Discovering lesser known molecular players and mechanistic patterns in Alzheimer's disease using an integrative disease modelling approach

Convergence of exponentially advancing technologies is driving medical research with life changing discoveries. On the contrary, repeated failures of high-profile drugs to battle Alzheimer's disease (AD) has made it one of the least successful therapeutic area. This failure pattern has provoked researchers to grapple with their beliefs about Alzheimer's aetiology. Thus, growing realisation that Amyloid-β and tau are not 'the' but rather 'one of the' factors necessitates the reassessment of pre-existing data to add new perspectives. To enable a holistic view of the disease, integrative modelling approaches are emerging as a powerful technique. Combining data at different scales and modes could considerably increase the predictive power of the integrative model by filling biological knowledge gaps. However, the reliability of the derived hypotheses largely depends on the completeness, quality, consistency, and context-specificity of the data. Thus, there is a need for agile methods and approaches that efficiently interrogate and utilise existing public data. This thesis presents the development of novel approaches and methods that address intrinsic issues of data integration and analysis in AD research. It aims to prioritise lesser-known AD candidates using highly curated and precise knowledge derived from integrated data. Here much of the emphasis is put on quality, reliability, and context-specificity. This thesis work showcases the benefit of integrating well-curated and disease-specific heterogeneous data in a semantic web-based framework for mining actionable knowledge. Furthermore, it introduces to the challenges encountered while harvesting information from literature and transcriptomic resources. State-of-the-art text-mining methodology is developed to extract miRNAs and its regulatory role in diseases and genes from the biomedical literature. To enable meta-analysis of biologically related transcriptomic data, a highly-curated metadata database has been developed, which explicates annotations specific to human and animal models. Finally, to corroborate common mechanistic patterns — embedded with novel candidates — across large-scale AD transcriptomic data, a new approach to generate gene regulatory networks has been developed. The work presented here has demonstrated its capability in identifying testable mechanistic hypotheses containing previously unknown or emerging knowledge from public data in two major publicly funded projects for Alzheimer's, Parkinson's and Epilepsy diseases

Word-sense disambiguation in biomedical ontologies

With the ever increase in biomedical literature, text-mining has emerged as an important technology to support bio-curation and search. Word sense disambiguation (WSD), the correct identification of terms in text in the light of ambiguity, is an important problem in text-mining. Since the late 1940s many approaches based on supervised (decision trees, naive Bayes, neural networks, support vector machines) and unsupervised machine learning (context-clustering, word-clustering, co-occurrence graphs) have been developed. Knowledge-based methods that make use of the WordNet computational lexicon have also been developed. But only few make use of ontologies, i.e. hierarchical controlled vocabularies, to solve the problem and none exploit inference over ontologies and the use of metadata from publications. This thesis addresses the WSD problem in biomedical ontologies by suggesting different approaches for word sense disambiguation that use ontologies and metadata. The "Closest Sense" method assumes that the ontology defines multiple senses of the term; it computes the shortest path of co-occurring terms in the document to one of these senses. The "Term Cooc" method defines a log-odds ratio for co-occurring terms including inferred co-occurrences. The "MetaData" approach trains a classifier on metadata; it does not require any ontology, but requires training data, which the other methods do not. These approaches are compared to each other when applied to a manually curated training corpus of 2600 documents for seven ambiguous terms from the Gene Ontology and MeSH. All approaches over all conditions achieve 80% success rate on average. The MetaData approach performs best with 96%, when trained on high-quality data. Its performance deteriorates as quality of the training data decreases. The Term Cooc approach performs better on Gene Ontology (92% success) than on MeSH (73% success) as MeSH is not a strict is-a/part-of, but rather a loose is-related-to hierarchy. The Closest Sense approach achieves on average 80% success rate. Furthermore, the thesis showcases applications ranging from ontology design to semantic search where WSD is important

Role of machine learning in early diagnosis of kidney diseases.

