteen nineties, biomedical research boosted new innovations, procedures and methods aiding in clinical care and patient management. This chapter provides an introduction to the basic concepts and strategies of data-driven biomedical research and application, an area that is explained using terms such as computational biomedicine or clinical/medical bioinformatics. After a brief motivation it starts with a survey on data sources and bioanalytic technologies for high-throughput data generation, a selection of experimental study designs and their applications, procedures and recommendations on how to handle data quality and privacy, followed by a discussion on basic data warehouse concepts utilized for life science data integration, data mining and knowledge discovery. Finally, five application examples are briefly delineated, emphazising the benefit and power of computational methods and tools in this field. The author trusts that this chapter will encourage the reader to handle and interpret the huge amount of data usually generated in research projects or clinical routine to exploit mined bioinformation and medical knowledge for individualized health care.

We present a method to change the volume of organs or tissues in computational anatomical models by simulating the human body as a biomechanical solid with initial strains causing local volume shrinkage or expansion. The non-linear hyperelastic material behavior is solved with the finite element method. The bone positions are prescribed and treated as rigid bodies surrounded by elastic soft tissue. A multi-domain mesh defines individual bones and at least one soft tissue region. Each region can have different material properties, volume growth rates or mesh settings. The method can be used to deform complex anatomical models, such as the Virtual Population models. The proposed strategy has been used to parametrize models by different BMI levels, change the volume of selected organs, and modify the posture of anatomical models.

In this chapter, methods of clinical bioinformatics in targeted metabolomics are discussed, with an emphasis on the discovery of metabolic biomarkers. The reader is introduced to general aspects such as initiatives in metabolomics standardization, regulatory guidelines and software validation, and is presented an overview of the bioinformatics workflow in metabolomics. Engineering-based concepts of clinical bioinformatics in supporting the storage and automated analysis of samples, the integration of data in public repositories, and in the management of data using metabolomics application software are discussed. Chemometrics algorithms for data processing are summarized, modalities of biostatistics and data analysis presented, as well as data mining and machine learning approaches, aiming at the discovery of biomarkers in targeted metabolomics. Methods of data interpretation in the context of annotated biochemical pathways are suggested, theoretical concepts of metabolic modeling and engineering are introduced, and the in-silico modeling and simulation of molecular processes is briefly touched. Finally, a short outlook on future perspectives in the application of clinical bioinformatics in targeted metabolomics is given, e.g. on the development of integrated mass spectrometry solutions, ready for routine clinical usage in laboratory medicine, or on the application of concepts of artificial intelligence in laboratory automation – liquid handling robots, autonomously performing experiments and generating hypotheses.

Machine learning has a great potential to mine potential markers from high-dimensional metabolic data without any a priori knowledge. Exemplarily, we investigated metabolic patterns of three severe metabolic disorders, PAHD, MCADD, and 3-MCCD, on which we constructed classification models for disease screening and diagnosis using a decision tree paradigm and logistic regression analysis (LRA). For the LRA model-building process we assessed the relevance of established diagnostic flags, which have been developed from the biochemical knowledge of newborn metabolism, and compared the models’ error rates with those of the decision tree classifier. Both approaches yielded comparable classification accuracy in terms of sensitivity (>95.2%), while the LRA models built on flags showed significantly enhanced specificity. The number of false positive cases did not exceed 0.001%.

High-throughput technologies such as mass spectrometry produce large amounts of data that require sophisticated computational methods to preprocess and identify highly discriminatory features (biomarker candidates) from these data. In this chapter, a computational workflow for the search and identification of biomarker candidates using mass spectrometry data is presented. First, preprocessing steps necessary to transform raw spectra into comparable data sets are described, followed by a novel three-step feature selection approach that combines the advantages of efficient filter and effective wrapper techniques. The proposed workflow has been integrated into the Knowledge Discovery in Databases (KD 3 ) Designer tool, our self-designed and cost-free software package. One of the main advantages of this tool is its straightforward design, which visualizes processing steps that can be easily connected to workflows. Due to its modular software architecture, new algorithms can be readily implemented into the system. This analysis strategy was evaluated using an example mass spectrometry data set.

Restoration concepts for large river systems are currently in an early stage of development. Possibilities for, and constraints of, rehabilitation—both from a process-oriented view as well as from the nature conservation perspective—differ strongly according to the degree of anthropogenic changes. This requires precisely formulated amelioration goals. Well-conceived and thoroughly analysed case studies are necessary to better understand reversibility, direction and time scale of changes, and the sustainability of various scenarios. It is important to plan controllable set-ups with long-term monitoring in the pre- and post-implementation phases of restoration programmes. In order to achieve these goals, monitoring instruments have to be developed and calibrated that allow the definition and analysis of improvements. Finally, controlled restoration programmes offer the opportunity for large-scale experiments to test overall concepts and hypotheses and have an important heuristic value to improve the understanding of river ecology in general. Copyright © 1999 John Wiley & Sons, Ltd.

