| 1. |
- Costa, Ivan G, et al.
(author)
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Constrained mixture estimation for analysis and robust classification of clinical time series.
- 2009
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In: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803. ; 25:12, s. i6-14
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Journal article (peer-reviewed)abstract
- Personalized medicine based on molecular aspects of diseases, such as gene expression profiling, has become increasingly popular. However, one faces multiple challenges when analyzing clinical gene expression data; most of the well-known theoretical issues such as high dimension of feature spaces versus few examples, noise and missing data apply. Special care is needed when designing classification procedures that support personalized diagnosis and choice of treatment. Here, we particularly focus on classification of interferon-beta (IFNbeta) treatment response in Multiple Sclerosis (MS) patients which has attracted substantial attention in the recent past. Half of the patients remain unaffected by IFNbeta treatment, which is still the standard. For them the treatment should be timely ceased to mitigate the side effects.We propose constrained estimation of mixtures of hidden Markov models as a methodology to classify patient response to IFNbeta treatment. The advantages of our approach are that it takes the temporal nature of the data into account and its robustness with respect to noise, missing data and mislabeled samples. Moreover, mixture estimation enables to explore the presence of response sub-groups of patients on the transcriptional level. We clearly outperformed all prior approaches in terms of prediction accuracy, raising it, for the first time, >90%. Additionally, we were able to identify potentially mislabeled samples and to sub-divide the good responders into two sub-groups that exhibited different transcriptional response programs. This is supported by recent findings on MS pathology and therefore may raise interesting clinical follow-up questions.The method is implemented in the GQL framework and is available at http://www.ghmm.org/gql. Datasets are available at http://www.cin.ufpe.br/ approximately igcf/MSConst.Supplementary data are available at Bioinformatics online.
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| 2. |
- Costa, Ivan G, et al.
(author)
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The Graphical Query Language: a tool for analysis of gene expression time-courses.
- 2005
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In: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4803 .- 1460-2059. ; 21:10, s. 2544-5
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Journal article (peer-reviewed)abstract
- The Graphical Query Language (GQL) is a set of tools for the analysis of gene expression time-courses. They allow a user to pre-process the data, to query it for interesting patterns, to perform model-based clustering or mixture estimation, to include subsequent refinements of clusters and, finally, to use other biological resources to evaluate the results. Analyses are carried out in a graphical and interactive environment, allowing expert intervention in all stages of the data analysis.The GQL package is freely available under the GNU general public license (GPL) at http://www.ghmm.org/gql
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| 3. |
- Hafemeister, Christoph, et al.
(author)
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Classifying short gene expression time-courses with Bayesian estimation of piecewise constant functions.
- 2011
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In: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803. ; 27:7, s. 946-52
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Journal article (peer-reviewed)abstract
- Analyzing short time-courses is a frequent and relevant problem in molecular biology, as, for example, 90% of gene expression time-course experiments span at most nine time-points. The biological or clinical questions addressed are elucidating gene regulation by identification of co-expressed genes, predicting response to treatment in clinical, trial-like settings or classifying novel toxic compounds based on similarity of gene expression time-courses to those of known toxic compounds. The latter problem is characterized by irregular and infrequent sample times and a total lack of prior assumptions about the incoming query, which comes in stark contrast to clinical settings and requires to implicitly perform a local, gapped alignment of time series. The current state-of-the-art method (SCOW) uses a variant of dynamic time warping and models time series as higher order polynomials (splines).We suggest to model time-courses monitoring response to toxins by piecewise constant functions, which are modeled as left-right Hidden Markov Models. A Bayesian approach to parameter estimation and inference helps to cope with the short, but highly multivariate time-courses. We improve prediction accuracy by 7% and 4%, respectively, when classifying toxicology and stress response data. We also reduce running times by at least a factor of 140; note that reasonable running times are crucial when classifying response to toxins. In conclusion, we have demonstrated that appropriate reduction of model complexity can result in substantial improvements both in classification performance and running time.A Python package implementing the methods described is freely available under the GPL from http://bioinformatics.rutgers.edu/Software/MVQueries/.
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| 4. |
- Johansson, Simon, 1994, et al.
(author)
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De novo generated combinatorial library design
- 2024
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In: Digital Discovery. - 2635-098X. ; 3:1, s. 122-135
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Journal article (peer-reviewed)abstract
- Artificial intelligence (AI) contributes new methods for designing compounds in drug discovery, ranging from de novo design models suggesting new molecular structures or optimizing existing leads to predictive models evaluating their toxicological properties. However, a limiting factor for the effectiveness of AI methods in drug discovery is the lack of access to high-quality data sets leading to a focus on approaches optimizing data generation. Combinatorial library design is a popular approach for bioactivity testing as a large number of molecules can be synthesized from a limited number of building blocks. We propose a framework for designing combinatorial libraries using a molecular generative model to generate building blocks de novo, followed by using k-determinantal point processes and Gibbs sampling to optimize a selection from the generated blocks. We explore optimization of biological activity, Quantitative Estimate of Drug-likeness (QED) and diversity and the trade-offs between them, both in single-objective and in multi-objective library design settings. Using retrosynthesis models to estimate building block availability, the proposed framework is able to explore the prospective benefit from expanding a stock of available building blocks by synthesis or by purchasing the preferred building blocks before designing a library. In simulation experiments with building block collections from all available commercial vendors near-optimal libraries could be found without synthesis of additional building blocks; in other simulation experiments we showed that even one synthesis step to increase the number of available building blocks could improve library designs when starting with an in-house building block collection of reasonable size.
