Complete populations of virtual patients for in silico clinical trials

2020 ◽  
Author(s):  
S Sinisi ◽  
V Alimguzhin ◽  
T Mancini ◽  
E Tronci ◽  
B Leeners
Keyword(s):  
In Silico ◽  
Medical Knowledge ◽  
Treatment Strategies ◽  
Absolute Error ◽  
Quantitative Model ◽  
University Hospital ◽  
Supplementary Information ◽  
Virtual Patients ◽  
Hannover Medical School ◽  
Efficacy Assessment

Abstract Motivation Model-based approaches to safety and efficacy assessment of pharmacological drugs, treatment strategies or medical devices (In Silico Clinical Trial, ISCT) aim to decrease time and cost for the needed experimentations, reduce animal and human testing, and enable precision medicine. Unfortunately, in presence of non-identifiable models (e.g. reaction networks), parameter estimation is not enough to generate complete populations of Virtual Patients (VPs), i.e. populations guaranteed to show the entire spectrum of model behaviours (phenotypes), thus ensuring representativeness of the trial. Results We present methods and software based on global search driven by statistical model checking that, starting from a (non-identifiable) quantitative model of the human physiology (plus drugs PK/PD) and suitable biological and medical knowledge elicited from experts, compute a population of VPs whose behaviours are representative of the whole spectrum of phenotypes entailed by the model (completeness) and pairwise distinguishable according to user-provided criteria. This enables full granularity control on the size of the population to employ in an ISCT, guaranteeing representativeness while avoiding over-representation of behaviours. We proved the effectiveness of our algorithm on a non-identifiable ODE-based model of the female Hypothalamic-Pituitary-Gonadal axis, by generating a population of 4 830 264 VPs stratified into 7 levels (at different granularity of behaviours), and assessed its representativeness against 86 retrospective health records from Pfizer, Hannover Medical School and University Hospital of Lausanne. The datasets are respectively covered by our VPs within Average Normalized Mean Absolute Error of 15%, 20% and 35% (90% of the latter dataset is covered within 20% error). Availability and implementation. Our open-source software is available at https://bitbucket.org/mclab/vipgenerator Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals A Mobile Medical Knowledge Dissemination Platform (HeadToToe): Mixed Methods Study

10.2196/17729 ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. e17729 ◽  
Author(s):  
Ido Zamberg ◽  
Olivier Windisch ◽  
Thomas Agoritsas ◽  
Mathieu Nendaz ◽  
Georges Savoldelli ◽  
...  
Keyword(s):  
Medical Students ◽  
User Experience ◽  
Clinical Skills ◽  
Medical Knowledge ◽  
Postgraduate Education ◽  
Third Party ◽  
University Hospital ◽  
Knowledge Dissemination ◽  
Easy Access ◽  
The University

Background Finding readily accessible, high-quality medical references can be a challenging task. HeadToToe is a mobile platform designed to allow easy and quick access to sound, up-to-date, and validated medical knowledge and guidance. It provides easy access to essential clinical medical content in the form of documents, videos, clinical scores, and other formats for the day-to-day access and use by medical students and physicians during their pre- and postgraduate education. Objective The aim of this paper is to describe the architecture, user interface, and potential strengths and limitations of an innovative knowledge dissemination platform developed at the University of Geneva, Switzerland. We also report preliminary results from a user-experience survey and usage statistics over a selected period. Methods The dissemination platform consists of a smartphone app. Through an administration interface, content is managed by senior university and hospital staff. The app includes the following sections: (1) main section of medical guidance, organized by clinical field; (2) checklists for history-taking and clinical examination, organized by body systems; (3) laboratory section with frequently used lab values; and (4) favorites section. Each content item is programmed to be available for a given duration as defined by the content’s author. Automatic notifications signal the author when the content is about to expire, hence, promoting its timely updating and reducing the risk of using obsolete content. In the background, a third-party statistical collecting tool records anonymous utilization statistics. Results We launched the final version of the platform in March 2019, both at the Faculty of Medicine at the University of Geneva and at the University Hospital of Geneva in Switzerland. A total of 622 students at the university and 613 health professionals at the hospital downloaded the app. Two-thirds of users at both institutions had an iOS device. During the practical examination period (ie, May 2019) there was a significant increase in the number of active users (P=.003), user activity (P<.001), and daily usage time (P<.001) among medical students. In addition, there were 1086 clinical skills video views during this period compared to a total of 484 in the preceding months (ie, a 108% increase). On a 10-point Likert scale, students and physicians rated the app with mean scores of 8.2 (SD 1.9) for user experience, 8.1 (SD 2.0) for usefulness, and 8.5 (SD 1.8) for relevance of content. In parallel, postgraduate trainees viewed more than 6000 documents during the first 3 months after the implementation in the Division of Neurology at our institution. Conclusions HeadToToe is an educator-driven, mobile dissemination platform, which provides rapid and user-friendly access to up-to-date medical content and guidance. The platform was given high ratings for user experience, usefulness, and content quality and was used more often during the exam period. This suggests that the platform could be used as tool for exam preparation.