A pooling design can be used as a powerful strategy to compensate for limited amounts of samples or high biological variation. In this paper, we perform a comparative study to model and quantify the effects of virtual pooling on the performance of the widely applied classifiers, support vector machines (SVMs), random forest (RF),k-nearest neighbors (k-NN), penalized logistic regression (PLR), and prediction analysis for microarrays (PAMs). We evaluate a variety of experimental designs using mock omics datasets with varying levels of pool sizes and considering effects from feature selection. Our results show that feature selection significantly improves classifier performance for non-pooled and pooled data. All investigated classifiers yield lower misclassification rates with smaller pool sizes. RF mainly outperforms other investigated algorithms, while accuracy levels are comparable among all the remaining ones. Guidelines are derived to identify an optimal pooling scheme for obtaining adequate predictive power and, hence, to motivate a study design that meets best experimental objectives and budgetary conditions, including time constraints.

OmicsMiner is a computational platform providing systematic access to state-of-the-art data processing and mining methods with the goal of facilitating the design of customized pipelines for processing a diverse range of biological data sets. Many built-in methods are provided for preprocessing, feature selection, clustering and classification of complex datasets. The platform supports convenient integration of additional algorithms that can further expand its functionality. OmicsMiner also provides convenient and concise interactive graphical user interfaces for data processing. OmicsMiner is a Java program that is platform-independent and does not require installation.

Based on the biotechnological revolution in the past years, molecular biology has become increasingly data-driven. Knowledge Discovery in Databases, a well-known process in the field of bioinformatics, is supporting the biological research process from data integration, knowledge mining to data interpretation. This work proposes a new software suite, termed Knowledge Discovery inDatabases Designer (KD3), covering the completeKnowledge Discovery in Databases process using a workflow-oriented architecture. Three different application-oriented modules are implemented in KD3: First, the Designer for designing specific workflows. These workflows can be used by the Interpreter, which allows to load and parameterize existing workflows. The Launcher encapsulates one dedicated workflow into an independent application to answer one specific biomedical question. KD3 offers a variety of implemented methods, which can be easily extended with new customized components using functional objects. All components can be connected to workflows, which may contain elements of other applications.

The target-decoy search strategy has been successfully applied in shotgun proteomics for validating peptide and protein identifications. If, on one hand, this method has proven to be very efficient for error estimation, on the other hand, little attention has been paid to the resulting sensitivity. Only two scores are normally used and thresholds are explored in a very simplistic way. In this work, a multivariate decoy analysis is described, where many quality parameters are considered. This analysis is treated in our approach as an optimization problem for sensitivity maximization. Furthermore, an efficient heuristic is proposed to solve this problem. Experiments comparing our method, termed MUDE (multivariate decoy database analysis), with traditional bivariate decoy analysis and with Peptide/ProteinProphet showed that our procedure significantly enhances the retrieved number of identifications when comparing the same false discovery rates. Particularly for phosphopeptide/protein identifications, we could demonstrate more than a two-fold increase in sensitivity compared with the Trans-Proteomic Pipeline tools.

Objective: To evaluate and compare the performance of different rule-ranking algorithms for rule-based classifiers on biomedical datasets. Methodology: Empirical evaluation of five rule ranking algorithms on two biomedical datasets, with performance evaluation based on ROC analysis and 5x2 cross-validation. Results: On a lung cancer dataset, the area under the ROC curve (AUC) of, on average, 14267.1 rules was 0.862. Multi-rule ranking found 13.3 rules with an AUC of 0.852. Four single-rule ranking algorithms, using the same number of rules, achieved average AUC values of 0.830, 0.823, 0.823, and 0.822, respectively. On a prostate cancer dataset, an average of 339265.3 rules had an AUC of 0.934, while 9.4 rules obtained from multi-rule and single-rule rankings had average AUCs of 0.932, 0.926, 0.925, 0.902 and 0.902, respectively. Conclusion: Multi-variate rule ranking performs better than the single-rule ranking algorithms. Both single-rule and multi-rule methods are able to substantially reduce the number of rules while keeping classification performance at a level comparable to the full rule set.

