Developing a national strategy to bring pathogen genomics into practiceExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Developing a national strategy to bring pathogen genomics into practice. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management and GMI-9, 23-25 May 2016, Rome, Italy.
RADx-UP CDCC presentation for the NIH Disaster Interest GroupWarren Kibbe
Presentation on the RADx-Underserved Populations Coordination and Data Collection Center with an emphasis on how it will help understand and reduce the disparities associated with the COVDI-19 pandemic
Hannes Smarason: Progress & Prospects in GenomicsHannes Smárason
The annual American Society of Human Genetics Meeting (ASHG 2016) is an excellent time for the field of genomics to take stock of the past and clarify our perspectives for the future.
Developing a national strategy to bring pathogen genomics into practiceExternalEvents
http://www.fao.org/about/meetings/wgs-on-food-safety-management/en/
Developing a national strategy to bring pathogen genomics into practice. Presentation from the Technical Meeting on the impact of Whole Genome Sequencing (WGS) on food safety management and GMI-9, 23-25 May 2016, Rome, Italy.
RADx-UP CDCC presentation for the NIH Disaster Interest GroupWarren Kibbe
Presentation on the RADx-Underserved Populations Coordination and Data Collection Center with an emphasis on how it will help understand and reduce the disparities associated with the COVDI-19 pandemic
Hannes Smarason: Progress & Prospects in GenomicsHannes Smárason
The annual American Society of Human Genetics Meeting (ASHG 2016) is an excellent time for the field of genomics to take stock of the past and clarify our perspectives for the future.
Slides as given for the i2b2 conference in October 2019. https://transmartfoundation.org/tubingen-symposium-2019-agenda/
Observational Health Data Sciences and Informatics (OHDSI) is a multi-stakeholder,
interdisciplinary, international collaborative with a mission to improve health by empowering
a community to collaboratively generate the evidence that promotes better health decisions
and better care. With 200 researchers from 25 countries and half a billion unique patients,
OHDSI carries out federated studies at sufficient scale to answer questions about diagnosis
and treatment. At the heart of the OHDSI platform is the OMOP Common Data Model,
currently at v6, around which a toolset is built for carrying out reusable, repeatable and
reproducible observational clinical research on a large scale.
DOE-NCI Pilots presentation at the Frederick National Laboratory Advisory Com...Warren Kibbe
May 2016 FNLAC presentation of the DOE-NCI partnership around three pilots focused on existing projects in NCI and existing NSCI directives and activities in DOE.
Hannes smarason next code-wuxi combined technologiesHannes Smárason
Lower-cost genome sequencing has reached a point of strong commercial viability. The remaining 2 legs of the “3-legged stool” of genomics-enabling technologies —genomic analysis tools database storage—are rapidly evolving to support the use of genomic information in medical care.
NCI Cancer Imaging Program - Cancer Research Data EcosystemWarren Kibbe
Given to the NCI Cancer Imaging Program monthly telecon on January 9th, 2017. NCI Genomic Data Commons, Beau Biden Cancer Moonshot Blue Ribbon Panel, Cancer Research Data Ecosystem and the role of imaging in precision medicine
2016 Data Commons and Data Science Workshop June 7th and June 8th 2016. Genomic Data Commons, FAIR, NCI and making data more findable, publicly accessible, interoperable (machine readable), reusable and support recognition and attribution
Use of open, curated variant databases: ethics? Liability? - Bartha KnoppersHuman Variome Project
Translation of genomics into medicine and drug development requires comprehensive, high-quality, genomic variant databases. To support translation, there is a movement towards sharing clinical annotations of variants (e.g., benign, unknown, pathogenic) internationally via open access. Despite the growing popularity of variant databases, ethical issues and liability risks have received scant attention. Ethical priorities for variant databases include 1) competence – ensuring that data is responsibly managed, curated, and used; 2) confidentiality – ensuring appropriate safeguards for patient data; 3) communication – clearly describing the purpose, quality standards, and data handling practices to contributing patients and potential users; and 4) continuous oversight to adapt database governance in a rapidly evolving environment. How can database managers fulfill these obligations when these responsibilities are increasingly distributed along the clinical pipeline? Legal issues include medical liability based on potential harm to patients; liability based on third-party intellectual property or privacy rights in the data; and regulatory risks as variant data is integrated into genetic tests or devices. Can these risks can be managed through appropriate governance structures – including adequate consents, access processes, contributor agreements, and disclaimers – while still facilitating sharing and clinical use?