scholarly journals Key Factors Contributing to Quality of Life for Breast Cancer Patients in Latvia: Supplementing Quantitative Surveys with Qualitative Interviews

2012 ◽  
Vol 12 (1) ◽  
pp. 3-10 ◽  
Author(s):  
Agnese Dzērvīte ◽  
Maruta Pranka ◽  
Tana Lace ◽  
Ritma Rungule ◽  
Edvins Miklasevics ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Quality Of Life ◽  
Cancer Patients ◽  
Qualitative Interviews ◽  
Treatment Strategies ◽  
Well Being ◽  
University Hospital ◽  
Breast Cancer Patients ◽  
Key Factors

Summary Introduction. Health related quality of life is a much debated topic in medicine with much quantitative and qualitative research contributing to the understanding of how to improve the lives of patients, yet little has been published in relation to the quality of life of Latvian breast cancer patients. Aim of the Study. To gather base measurements of subjective and objective quality of life factors for breast cancer patients in Latvia and discover which key factors contribute most to quality of life of Latvian breast cancer patients at the start of treatment. Materials and Methods. This paper presents data collected from April 2010 to June 2011 at the Pauls Stradins Clinical University hospital on key factors influencing quality of life for breast cancer patients: health and physical well-being; state of surroundings and environment; social support and functionality; financial state, employment and leisure. Quantitative survey material has been supplemented with insight from qualitative in-depth interviews to better explain the objective and subjective implications for breast cancer patients’ quality of life. Results. Interviewed breast cancer patients rated their quality of life as being average or good at the beginning of treatment. Negative factors contributing to lowered quality of life were mainly linked to patient financial, social and emotional state at the first weeks of treatment and correspond to previous research done in Latvia on quality of life issues. Conclusions. Further follow-up surveys will contribute to the evaluation of breast cancer patients’ needs while undergoing treatment to further improve treatment strategies, especially if validated quality of life measurement surveys were to be implemented in Latvian hospitals.

scholarly journals CRISPRitz: rapid, high-throughput and variant-aware in silico off-target site identification for CRISPR genome editing

2019 ◽  
Vol 36 (7) ◽  
pp. 2001-2008 ◽  
Author(s):  
Samuele Cancellieri ◽  
Matthew C Canver ◽  
Nicola Bombieri ◽  
Rosalba Giugno ◽  
Luca Pinello
Keyword(s):  
In Silico ◽  
Supplementary Information ◽  
Guide Rnas ◽  
Computational Performance ◽  
Search Mechanism ◽  
Genomic Annotation ◽  
Target Sites ◽  
Dna Elements ◽  
Efficient Data ◽  
A Site