Machine learning (ML) and deep learning (DL) approaches have been used as indispensable tools in modern artificial intelligence-based computer-aided diagnostic (AIbased CAD) systems that can provide non-invasive, early, and accurate diagnosis of a given medical condition. These AI-based CAD systems have proven themselves to be reproducible and have the generalization ability to diagnose new unseen cases with several diseases and medical conditions in different organs (e.g., kidneys, prostate, brain, liver, lung, breast, and bladder). In this dissertation, we will focus on the role of such AI-based CAD systems in early diagnosis of two kidney diseases, namely: acute rejection (AR) post kidney transplantation and renal cancer (RC). A new renal computer-assisted diagnostic (Renal-CAD) system was developed to precisely diagnose AR post kidney transplantation at an early stage. The developed Renal-CAD system perform the following main steps: (1) auto-segmentation of the renal allograft from surrounding tissues from diffusion weighted magnetic resonance imaging (DW-MRI) and blood oxygen level-dependent MRI (BOLD-MRI), (2) extraction of image markers, namely: voxel-wise apparent diffusion coefficients (ADCs) are calculated from DW-MRI scans at 11 different low and high b-values and then represented as cumulative distribution functions (CDFs) and extraction of the transverse relaxation rate (R2*) values from the segmented kidneys using BOLD-MRI scans at different echotimes, (3) integration of multimodal image markers with the associated clinical biomarkers, serum creatinine (SCr) and creatinine clearance (CrCl), and (4) diagnosing renal allograft status as nonrejection (NR) or AR by utilizing these integrated biomarkers and the developed deep learning classification model built on stacked auto-encoders (SAEs). Using a leaveone- subject-out cross-validation approach along with SAEs on a total of 30 patients with transplanted kidney (AR = 10 and NR = 20), the Renal-CAD system demonstrated 93.3% accuracy, 90.0% sensitivity, and 95.0% specificity in differentiating AR from NR. Robustness of the Renal-CAD system was also confirmed by the area under the curve value of 0.92. Using a stratified 10-fold cross-validation approach, the Renal-CAD system demonstrated its reproduciblity and robustness with a diagnostic accuracy of 86.7%, sensitivity of 80.0%, specificity of 90.0%, and AUC of 0.88. In addition, a new renal cancer CAD (RC-CAD) system for precise diagnosis of RC at an early stage was developed, which incorporates the following main steps: (1) estimating the morphological features by applying a new parametric spherical harmonic technique, (2) extracting appearance-based features, namely: first order textural features are calculated and second order textural features are extracted after constructing the graylevel co-occurrence matrix (GLCM), (3) estimating the functional features by constructing wash-in/wash-out slopes to quantify the enhancement variations across different contrast enhanced computed tomography (CE-CT) phases, (4) integrating all the aforementioned features and modeling a two-stage multilayer perceptron artificial neural network (MLPANN) classifier to classify the renal tumor as benign or malignant and identify the malignancy subtype. On a total of 140 RC patients (malignant = 70 patients (ccRCC = 40 and nccRCC = 30) and benign angiomyolipoma tumors = 70), the developed RC-CAD system was validated using a leave-one-subject-out cross-validation approach. The developed RC-CAD system achieved a sensitivity of 95.3% ± 2.0%, a specificity of 99.9% ± 0.4%, and Dice similarity coefficient of 0.98 ± 0.01 in differentiating malignant from benign renal tumors, as well as an overall accuracy of 89.6% ± 5.0% in the sub-typing of RCC. The diagnostic abilities of the developed RC-CAD system were further validated using a randomly stratified 10-fold cross-validation approach. The results obtained using the proposed MLP-ANN classification model outperformed other machine learning classifiers (e.g., support vector machine, random forests, and relational functional gradient boosting) as well as other different approaches from the literature. In summary, machine and deep learning approaches have shown potential abilities to be utilized to build AI-based CAD systems. This is evidenced by the promising diagnostic performance obtained by both Renal-CAD and RC-CAD systems. For the Renal- CAD, the integration of functional markers extracted from multimodal MRIs with clinical biomarkers using SAEs classification model, potentially improved the final diagnostic results evidenced by high accuracy, sensitivity, and specificity. The developed Renal-CAD demonstrated high feasibility and efficacy for early, accurate, and non-invasive identification of AR. For the RC-CAD, integrating morphological, textural, and functional features extracted from CE-CT images using a MLP-ANN classification model eventually enhanced the final results in terms of accuracy, sensitivity, and specificity, making the proposed RC-CAD a reliable noninvasive diagnostic tool for RC. The early and accurate diagnosis of AR or RC will help physicians to provide early intervention with the appropriate treatment plan to prolong the life span of the diseased kidney, increase the survival chance of the patient, and thus improve the healthcare outcome in the U.S. and worldwide