Day 2: Innovation to optimise therapeutic options for prevention and treatmen...KTN
The focus of this day is to explore unmet clinical needs in the effective treatment and therapy of patients with multiple long term conditions. Such patients have been historically excluded from clinical trials and also suffer from the burden of polypharmacy complications that affect quality of life. Innovation that supports a more holistic and personalised intervention, that applies patient stratification and pharmacogenomics, could dramatically improve health outcomes for diverse patient groups.
Slides as given for the i2b2 conference in October 2019. https://transmartfoundation.org/tubingen-symposium-2019-agenda/
Observational Health Data Sciences and Informatics (OHDSI) is a multi-stakeholder,
interdisciplinary, international collaborative with a mission to improve health by empowering
a community to collaboratively generate the evidence that promotes better health decisions
and better care. With 200 researchers from 25 countries and half a billion unique patients,
OHDSI carries out federated studies at sufficient scale to answer questions about diagnosis
and treatment. At the heart of the OHDSI platform is the OMOP Common Data Model,
currently at v6, around which a toolset is built for carrying out reusable, repeatable and
reproducible observational clinical research on a large scale.
DOE-NCI Pilots presentation at the Frederick National Laboratory Advisory Com...Warren Kibbe
May 2016 FNLAC presentation of the DOE-NCI partnership around three pilots focused on existing projects in NCI and existing NSCI directives and activities in DOE.
Hannes smarason next code-wuxi combined technologiesHannes Smárason
Lower-cost genome sequencing has reached a point of strong commercial viability. The remaining 2 legs of the “3-legged stool” of genomics-enabling technologies —genomic analysis tools database storage—are rapidly evolving to support the use of genomic information in medical care.
NCI Cancer Imaging Program - Cancer Research Data EcosystemWarren Kibbe
Given to the NCI Cancer Imaging Program monthly telecon on January 9th, 2017. NCI Genomic Data Commons, Beau Biden Cancer Moonshot Blue Ribbon Panel, Cancer Research Data Ecosystem and the role of imaging in precision medicine
2016 Data Commons and Data Science Workshop June 7th and June 8th 2016. Genomic Data Commons, FAIR, NCI and making data more findable, publicly accessible, interoperable (machine readable), reusable and support recognition and attribution
Use of open, curated variant databases: ethics? Liability? - Bartha KnoppersHuman Variome Project
Translation of genomics into medicine and drug development requires comprehensive, high-quality, genomic variant databases. To support translation, there is a movement towards sharing clinical annotations of variants (e.g., benign, unknown, pathogenic) internationally via open access. Despite the growing popularity of variant databases, ethical issues and liability risks have received scant attention. Ethical priorities for variant databases include 1) competence – ensuring that data is responsibly managed, curated, and used; 2) confidentiality – ensuring appropriate safeguards for patient data; 3) communication – clearly describing the purpose, quality standards, and data handling practices to contributing patients and potential users; and 4) continuous oversight to adapt database governance in a rapidly evolving environment. How can database managers fulfill these obligations when these responsibilities are increasingly distributed along the clinical pipeline? Legal issues include medical liability based on potential harm to patients; liability based on third-party intellectual property or privacy rights in the data; and regulatory risks as variant data is integrated into genetic tests or devices. Can these risks can be managed through appropriate governance structures – including adequate consents, access processes, contributor agreements, and disclaimers – while still facilitating sharing and clinical use?