ABSTRACT Motivation Clustered regularly interspaced short palindromic repeats (CRISPR) technologies allow for facile genomic modification in a site-specific manner. A key step in this process is the in silico design of single guide RNAs to efficiently and specifically target a site of interest. To this end, it is necessary to enumerate all potential off-target sites within a given genome that could be inadvertently altered by nuclease-mediated cleavage. Currently available software for this task is limited by computational efficiency, variant support or annotation, and assessment of the functional impact of potential off-target effects. Results To overcome these limitations, we have developed CRISPRitz, a suite of software tools to support the design and analysis of CRISPR/CRISPR-associated (Cas) experiments. Using efficient data structures combined with parallel computation, we offer a rapid, reliable, and exhaustive search mechanism to enumerate a comprehensive list of putative off-target sites. As proof-of-principle, we performed a head-to-head comparison with other available tools on several datasets. This analysis highlighted the unique features and superior computational performance of CRISPRitz including support for genomic searching with DNA/RNA bulges and mismatches of arbitrary size as specified by the user as well as consideration of genetic variants (variant-aware). In addition, graphical reports are offered for coding and non-coding regions that annotate the potential impact of putative off-target sites that lie within regions of functional genomic annotation (e.g. insulator and chromatin accessible sites from the ENCyclopedia Of DNA Elements [ENCODE] project). Availability and implementation The software is freely available at: https://github.com/pinellolab/CRISPRitzhttps://github.com/InfOmics/CRISPRitz. Supplementary information Supplementary data are available at Bioinformatics online.

INTERNIST-1/CADUCEUS: Problems Facing Expert Consultant Programs

1984 ◽  
Vol 23 (01) ◽  
pp. 9-14 ◽  
Author(s):  
R. A. Miller
Keyword(s):  
Medical Knowledge ◽  
Knowledge Bases ◽  
University Hospital ◽  
Medical Community ◽  
Diagnostic Algorithms ◽  
Human Interface ◽  
General Internal ◽  
Reasoning Strategies ◽  
Medical Diagnostic ◽  
Degrees Of Severity

SummaryINTERNIST-1 is an experimental computer program for consultation in general internal medicine. On a series of test cases, its performance has been shown to be similar to that of staff physicians at a university hospital. Despite INTERNIST-1’s apparent success in dealing with complex cases involving multiple diagnoses in the same patient, many shortcomings in both its knowledge representation schemes and its diagnostic algorithms still remain. Among the known problems are lack of anatomical and temporal reasoning, inadequate representation of degrees of severity of findings and illnesses, and failure to reason properly about causality. These drawbacks must be corrected before INTERNIST-1’s successor program, CADUCEUS, can be used. It is estimated that CADUCEUS will not be ready for release to the general medical community for five to ten years.Broader problems faced by all medical diagnostic consultant systems are: design of an efficient human interface; development and completion of medical knowledge bases; expansion of diagnostic algorithms from simple heuristic rules to include a range of complex reasoning strategies, and development of a method for validating computer programs for clinical use.

scholarly journals Inferring clonal heterogeneity in cancer using SNP arrays and whole genome sequencing

2019 ◽  
Vol 35 (17) ◽  
pp. 2924-2931
Author(s):  
Mark R Zucker ◽  
Lynne V Abruzzo ◽  
Carmen D Herling ◽  
Lynn L Barron ◽  
Michael J Keating ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Snp Array ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Response To Treatment ◽  
Supplementary Information ◽  
Sequencing Data ◽  
Clonal Heterogeneity ◽  
Array Data ◽  
Copy Numbers

Abstract Motivation Clonal heterogeneity is common in many types of cancer, including chronic lymphocytic leukemia (CLL). Previous research suggests that the presence of multiple distinct cancer clones is associated with clinical outcome. Detection of clonal heterogeneity from high throughput data, such as sequencing or single nucleotide polymorphism (SNP) array data, is important for gaining a better understanding of cancer and may improve prediction of clinical outcome or response to treatment. Here, we present a new method, CloneSeeker, for inferring clinical heterogeneity from sequencing data, SNP array data, or both. Results We generated simulated SNP array and sequencing data and applied CloneSeeker along with two other methods. We demonstrate that CloneSeeker is more accurate than existing algorithms at determining the number of clones, distribution of cancer cells among clones, and mutation and/or copy numbers belonging to each clone. Next, we applied CloneSeeker to SNP array data from samples of 258 previously untreated CLL patients to gain a better understanding of the characteristics of CLL tumors and to elucidate the relationship between clonal heterogeneity and clinical outcome. We found that a significant majority of CLL patients appear to have multiple clones distinguished by copy number alterations alone. We also found that the presence of multiple clones corresponded with significantly worse survival among CLL patients. These findings may prove useful for improving the accuracy of prognosis and design of treatment strategies. Availability and implementation Code available on R-Forge: https://r-forge.r-project.org/projects/CloneSeeker/ Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Drug safety profiles in geriatric patients with Parkinson’s disease using the FORTA (Fit fOR The Aged) classification: results from a mono-centric retrospective analysis