Fusion and Analysis of Multidimensional Medical Image Data

Analýza medicínských obrazů je předmětem základního výzkumu již řadu let. Za tu dobu bylo v této oblasti publikováno mnoho výzkumných prací zabývajících se dílčími částmi jako je rekonstrukce obrazů, restaurace, segmentace, klasifikace, registrace (lícování) a fúze. Kromě obecného úvodu, pojednává tato disertační práce o dvou medicínsky orientovaných tématech, jež byla formulována ve spolupráci s Philips Netherland BV, divizí Philips Healthcare. První téma je zaměřeno na oblast zpracování obrazů subtrakční angiografie dolních končetin člověka získaných pomocí výpočetní X-Ray tomografie (CT). Subtrakční angiografie je obvykle využívaná při podezření na periferní cévní onemocnění (PAOD) nebo při akutním poškození dolních končetin jako jsou fraktury apod. Současné komerční metody nejsou dostatečně spolehlivé už v předzpracování, jako je například odstranění pacientského stolu, pokrývky, dlahy, apod. Spolehlivost a přesnost identifikace cév v subtrahovaných datech vedoucích v blízkosti kostí je v důsledku Partial Volume artefaktu rovněž nízká. Automatické odstranění kalcifikací nebo detekce malých cév doplňujících nezbytnou informaci o náhradním zásobení dolních končetin krví v případě přerušení hlavních zásobujících cév v současné době rovněž nesplňují kritéria pro plně automatické zpracování. Proto hlavním cílem týkající se tohoto tématu bylo vyvinout automatický systém, který by mohl současné nedostatky v CTSA vyšetření odstranit. Druhé téma je orientováno na identifikaci patologických změn na páteři člověka v CT obrazech se zaměřením na osteolytické a osteoblastické léze u jednotlivých obratlů. Tyto změny obvykle nastávají v důsledků postižení metastazujícím procesem rakovinového onemocnění. Pro detekci patologických změn je pak potřeba identifikace a segmentace jednotlivých obratlů. Přesnost analýzy jednotlivých lézí však závisí rovněž na správné identifikaci těla a zadních segmentů u jednotlivých obratlů a na segmentaci trabekulárního centra obratlů, tj. odstranění kortikální kosti. Během léčby mohou být pacienti skenováni vícekrát, obvykle s několika-mesíčním odstupem. Hodnocení případného vývoje již detekovaných patologických změn pak logicky vychází ze správné detekce patologií v jednotlivých obratlech korespondujících si v jednotlivých akvizicích. Jelikož jsou příslušné obratle v jednotlivých akvizicích obvykle na různé pozici, jejich fúze, vedoucí k analýze časového vývoje detekovaných patologií, je komplikovaná. Požadovaným výsledkem v tomto tématu je vytvoření komplexního systému pro detekci patologických změn v páteři, především osteoblastických a osteolytických lézí. Takový systém tedy musí umožnovat jak segmentaci jednotlivých obratlů, jejich automatické rozdělení na hlavní části a odstranění kortikální kosti, tak také detekci patologických změn a jejich hodnocení. Ačkoliv je tato disertační práce v obou výše zmíněných tématech primárně zaměřena na experimentální část zpracování medicínských obrazů, zabývá se všemi nezbytnými kroky, jako je předzpracování, registrace, dodatečné zpracování a hodnocení výsledků, vedoucími k možné aplikovatelnosti obou systému v klinické praxi. Jelikož oba systémy byly řešeny v rámci týmové spolupráce jako celek, u obou témat jsou pro některé konkrétní kroky uvedeny odkazy na doktorskou práci Miloše Malínského.Analysis of medical images has been subject of basic research for many years. Many research