Day 2: Innovation to optimise therapeutic options for prevention and treatmen...KTN
The focus of this day is to explore unmet clinical needs in the effective treatment and therapy of patients with multiple long term conditions. Such patients have been historically excluded from clinical trials and also suffer from the burden of polypharmacy complications that affect quality of life. Innovation that supports a more holistic and personalised intervention, that applies patient stratification and pharmacogenomics, could dramatically improve health outcomes for diverse patient groups.
Medical genetics in egypt situation and perspectivesPasteur_Tunis
Présentation de Ghada El-Kamah réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
Standards for public health genomic epidemiology - Biocuration 2015Melanie Courtot
A presentation introducing genomic epidemiology and its application in public health. It also explains the need for standards to support the Canadian Integrated Rapid Infectious Disease Analysis platform which implements genomic epidemiology analyses for detection and investigation of infectious disease outbreaks caused by food-borne pathogens.
Professor Michael Levin's presentation at Meningitis Research Foundation's 2013 conference Meningitis & Septicaemia in Children & Adults www.meningitis.org/conference2013
A presentation by Osman Sankoh as part of the Innovations in design and measurement panel discussion at the International Symposium on Cohort and Longitudinal Studies in Developing Contexts, UNICEF Office of Research - Innocenti, Florence, Italy 13-15 October 2014
Overcoming the challenges of molecular diagnostics in government health insti...Yakubu Sunday Bot
overcoming the challenges of molecular diagnostics in government owned health institution in nigeria.Several challenges abound in the Nigerian health sector ranging from financial,political and lack of commitment.Its obvious and no wonder the state of health care deliveryy, vis a vis its quality of care to its citizenry.
ClinVar: Aggregating Data to Improve Variant Interpretation - Melissa LandrumHuman Variome Project
The rate of variant discovery continues to surpass the rate of clinicalgrade interpretation. This is a challenge for precision medicine, because fast, reliable access to variant interpretations is necessary to provide well-informed and timely interpretations of test results to patients. ClinVar is a public repository for interpretations of clinical significance and functional effects of variants in any gene and for any disease. Interpretations are submitted by many sources, including clinical testing laboratories, research laboratories, locus-specific databases, expert panels, practice guidelines, as well as OMIM® and GeneReviews™. Collecting variant interpretations in ClinVar depends on integrating data from these different sources, which has several benefits. First, data integration requires standardizing the data from each source. This improves the quality of the data in ClinVar as well as in each of the individual datasets. ClinVar staff validate HGVS expressions as a routine part of ClinVar submission processing. Submitters are encouraged to use standard terms in MedGen for diseases and phenotypes. Standard terms for clinical significance are used in ClinVar when available; for example, ClinVar uses the terms recommended by ACMG to classify variants for Mendelian diseases. Secondly, ClinVar aggregates all data for a variant defined by its genomic location. Therefore, HGVS descriptions on different transcripts or on different genomic sequences can be recognized as the same variant. Thirdly, integrating data from multiple submitters allows the evidence from all sources to be pooled together. This larger collection of evidence aids the re-evaluation of variant classifications, and is especially valuable for rare variants and novel gene-disease relationships. Fourthly, data integration means that variant interpretations from different sources can be viewed together and compared. Thus a ClinVar user has access to interpretations outside any internal system and knows when there is consensus in the interpretation or not. Submitting laboratories use reports of conflicting interpretations in ClinVar to prioritize variants that they should re-evaluate. ClinVar receives data from many data providers, and therefore provides clear attribution to each contributing group, including links to records in LSDBs. Each source may update their submission to ClinVar at any time. For example, a record may be updated when a variant is re-classified or when additional evidence is available to support the interpretation. Submitters may consider providing regular updates to ClinVar to prevent their interpretations from becoming out of date. Submissions to ClinVar describe variants that range in complexity from simple alleles with explicit sequence locations through copy number changes and cytogenetic rearrangements with fuzzy boundaries.