2020 ◽  
Author(s):  
S. Greten ◽  
J. I. Müller-Funogea ◽  
F. Wegner ◽  
G. U. Höglinger ◽  
N. Simon ◽  
...  
Keyword(s):  
Drug Safety ◽  
Geriatric Patients ◽  
Demographic Data ◽  
University Hospital ◽  
Potentially Inappropriate Medications ◽  
Hannover Medical School ◽  
The Common ◽  
The University ◽  
Geriatric Inpatients ◽  
Inappropriate Medications

AbstractTo reduce potentially inappropriate medications, the FORTA (Fit fOR The Aged) concept classifies drugs in terms of their suitability for geriatric patients with different labels, namely A (indispensable), B (beneficial), C (questionable), and D (avoid). The aims of our study were to assess the medication appropriateness in PD inpatients applying the FORTA list and drug-drug interaction software, further to assess the adequacy of FORTA list for patients with PD. We retrospectively collected demographic data, comorbidities, laboratory values, and the medication from the discharge letters of 123 geriatric inpatients with PD at the university hospital of Hannover Medical School. Patients suffered on average from 8.2 comorbidities. The majority of the medication was labeled A (60.6% of PD-specific and 40.9% of other medication) or B (22.3% of PD-specific and 26.9% of other medication). Administered drugs labeled with D were amantadine, clozapine, oxazepam, lorazepam, amitriptyline, and clonidine. Overall, 545 interactions were identified, thereof 11.9% severe interactions, and 1.7% contraindicated combinations. 81.3% of patients had at least one moderate or severe interaction. The FORTA list gives rational recommendations for PD-specific and other medication, especially for general practitioners. Considering the demographic characteristics and the common multimorbidity of geriatric PD patients, this study underlines the importance of awareness, education, and preventive interventions to increase drug safety.

In silico biology of bone modelling and remodelling: regeneration

2009 ◽  
Vol 367 (1895) ◽  
pp. 2031-2053 ◽  
Author(s):  
L. Geris ◽  
J. Vander Sloten ◽  
H. Van Oosterwyck
Keyword(s):  
Mathematical Models ◽  
Experimental Research ◽  
In Silico ◽  
Healing Process ◽  
Treatment Strategies ◽  
Added Value ◽  
Mechanical Stimuli ◽  
Implant Placement ◽  
Bone Modelling ◽  
In Silico Biology

Bone regeneration is the process whereby bone is able to (scarlessly) repair itself from trauma, such as fractures or implant placement. Despite extensive experimental research, many of the mechanisms involved still remain to be elucidated. Over the last decade, many mathematical models have been established to investigate the regeneration process in silico . The first models considered only the influence of the mechanical environment as a regulator of the healing process. These models were followed by the development of bioregulatory models where mechanics was neglected and regeneration was regulated only by biological stimuli such as growth factors. The most recent mathematical models couple the influences of both biological and mechanical stimuli. Examples are given to illustrate the added value of mathematical regeneration research, specifically in the in silico design of treatment strategies for non-unions. Drawbacks of the current continuum-type models, together with possible solutions in extending the models towards other time and length scales are discussed. Finally, the demands for dedicated and more quantitative experimental research are presented.

scholarly journals Co-existence of virulence factors and antibiotic resistance in new Klebsiella pneumoniae clones emerging in south of Italy