papers have been published in the field related to image analysis and focused on partial aspects such as reconstruction, restoration, segmentation and classification, registration (spatial alignment) and fusion. Besides the introduction of related general concepts used in medical image processing, this thesis deals with two specific medical problems formulated in cooperation with Philips Netherland BV, Philips Healthcare division. The first topic is focused on subtraction angiography in patients’ lower legs utilizing image data from X-Ray computed tomography (CT). CT subtraction angiography (CTSA) is typically used for indication of the Peripheral Artery Occlusive Disease (PAOD) and for examination of acute injuries of lower legs such as acute fractures, etc. Current methods in clinical praxis are not sufficient regarding the pre-processing such as masking of patient desk, cover, splint, etc. The subtraction of blood vessels adjacent to neighboring bones in lower legs is of low accuracy due to the Partial Volume artifact. Masking of calcifications and detection of tiny blood vessels complementing necessary information about the alternative blood supply in lower legs in case of obstruction in main arteries is also not reliable for fully automated process presently. Therefore, the main aim regarding this topic was to develop an automated framework that could overcome current shortcomings in CTSA examination. The second topic is oriented on the identification and evaluation of pathologic changes in human spine, focusing on osteolytic and osteoblastic lesions in individual vertebrae in CT images. Such changes occur typically as a consequence of metastasizing process of cancerous disease. For the detection of pathologic changes, an identification and segmentation of individual vertebrae is necessary. Moreover, the analysis of individual lesions in vertebrae depends also on correct identification of vertebral body and posterior segments of each vertebra, and on segmentation of their trabecular centers. Patients are typically examined more than once during their therapy. Then, the evaluation of possible tumorous progression is based on accurate detection of pathologies in individual vertebrae in the base-line and corresponding follow-up images. Since the corresponding vertebrae are in mutually different positions in the follow-up images, their fusion leading to the analysis of the lesion progression is complicated. The main aim regarding this topic is to develop a complex framework for detection of pathologic lesions on spine, with the main focus on osteoblastic and osteolystic lesions. Such system has to provide not only reliable segmentation of individual vertebrae and detection of their main regions but also the masking of their cortical bone, detection of their pathologic changes and their evaluation. Although this dissertation thesis is primarily oriented at the experimental part of medical image processing considering both the above mentioned topics, it deals with all necessary processing steps, i.e. preprocessing, image registration, post-processing and evaluation of results, leading to the future use of both frameworks in clinical practice. Since both frameworks were developed in a team, there are some chapters referring to the dissertation thesis of Milos Malinsky.

Towards a system of concepts for Family Medicine. Multilingual indexing in General Practice/ Family Medicine in the era of Semantic Web