Establishing validity, reproducibility, and utility of highly scalable geneti...Human Variome Project
Background: New technologies and increased competition have, and will continue to improve the cost-effectiveness of genetic testing, making genetic analysis more accessible to medical practices worldwide. However, challenges remain to establishing the validity of such tests. Moreover many patients harbor rare or novel variants and classification is likely to remain a bottleneck in broader deployment of genetic medicine.
The PhenX Toolkit: Standard Measures for Collaborative Research - Wayne HugginsHuman Variome Project
Introduction and Background: The Web-based PhenX Toolkit (consensus measures for Phenotypes and eXposures, https://www. phenxtoolkit.org/) is a catalog of standard measures designed to facilitate collaborative biomedical research. PhenX measures help ensure that phenotypes from different studies are collected and represented in a consistent format. This consistency can enable data comparability across sites in large cohorts (e.g., Precision Medicine Initiative) and facilitates combining data to validate clinically actionable variants, increase statistical power (e.g., studies of rare genetic conditions or gene-enviroment interactions), or compare treatments and outcomes between patients.
Legal and regulatory challenges to data sharing for clinical genetics and ge...Human Variome Project
There are many factors that impede genomic variant sharing in the UK, despite it becoming a necessary part of clinical care. These include the lack of a designated infrastructure or mechanism aggravated by the complexity of laws that apply, and fragmented and variable advice from local ‘Caldicott guardians’ who guide NHS trusts on their responsibilities concerning data protection and confidentiality. Since the legitimacy of data sharing in the UK is framed in terms of ‘personal data’ being shared for ‘direct care’ (subject to legal exceptions), the blurred boundaries between clinical care and research, and the spectrum of identifiability of data also lead to differing interpretations resulting in inconsistent practices.
In a multidisciplinary collaboration, the PHG Foundation and the UK’s Association for Clinical Genetic Science co-hosted a workshop to examine the clinical necessity for sharing variant data and associated phenotypic information, the technical feasibility and the legal and regulatory impediments to such sharing. Delegates included clinicians, laboratory scientists, and key policy makers, including the National Data Guardian for Health and Care and representatives from the 100,000 Genomes Project, a pioneering research project which promises to build a legacy for future genomics services in the UK. The key finding from our work was that current arrangements for sharing genomic variants within the NHS are unsatisfactory and inconsistent practices are compromising safety and quality. Our workshop report [1] highlights the urgent need for (i) national agreement to optimise sharing within the NHS and develop consensus on the legitimacy of data sharing, (ii) standardised operational processes, including a designated sustainable database or mechanism for sharing, and (iii) strong leadership by the multiple relevant health organisations to demonstrate the benefits and risks associated with sharing and not sharing data.
Since publication of the workshop report, the NHS Consortium (operating within the DECIPHER database) has reported a 120% increase in the number of cases shared, the 100,000 Genomes Project and associated data embassy have got underway and the EU Data Protection Regulation has been finalised. However research highlights continuing public reservations about some aspects of data sharing including commercial access and misgivings around secondary uses of data. Publication of the National Data Guardian’s long-awaited review of consent and security provisions to provide guidance on a new consent and opt-out model for sharing patient information in the NHS, has been delayed pending the results of the EU referendum being known. Against this backdrop, the imperative to develop robust, proportionate policies for genomic data sharing becomes increasingly acute.
Funding from the PHG Foundation and the Association for Clinical Genetic Science.
Human variome project quality assessment criteria for variation databases - M...Human Variome Project
Numerous databases containing information about DNA, RNA and protein variations are available. Gene-specific variant databases (locus specific variation databases, LSDBs) are typically curated and maintained for single genes or groups of genes for a certain disease(s). These databases are widely considered as the most reliable information source for a particular gene/protein/disease, but it should also be made clear they may have widely varying contents, infrastructure, and quality. Quality is very important to evaluate because these databases may affect health decision-making, research and clinical practice. The Human Variome Project (HVP) established a Working Group for Variant Database Quality Assessment. The basic principle was to develop a simple system that nevertheless provides a good overview of the quality of a database [1]. The HVP quality evaluation criteria that resulted are divided into four main components: data quality, technical quality, accessibility, and timeliness. Instructions are available for the developed quality criteria and how implementation of the quality scheme can be achieved ([1], http://www.humanvariomeproject.org/finish/19/255.html). Examples are provided for the current status of the quality items in two different databases, BTKbase, an LSDB, and ClinVar, a central archive of submissions about variants and their clinical significance.