This chapter provides an overview of the knowledge discovery process in metabolomics, a young discipline in the life sciences arena. It introduces two emerging bioanalytical concepts for generating biomolecular information, followed by various data mining and information retrieval procedures such as feature selection, classification, clustering and biochemical interpretation of mined data, illustrated by real examples from preclinical and clinical studies. The authors trust that this chapter will provide an acceptable balance between bioanalytics background information, essential to understanding the complexity of data generation, and information on data mining principals, specific methods and processes, and biomedical application. Thus, this chapter is anticipated to appeal to those with a metabolomics background as well as to basic researchers within the data mining community who are interested in novel life science applications.

The combination of different feature selection approaches has shown to produce feasible feature subsets with high predictive value. We here introduce a modified version of Stacked Feature Ranking (SFR), using a two level learning architecture with a suggestion and a decision layer aggregating different feature selectors to a consensus feature ranking. Ion molecule reaction mass spectrometry (IMR-MS) was applied to breath gas samples of a total of 57 patients suffering from alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD), and 35 healthy controls with the objective of identifying breath gas marker candidates at disease versus non-disease state. We compared SFR with four common feature selection methods and one ensemble-based approach, indicating a significantly higher discriminatory ability of up to 10% for the selected subsets using ROC analysis. SFR is a powerful tool for the identification of highly discriminating biomarkers in complex biological mixtures.

This chapter provides an overview of emerging bioinformatics methods for the biomarker discovery process and medical decision support. It introduces study design consideration and bioanalytic concepts for generating biomedical data, followed by various data mining and information retrieval procedures such as feature selection, classification as well as statistical and clinical validation. The reviewed methods are illustrated by real examples from preclinical and clinical studies, and the application in medical decision making is discussed. This chapter is anticipated to address to those with a bioinformatics background as well as biomedical researchers who are interested in the application of computational methods in biomarker discovery and medical decision making.

Motivation: During the Bavarian newborn screening programme all newborns have been tested for about 20 inherited metabolic disorders. Owing to the amount and complexity of the generated experimental data, machine learning techniques provide a promising approach to investigate novel patterns in high-dimensional metabolic data which form the source for constructing classification rules with high discriminatory power. Results: Six machine learning techniques have been investigated for their classification accuracy focusing on two metabolic disorders, phenylketo nuria (PKU) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Logistic regression analysis led to superior classification rules (sensitivity >96.8%, specificity >99.98%) compared to all investigated algorithms. Including novel constellations of metabolites into the models, the positive predictive value could be strongly increased (PKU 71.9% versus 16.2%, MCADD 88.4% versus 54.6% compared to the established diagnostic markers). Our results clearly prove that the mined data confirm the known and indicate some novel metabolic patterns which may contribute to a better understanding of newborn metabolism. Availability: WEKA machine learning package: www.cs.waikato.ac.nz/~ml/weka and statistical software package ADE-4: http://pbil.univ-lyon1.fr/ADE-4

Classifiers based on parametric or non-parametric learning methods have different advantages and disadvantages. To take advantage of the strengths of both methods, we propose an algorithm that combines a parametric model (logistic regression) with a non-parametric classification method (k-nearest neighbors). This combination is based on a measure of appropriateness that uses a heuristic to decide which of the two components should contribute more to the final classification output. We measure the performance of this combination method on two data sets (one from medical informatics, and one consisting of simulated data) in terms of areas under the ROC curves (AUCs). We are able to demonstrate that our method of combining classifiers exceeds the performance of both individual classifiers taken separately.

Summary Introduction: Understanding the biological processes of signaling pathways as a whole system requires an integrative software environment that has comprehensive capabilities. The environment should include tools for pathway design, visualization, simulation and a knowledge base concerning signaling pathways as one. In this paper we introduce a new integrative environment for the systematic analysis of signaling pathways. Methods: This system includes environments for pathway design, visualization, simulation and a knowledge base that combines biological and modeling information concerning signaling pathways that provides the basic understanding of the biological system, its structure and functioning. The system is designed with a client-server architecture. It contains a pathway designing environment and a simulation environment as upper layers with a relational knowledge base as the underlying layer. Results: The TNFα-mediated NF-κB signal transduction pathway model was designed and tested using our integrative framework. It was also useful to define the structure of the knowledge base. Sensitivity analysis of this specific pathway was performed providing simulation data. Then the model was extended showing promising initial results. Conclusion: The proposed system offers a holistic view of pathways containing biological and modeling data. It will help us to perform biological interpretation of the simulation results and thus contribute to a better understanding of the biological system for drug identification.

High-throughput mass-spectrometry screening has the potential of superior results in detecting early stage cancer than traditional biomarkers. Proteomic data poses novel challenges for data mining, especially concerning the curse of dimensionality. In this paper, we present a 3-step feature selection framework combining the advantages of efficient filter and effective wrapper techniques. We demonstrate the performance of our framework on two SELDITOF- MS data sets for identifying biomarker candidates in ovarian and prostate cancer.