UNIVERSITY OF LIÈGE, BELGIUM Executive Summary Faculty of Medicine Département Universitaire de Médecine Générale. Unité de recherche Soins Primaires et Santé Doctor in biomedical sciences Towards a system of concepts for Family Medicine. Multilingual indexing in General Practice/ Family Medicine in the era of SemanticWeb by Dr. Marc JAMOULLE Introduction This thesis is about giving visibility to the often overlooked work of family physicians and consequently, is about grey literature in General Practice and Family Medicine (GP/FM). It often seems that conference organizers do not think of GP/FM as a knowledge-producing discipline that deserves active dissemination. A conference is organized, but not much is done with the knowledge shared at these meetings. In turn, the knowledge cannot be reused or reapplied. This these is also about indexing. To find knowledge back, indexing is mandatory. We must prepare tools that will automatically index the thousands of abstracts that family doctors produce each year in various languages. And finally this work is about semantics1. It is an introduction to health terminologies, ontologies, semantic data, and linked open data. All are expressions of the next step: Semantic Web for health care data. Concepts, units of thought expressed by terms, will be our target and must have the ability to be expressed in multiple languages. In turn, three areas of knowledge are at stake in this study: (i) Family Medicine as a pillar of primary health care, (ii) computational linguistics, and (iii) health information systems. Aim • To identify knowledge produced by General practitioners (GPs) by improving annotation of grey literature in Primary Health Care • To propose an experimental indexing system, acting as draft for a standardized table of content of GP/GM • To improve the searchability of repositories for grey literature in GP/GM. 1For specific terms, see the Glossary page 257 x Methods The first step aimed to design the taxonomy by identifying relevant concepts in a compiled corpus of GP/FM texts. We have studied the concepts identified in nearly two thousand communications of GPs during conferences. The relevant concepts belong to the fields that are focusing on GP/FM activities (e.g. teaching, ethics, management or environmental hazard issues). The second step was the development of an on-line, multilingual, terminological resource for each category of the resulting taxonomy, named Q-Codes. We have designed this terminology in the form of a lightweight ontology, accessible on-line for readers and ready for use by computers of the semantic web. It is also fit for the Linked Open Data universe. Results We propose 182 Q-Codes in an on-line multilingual database (10 languages) (www.hetop.eu/Q) acting each as a filter for Medline. Q-Codes are also available under the form of Unique Resource Identifiers (URIs) and are exportable in Web Ontology Language (OWL). The International Classification of Primary Care (ICPC) is linked to Q-Codes in order to form the Core Content Classification in General Practice/Family Medicine (3CGP). So far, 3CGP is in use by humans in pedagogy, in bibliographic studies, in indexing congresses, master theses and other forms of grey literature in GP/FM. Use by computers is experimented in automatic classifiers, annotators and natural language processing. Discussion To the best of our knowledge, this is the first attempt to expand the ICPC coding system with an extension for family physician contextual issues, thus covering non-clinical content of practice. It remains to be proven that our proposed terminology will help in dealing with more complex systems, such as MeSH, to support information storage and retrieval activities. However, this exercise is proposed as a first step in the creation of an ontology of GP/FM and as an opening to the complex world of Semantic Web technologies. Conclusion We expect that the creation of this terminological resource for indexing abstracts and for facilitating Medline searches for general practitioners, researchers and students in medicine will reduce loss of knowledge in the domain of GP/FM. In addition, through better indexing of the grey literature (congress abstracts, master’s and doctoral theses), we hope to enhance the accessibility of research results and give visibility to the invisible work of family physicians

Writing in the Disciplines and Within-discipline Variations: A Comparison of the Formulaic Profiles of the Medical Research Article and the Medical Case Report