Reference: [1] Vihinen, M., Hancock, J. M., Maglott, D. R., Landrum, M. J., Schaafsma, C. P., Taschner, P. Human Variome Project quality assessment scheme for variation databases. Hum. Mutat. (in press).
Mitochondrial diseases are characterized by a high clinical and genetic heterogeneity and a growing number of genes of mitochondrial disease has been identified. Mitochondrial diseases follow any mode of inheritance, due to the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). 1 000 to 1 500 nuclear genes encode mitochondrial proteins. Approximately 250 of these genes have been reported as disease causing. These genes not only encode the various subunits of each respiratory chain complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA maintenance. Some of these genes are associated with well defined syndromes but more and more are specific to one patient or family only, hampering to establish genotype-phenotype correlations. The clinical heterogeneity of these disorders makes the diagnosis difficult especially in the first years of the clinical course and other genetic diseases can present an overlapping phenotype. Therefore only the identification of the disease causing mutation allows to certainly establish the diagnosis of mitochondrial disease.
Dr. Rötig (PhD) is the head of the group working on mitochondrial diseases in Necker Hospital (Paris). This group has initially settled and integrated platform of clinic, biochemistry and molecular analysis to investigate patients with OXPHOS disease. The scientific field of this group is the identification of genes involved in mitochondrial disorders and the investigation of their pathophysiology. They have described the first non-neuromuscular presentation of mitochondrial diseases and characterized the very first mutations in nuclear genes resulting in defects of Krebs’s cycle or the respiratory chain.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Travis Hills' Endeavors in Minnesota: Fostering Environmental and Economic Pr...Travis Hills MN
Travis Hills of Minnesota developed a method to convert waste into high-value dry fertilizer, significantly enriching soil quality. By providing farmers with a valuable resource derived from waste, Travis Hills helps enhance farm profitability while promoting environmental stewardship. Travis Hills' sustainable practices lead to cost savings and increased revenue for farmers by improving resource efficiency and reducing waste.
ANAMOLOUS SECONDARY GROWTH IN DICOT ROOTS.pptxRASHMI M G
Abnormal or anomalous secondary growth in plants. It defines secondary growth as an increase in plant girth due to vascular cambium or cork cambium. Anomalous secondary growth does not follow the normal pattern of a single vascular cambium producing xylem internally and phloem externally.
This presentation explores a brief idea about the structural and functional attributes of nucleotides, the structure and function of genetic materials along with the impact of UV rays and pH upon them.
Phenomics assisted breeding in crop improvementIshaGoswami9
As the population is increasing and will reach about 9 billion upto 2050. Also due to climate change, it is difficult to meet the food requirement of such a large population. Facing the challenges presented by resource shortages, climate
change, and increasing global population, crop yield and quality need to be improved in a sustainable way over the coming decades. Genetic improvement by breeding is the best way to increase crop productivity. With the rapid progression of functional
genomics, an increasing number of crop genomes have been sequenced and dozens of genes influencing key agronomic traits have been identified. However, current genome sequence information has not been adequately exploited for understanding
the complex characteristics of multiple gene, owing to a lack of crop phenotypic data. Efficient, automatic, and accurate technologies and platforms that can capture phenotypic data that can
be linked to genomics information for crop improvement at all growth stages have become as important as genotyping. Thus,
high-throughput phenotyping has become the major bottleneck restricting crop breeding. Plant phenomics has been defined as the high-throughput, accurate acquisition and analysis of multi-dimensional phenotypes
during crop growing stages at the organism level, including the cell, tissue, organ, individual plant, plot, and field levels. With the rapid development of novel sensors, imaging technology,
and analysis methods, numerous infrastructure platforms have been developed for phenotyping.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Remote Sensing and Computational, Evolutionary, Supercomputing, and Intellige...University of Maribor
Slides from talk:
Aleš Zamuda: Remote Sensing and Computational, Evolutionary, Supercomputing, and Intelligent Systems.