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| 5. |
- Johansson, Simon, 1994, et al.
(author)
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Using Active Learning to Develop Machine Learning Models for Reaction Yield Prediction
- 2022
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In: Molecular Informatics. - : Wiley. - 1868-1743 .- 1868-1751. ; 41:12
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Journal article (peer-reviewed)abstract
- Computer aided synthesis planning, suggesting synthetic routes for molecules of interest, is a rapidly growing field. The machine learning methods used are often dependent on access to large datasets for training, but finite experimental budgets limit how much data can be obtained from experiments. This suggests the use of schemes for data collection such as active learning, which identifies the data points of highest impact for model accuracy, and which has been used in recent studies with success. However, little has been done to explore the robustness of the methods predicting reaction yield when used together with active learning to reduce the amount of experimental data needed for training. This study aims to investigate the influence of machine learning algorithms and the number of initial data points on reaction yield prediction for two public high-throughput experimentation datasets. Our results show that active learning based on output margin reached a pre-defined AUROC faster than random sampling on both datasets. Analysis of feature importance of the trained machine learning models suggests active learning had a larger influence on the model accuracy when only a few features were important for the model prediction.
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| 6. |
- Marschall, Tobias, et al.
(author)
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CLEVER: clique-enumerating variant finder.
- 2012
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In: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803. ; 28:22, s. 2875-82
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Journal article (peer-reviewed)abstract
- Next-generation sequencing techniques have facilitated a large-scale analysis of human genetic variation. Despite the advances in sequencing speed, the computational discovery of structural variants is not yet standard. It is likely that many variants have remained undiscovered in most sequenced individuals.Here, we present a novel internal segment size based approach, which organizes all, including concordant, reads into a read alignment graph, where max-cliques represent maximal contradiction-free groups of alignments. A novel algorithm then enumerates all max-cliques and statistically evaluates them for their potential to reflect insertions or deletions. For the first time in the literature, we compare a large range of state-of-the-art approaches using simulated Illumina reads from a fully annotated genome and present relevant performance statistics. We achieve superior performance, in particular, for deletions or insertions (indels) of length 20-100 nt. This has been previously identified as a remaining major challenge in structural variation discovery, in particular, for insert size based approaches. In this size range, we even outperform split-read aligners. We achieve competitive results also on biological data, where our method is the only one to make a substantial amount of correct predictions, which, additionally, are disjoint from those by split-read aligners.CLEVER is open source (GPL) and available from http://clever-sv.googlecode.com.as@cwi.nl or tm@cwi.nl.Supplementary data are available at Bioinformatics online.
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| 7. |
- Schliep, Alexander, 1967, et al.
(author)
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Analyzing gene expression time-courses.
- 2005
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In: IEEE/ACM transactions on computational biology and bioinformatics. - 1545-5963. ; 2:3, s. 179-93
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Journal article (peer-reviewed)abstract
- Measuring gene expression over time can provide important insights into basic cellular processes. Identifying groups of genes with similar expression time-courses is a crucial first step in the analysis. As biologically relevant groups frequently overlap, due to genes having several distinct roles in those cellular processes, this is a difficult problem for classical clustering methods. We use a mixture model to circumvent this principal problem, with hidden Markov models (HMMs) as effective and flexible components. We show that the ensuing estimation problem can be addressed with additional labeled data-partially supervised learning of mixtures-through a modification of the Expectation-Maximization (EM) algorithm. Good starting points for the mixture estimation are obtained through a modification to Bayesian model merging, which allows us to learn a collection of initial HMMs. We infer groups from mixtures with a simple information-theoretic decoding heuristic, which quantifies the level of ambiguity in group assignment. The effectiveness is shown with high-quality annotation data. As the HMMs we propose capture asynchronous behavior by design, the groups we find are also asynchronous. Synchronous subgroups are obtained from a novel algorithm based on Viterbi paths. We show the suitability of our HMM mixture approach on biological and simulated data and through the favorable comparison with previous approaches. A software implementing the method is freely available under the GPL from http://ghmm.org/gql.
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| 8. |
- Schliep, Alexander, 1967, et al.
(author)
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Robust inference of groups in gene expression time-courses using mixtures of HMMs.