Research of formulaic language in academic writing has primarily investigated the use of single types of formulaic sequences in academic research articles in various disciplines. Studies in this line of research have revealed dramatic variations in the use of formulaic language across academic disciplines (e.g., Cortes, 2004; Hyland, 2008a; Jalali & Moini, 2014; Shahriari, 2017). However, there is evidence that discipline alone does not tell the whole story about linguistic variation (Gray, 2015). Different varieties of texts within one discipline may reflect different linguistic characteristics depending on specific communicative purposes (Biber & Conrad, 2009). It follows that the almost exclusive focus on the academic research article may “limit our knowledge of the discourse practices within discipline” (Gray, 2015, p. 19). Moreover, formulaic language encompasses different types of sequences (e.g., collocations, lexical bundles, frames, etc.) each of which only reveals a partial picture of formulaicity in discourse (Wray, 2005). Thus, studies that investigate the use of single types of formulaic sequences may provide only partial descriptions of the registers they investigate. Therefore, to better serve disciplinary writing instruction, there is a need for studies that provide more comprehensive descriptions of formulaic language in various registers within one discipline. The present dissertation takes a step in that direction by investigating within-discipline linguistic variation through the comparison of the formulaic profiles of two registers in the field of medicine: the medical research article (MRA) and the medical case report (MCR). These two registers that have both been reported in the medical literature to contribute to advancing research, clinical practice, and education in the field (e.g., Man et al., 2004; Rison et al., 2017). The study proposes a more comprehensive approach to the description of formulaic language and investigates the use of various formulaic sequences that have been described as accounting for the formulaicity of discourse. Such sequences include: (a) collocations, pairs of words that tend to co-occur, (b) multiword collocations, sequences of three or more words with strong mutual attraction (such sequences consist primarily of lexical words, most of which are technical terms), (c) lexical bundles, most frequent sequences of three or more words in a register, described as the building blocks of academic writing (Cortes, 2013), and (d) frames, sequences of three or more items with one variable slot. Frames have been described as allowing writers to make more creative use of formulaic language (e.g., Biber, 2009; Gray & Biber, 2013). The analyses of the formulaic sequences in the two registers often revealed structural similarities but noticeable variations in terms of the discourse functions of the sequences. Such variations reflect the differences in the situational characteristics of the two registers such as communicative purposes, nature of data and evidence, textual organization, to name but a few. The findings of the present study portray MRAs and MCRs as two distinct registers, thus highlighting the importance of investing within-discipline variations to better serve disciplinary writing instruction

Language modelling for clinical natural language understanding and generation

One of the long-standing objectives of Artificial Intelligence (AI) is to design and develop algorithms for social good including tackling public health challenges. In the era of digitisation, with an unprecedented amount of healthcare data being captured in digital form, the analysis of the healthcare data at scale can lead to better research of diseases, better monitoring patient conditions and more importantly improving patient outcomes. However, many AI-based analytic algorithms rely solely on structured healthcare data such as bedside measurements and test results which only account for 20% of all healthcare data, whereas the remaining 80% of healthcare data is unstructured including textual data such as clinical notes and discharge summaries which is still underexplored. Conventional Natural Language Processing (NLP) algorithms that are designed for clinical applications rely on the shallow matching, templates and non-contextualised word embeddings which lead to limited understanding of contextual semantics. Though recent advances in NLP algorithms have demonstrated promising performance on a variety of NLP tasks in the general domain with contextualised language models, most of these generic NLP algorithms struggle at specific clinical NLP tasks which require biomedical knowledge and reasoning. Besides, there is limited research to study generative NLP algorithms to generate clinical reports and summaries automatically by considering salient clinical information. This thesis aims to design and develop novel NLP algorithms especially clinical-driven contextualised language models to understand textual healthcare data and generate clinical narratives which can potentially support clinicians, medical scientists and patients. The first contribution of this thesis focuses on capturing phenotypic information of patients from clinical notes which is important to profile patient situation and improve patient outcomes. The thesis proposes a novel self-supervised language model, named Phenotypic Intelligence Extraction (PIE), to annotate phenotypes from clinical notes with the detection of contextual synonyms and the enhancement to reason with numerical values. The second contribution is to demonstrate the utility and benefits of using phenotypic features of patients in clinical use cases by predicting patient outcomes in Intensive Care Units (ICU) and identifying patients at risk of specific diseases with better accuracy and model interpretability. The third contribution is to propose generative models to generate clinical narratives to automate and accelerate the process of report writing and summarisation by clinicians. This thesis first proposes a novel summarisation language model named PEGASUS which surpasses or is on par with the state-of-the-art performance on 12 downstream datasets including biomedical literature from PubMed. PEGASUS is further extended to generate medical scientific documents from input tabular data.Open Acces

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)