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Inter-Society Networking Panel GRSS/MTT-S/CIS Panel Session: Promoting Connection and Cooperation
https://www.etran.rs/2024/en/home-english/
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
1. Cyprus Case Study
What can other countries learn from this experience?
Carsten W. Lederer
The Cyprus Institute of Neurology and Genetics
The Cyprus School of Molecular Medicine
Lederer@cing.ac.cy
The Cyprus
Institute of
Neurology
and Genetics
UNESCO Headquarters
Paris, France
30 – 31st May 2016
Human Variome Project
Consortium
6th Biennial Meeting
GG2020 Fringe Meeting
http://mycyprusinsider.com/wp-content/uploads/2015/06/Tzelefos-Bridge.jpg
4. The Cyprus
Institute of
Neurology
and Genetics
Haemoglobin
Two loci for H.s. globin genes
Haemoglobin, a tetrameric
metalloprotein
2 α-like globin chains
2 β-like globin chains
4 haeme molecules with central Fe2+/3+
Human adult haemoglobins
α
ε
γ
Chr. 16 Chr. 11
ζ δ
β
β
α
α
β HbA
>95 % δ
α
α
δ HbA2
<3.5 %
γα
αγ
HbF
<1.0 %
4
5. The Cyprus
Institute of
Neurology
and Genetics
Key Features of β-thalassaemia
β
α
α
β
α
α
α
α
γα
αγ
γ
γ
Toxicity of α-globin
(Myeloid) ineffective
erythropoiesis
(Splenic) haemolysis
Iron overload ( iron chelation)
Secondary endocrinopathology
Organ failure (liver, pancreas, heart)
δα
αδ
Anaemia ( blood transfusions)
Tissue hypoxia & myeloid expansion
Osteoporosis
Skeletal deformities
Diagnostic: HbF & HbA2 increase
Modifier: high HbF
Genetic (HPFH)
Pharmacological induction
Gene-therapeutic induction
Modifier:
low/high α
ε δ βAγGγ
β-globin locus
5
6. The Cyprus
Institute of
Neurology
and Genetics
Critical Factors
Blood transfusions
Supply
Biosafety
Increased iron absorption
Iron chelation
Risk of noncompliance
Cost
Genotype-phenotype correlation & HPFH
Known and unknown modifiers, mutations and variants
Personalised therapies
http://thetab.comhttp://bernsteincrisismanagement.comcreativebits.orggenius.com
€£
8. The Cyprus
Institute of
Neurology
and Genetics
Provision of Care
1969 Governmental policy for thalassaemia
Iron chelation (defer(ri)oxamine) and transfusion to [Hb]=11 g/dL
1 paediatrician/government hospital responsible for thalassaemia
1977 Introduction of a voluntary blood donation scheme
Committee for blood donation with political, medical and patient representatives
Provision of deferoxamine by the government
Increased societal awareness of blood requirements
Voluntary blood donations rise from 6% to 50%
1981 Thalassaemia outpatient clinics with dedicated premises
Addition of experts for complications in puberty and adulthood
1983 Deferoxamine 44% of governmental drug cost
1999 Introduction of oral chelator deferiprone
Increase in compliance and rate of successful chelation
2007 Introduction of 2nd oral chelator deferasirox
Angastiniotis et al. 1986; Kolnagou et al. 2015
8
9. The Cyprus
Institute of
Neurology
and Genetics
Need to Act
Status quo 1969