- 2004
-
In: Bioinformatics (Oxford, England). - : Oxford University Press (OUP). - 1367-4811 .- 1367-4803 .- 1460-2059. ; 20 Suppl 1, s. i283-9
-
Journal article (peer-reviewed)abstract
- Genetic regulation of cellular processes is frequently investigated using large-scale gene expression experiments to observe changes in expression over time. This temporal data poses a challenge to classical distance-based clustering methods due to its horizontal dependencies along the time-axis. We propose to use hidden Markov models (HMMs) to explicitly model these time-dependencies. The HMMs are used in a mixture approach that we show to be superior over clustering. Furthermore, mixtures are a more realistic model of the biological reality, as an unambiguous partitioning of genes into clusters of unique functional assignment is impossible. Use of the mixture increases robustness with respect to noise and allows an inference of groups at varying level of assignment ambiguity. A simple approach, partially supervised learning, allows to benefit from prior biological knowledge during the training. Our method allows simultaneous analysis of cyclic and non-cyclic genes and copes well with noise and missing values.We demonstrate biological relevance by detection of phase-specific groupings in HeLa time-course data. A benchmark using simulated data, derived using assumptions independent of those in our method, shows very favorable results compared to the baseline supplied by k-means and two prior approaches implementing model-based clustering. The results stress the benefits of incorporating prior knowledge, whenever available.A software package implementing our method is freely available under the GNU general public license (GPL) at http://ghmm.org/gql
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| 9. |
- Schliep, Alexander, 1967, et al.
(author)
-
Using hidden Markov models to analyze gene expression time course data.
- 2003
-
In: Bioinformatics (Oxford, England). - 1367-4803. ; 19 Suppl 1, s. i255-63
-
Journal article (peer-reviewed)abstract
- Cellular processes cause changes over time. Observing and measuring those changes over time allows insights into the how and why of regulation. The experimental platform for doing the appropriate large-scale experiments to obtain time-courses of expression levels is provided by microarray technology. However, the proper way of analyzing the resulting time course data is still very much an issue under investigation. The inherent time dependencies in the data suggest that clustering techniques which reflect those dependencies yield improved performance.We propose to use Hidden Markov Models (HMMs) to account for the horizontal dependencies along the time axis in time course data and to cope with the prevalent errors and missing values. The HMMs are used within a model-based clustering framework. We are given a number of clusters, each represented by one Hidden Markov Model from a finite collection encompassing typical qualitative behavior. Then, our method finds in an iterative procedure cluster models and an assignment of data points to these models that maximizes the joint likelihood of clustering and models. Partially supervised learning--adding groups of labeled data to the initial collection of clusters--is supported. A graphical user interface allows querying an expression profile dataset for time course similar to a prototype graphically defined as a sequence of levels and durations. We also propose a heuristic approach to automate determination of the number of clusters. We evaluate the method on published yeast cell cycle and fibroblasts serum response datasets, and compare them, with favorable results, to the autoregressive curves method.
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| 10. |
- Bakker, F. T., et al.
(author)
-
The Global Museum: natural history collections and the future of evolutionary science and public education
- 2020
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In: PeerJ. - : PeerJ. - 2167-8359. ; 8
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Journal article (peer-reviewed)abstract
- Natural history museums are unique spaces for interdisciplinary research and educational innovation. Through extensive exhibits and public programming and by hosting rich communities of amateurs, students, and researchers at all stages of their careers, they can provide a place-based window to focus on integration of science and discovery, as well as a locus for community engagement. At the same time, like a synthesis radio telescope, when joined together through emerging digital resources, the global community of museums (the 'Global Museum') is more than the sum of its parts, allowing insights and answers to diverse biological, environmental, and societal questions at the global scale, across eons of time, and spanning vast diversity across the Tree of Life. We argue that, whereas natural history collections and museums began with a focus on describing the diversity and peculiarities of species on Earth, they are now increasingly leveraged in new ways that significantly expand their impact and relevance. These new directions include the possibility to ask new, often interdisciplinary questions in basic and applied science, such as in biomimetic design, and by contributing to solutions to climate change, global health and food security challenges. As institutions, they have long been incubators for cutting-edge research in biology while simultaneously providing core infrastructure for research on present and future societal needs. Here we explore how the intersection between pressing issues in environmental and human health and rapid technological innovation have reinforced the relevance of museum collections. We do this by providing examples as food for thought for both the broader academic community and museum scientists on the evolving role of museums. We also identify challenges to the realization of the full potential of natural history collections and the Global Museum to science and society and discuss the critical need to grow these collections. We then focus on mapping and modelling of museum data (including place-based approaches and discovery), and explore the main projects, platforms and databases enabling this growth. Finally, we aim to improve relevant protocols for the long-term storage of specimens and tissues, ensuring proper connection with tomorrow's technologies and hence further increasing the relevance of natural history museums.
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