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Teresa Fasciana ◽  
Bernardina Gentile ◽  
Maria Aquilina ◽  
Andrea Ciammaruconi ◽  
Chiara Mascarella ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Klebsiella Pneumoniae ◽  
Virulence Factors ◽  
In Silico ◽  
Geographical Area ◽  
In Silico Analysis ◽  
University Hospital ◽  
Uptake System ◽  
Genes Encoding ◽  
Silico Analysis

Abstract Background Endemic presence of Klebsiella pneumoniae resistant to carbapenem in Italy has been due principally to the clonal expansion of CC258 isolates; however, recent studies suggest an ongoing epidemiological change in this geographical area. Methods 50 K. pneumoniae strains, 25 carbapenem-resistant (CR-Kp) and 25 susceptible (CS-Kp), collected from march 2014 to march 2016 at the Laboratory of Bacteriology of the Paolo Giaccone Polyclinic University hospital of Palermo, Italy, were characterized for antibiotic susceptibility and fully sequenced by next generation sequencing (NGS) for the in silico analysis of resistome, virulome, multi-locus sequence typing (MLST) and core single nucleotide polymorphism (SNP) genotypes Results MLST in silico analysis of CR-Kp showed that 52% of isolates belonged to CC258, followed by ST395 (12%), ST307 (12%), ST392 (8%), ST348 (8%), ST405 (4%) and ST101 (4%). In the CS-Kp group, the most represented isolate was ST405 (20%), followed by ST392 and ST15 (12%), ST395, ST307 and ST1727 (8%). The in silico β-lactamase analysis of the CR-Kp group showed that the most detected gene was blaSHV (100%), followed by blaTEM (92%), blaKPC (88%), blaOXA (88%) and blaCTX-M (32%). The virulome analysis detected mrk operon in all studied isolates, and wzi-2 was found in three CR-Kp isolates (12%). Furthermore, the distribution of virulence genes encoding for the yersiniabactin system, its receptor fyuA and the aerobactin system did not show significant distribution differences between CR-Kp and CS-Kp, whereas the Klebsiella ferrous iron uptake system (kfuA, kfuB and kfuC genes), the two-component system kvgAS and the microcin E495 were significantly (p < 0.05) prevalent in the CS-Kp group compared to the CR-Kp group. Core SNP genotyping, correlating with the MLST data, allowed greater strain tracking and discrimination than MLST analysis. Conclusions Our data support the idea that an epidemiological change is ongoing in the Palermo area (Sicily, Italy). In addition, our analysis revealed the co-existence of antibiotic resistance and virulence factors in CR-Kp isolates; this characteristic should be considered for future genomic surveillance studies.

Grenzstrahlung bei refraktärer aktinischer Porokeratose: eine verträgliche und effektive Therapieoption

2018 ◽  
Vol 6 (1) ◽  
pp. 32-33
Author(s):  
Bastian Schilling
Keyword(s):  
Data Analysis ◽  
Side Effects ◽  
Malignant Transformation ◽  
Treatment Strategies ◽  
Treatment Session ◽  
University Hospital ◽  
Study Cohort ◽  
Present Treatment ◽  
Limited Success ◽  
Disseminated Superficial Actinic Porokeratosis

Background: Disseminated superficial actinic porokeratosis (DSAP) is a rare keratinization disorder with potential malignant transformation, for which present treatment strategies show limited success. Aim: To evaluate the response of DSAP lesions to grenz ray radiotherapy (RTx). Methods: Data of patients treated with RTx at University Hospital Zurich, Switzerland, between 2004 and 2015, were reviewed. Patients with DSAP, who received at least 1 RTx treatment session and who had been followed up for at least 4 weeks were included in the further data analysis. Results: The study cohort consisted of 8 patients with a median age of 73 years (range 54-84). All were treated with grenz rays for DSAP. Most (7/8) patients showed complete clinical clearing of the lesions. All patients experienced temporary side effects of RTx, which resolved within 4 weeks after the last irradiation. Conclusion: We suggest radiotherapy with grenz rays as a treatment option for DSAP.

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