1/7 of Cypriots carriers for β-thalassaemia
1/49 couples are at risk (i.e. both partners carriers)
1/158 birth expected to be affected
1/1000 disease prevalence
Projected rise for thalassaemics by 2010
Unmanageable drug cost
Impossible transfusion requirements
To maintain level of care and quality of life for existing patients:
Need for a national prevention programme
9
10. The Cyprus
Institute of
Neurology
and Genetics
Prevention
1973 Testing of patients’ relatives
High detection rate
No prenatal diagnosis
The “stigma” implicit discouragement for carrier couples
of pregnancies
of marriages
1977 Foetal diagnosis abroad
Gradual removal of the “stigma”
1981 Foetal diagnosis in Cyprus
1983 Introduction of a premarital certificate
1984 National cost/benefit analysis
On-going education of patients, public and clinicians
Undiminished need for screening and blood donations
Disease-management, reproductive, and diagnostic options
10
11. The Cyprus
Institute of
Neurology
and Genetics
Prevention
Ministry of Health
4 Branches of the Thalassaemia Centre
Disease Management
Patient counselling
1 central haematological laboratory
Sample referral
CING (a not-for-profit, semi-GO) – Department of
Genetics Thalassaemia
>800 test cases/year
β-thalassaemia
α-thalassaemia
Hb Variants
δβ-thalassaemias
δ-thalassaemias
HPFH
12. The Cyprus
Institute of
Neurology
and Genetics
chorionic
villus sampling
ultrasound
sensor
placenta
Diagnostic Methods
Diagnostic methods for routine CVS & PB samples
For α-thalassaemia
Sequencing
MLPA
GAP-ARMs
For β-thalassaemia
Sequencing
MLPA
NIPD (cf-mDNA-based)
RHD status
Thalassaemia
(SNP-based, experimental)
PGD (in conjunction with IVF)
qPCR- and HRM-based
Online list of services
Immunosuppression!
2004 – 2011
Total cases: 52
Pregnancies: 14
Births: 12
PMID23362932 Papasavva et al. 2013
13. The Cyprus
Institute of
Neurology
and Genetics
Decision Trees (Simplified!)
Population-wide
Screening
Normal Haematology
Go Forth and
Multiply
Abnormal
Haematology (MCV,
MCH)
Elevated HbA2
Test for β-
thalassaemia
Normal HbA2
Test for α-
thalassaemia
Test for δ/δβ-
thalassaemia
Abnormal CE-HPLC
Peaks
Sequence for α/β/δ
Variants
Results for Both
Partners
Single Carrier or
Alternate-locus
Carriers
Go Forth and
Multiply
Both Partners Same-
locus Carriers
Counselling
Advise: in Case of
Pregnancy PD
No Conception /
Repeatedly Affected
IVF/PGD
15. The Cyprus
Institute of
Neurology
and Genetics
Electronic Patient Database
Knowing your patient population
Geographical fine-mapping of epidemiologies
Mutations in patients and patient genotypes
Mutation-specific carrier frequencies
Longitudinal nationwide studies
Basis for genotype/phenotype studies
Feeding into international summary databases, such as IthaGenes
Enabling collaborative studies
PMID: 24006929 Kyrri et al. 2013
PMID: 25058394 Kountouris et al. 2014
PMID: 27199182 Kountouris et al. 2016
16. The Cyprus
Institute of
Neurology
and Genetics
16
Result!
Annual Number of Thalassaemic Births in Cyprus
Actual (x) vs. Expected (x)
0
10
20
30
40
50
60
70
1974
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Annual Number of Thalassaemic Births
% of Expected
Carrier Database
α-thalassaemia: 8,412
β-thalassaemia: 2,335
δ-thalassaemia: 428
Cypriot population: 659115
Patient Database
H-disease (--/α-): 595 [608]
β-thalassaemia: 592 [630]
17. The Cyprus
Institute of
Neurology
and Genetics
Beyond the Primary Mutation
β-globin locus
δ βAγGγε
HbF
HbA
HbA2
HPFH
HbF
HbA
HbA2
Normal
PMID 25737641 Finotti et al. 2015
Patient
stratification
Mild and severe
thalassaemia
High and low
HbF levels
Response in
cell culture to
chemical and
gene-
therapeutic HbF
induction
Identification of
population-wide
key modifiers,
such as BCL11A
and KLF1
variants
19. The Cyprus
Institute of
Neurology
and Genetics
Small size (9,251 km2) and population (0.7 / 1.1 Mio)
Regular meetings of all key clinicians, molecular researchers and patients
Homogeneity and community spirit at the country level
Universal awareness of screening requirement and the need for blood donations
Strength of the Greek Orthodox Church
Church influence on society and politics
Greek Orthodox weddings before (or early during) most pregnancies
Dedicated diagnostic infrastructure of the Thalassaemia Centre
Four haematology and care centres in each major city (Nicosia, Larnaca, Limassol and Paphos)
Central haematology laboratory
Central molecular testing and database at the CING
Integration of diagnostic work and molecular research
Availability of sample material for research
(novel diagnostics, e.g. NIPD)
Research programs involving all
stakeholders
Family, Church and State 19
20. The Cyprus
Institute of
Neurology
and Genetics
Annual Number of Thalassaemic Births in Cyprus
Challenges
For Cyprus: changing attitudes
Changing societal structure
Secularisation of society
Pregnancies out of wedlock
Success its own worst enemy
Sinking awareness amongst the young
Increasing choice to have thalassaemic children
For others: horses for courses
Religious or ethical homogeneity is an exception
Coordination problems for larger or geographically dispersed countries
Legality and social acceptance of abortion as key factor
Compulsory screening (and church interference) untenable elsewhere
EU law: Cyprus as a special case
20
www.oecd.org/social/family/database
19
7
20
10
18
22
24
16
27
17
36
42
3940
54
52
37
39
29
32
23
12
1010 9
3 2 3
0
2
5
2 1
3 3 2 2 2 2 2
4
2 3
1 0 1
5 4 3
5
1 2
6
0
10
20
30
40
50
60
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
21. The Cyprus
Institute of
Neurology
and Genetics
Challenges! 21
MY
Malay, Peninsular
Han Chinese, Hokkien
Tamil
Han Chinese, Hakka
Han Chinese, Cantonese
Banjar Malay
Han Chinese, Teochew
Han Chinese, Mandarin
Minangkabau
F
NG
Yoruba
Hausa
Igbo
Fulani
Urhobo-Isoko
Efik-Ibibio
Kanuri
Edo
Tiv
Ijaw
CY
Greek Cypriot
Foreign Residents
Illegal immigrants
22. The Cyprus
Institute of
Neurology
and Genetics
This project has received funding from
the European Union’s Seventh
Framework Programme for research,
technological development and
demonstration under grant agreement
no. 306201 and from the Research
Promotion Foundation of Cyprus under
grant agreement ΥΓΕΙΑ/ΒΙΟΣ/0311(ΒΕ).
Acknowledgements
CING & ITHANET
Marina Kleanthous
Petros Kountouris
Pavlos Fanis
Coralea Stephanou
Xenia Felekki
The whole diagnostics team
Ministry of Health/Thalassaemia Centre
Soteroulla Christou
Maria Sitarou
Annita Kolnagou
Michael Hadjigavriel
Haematology Laboratory
All our collaborators and patients!
22
24. The Cyprus
Institute of
Neurology
and Genetics
Acknowledgements
Thalassaemia Centre & General
Hospital
Σωτηρούλα Χρίστου
Ελένη Καλογήρου
Μαρία Σίταρου
Μιχάλης Ηατζηγαβριήλ
Ανίτα Κολνάγου
Μάριος Αντωνιάδης
Μιχάλης Αγκαστινιώτης
Cyprus Antianaemia Association
Ναταλία Μιχαηλίδου
Λοΐζος Περικλέους
All patients and sample volunteers!
«Genome Editing»
University of Freiburg
Toni Cathomen
Claudio Mussolino
«Advancing Lentiviral Vector»
King’s College London, ΗΒ
Mike Antoniou
University of Ferrara, Italy
Roberto Gambari
Lederer@cing.ac.cy
«ThalaMoSS»
University of Ferrara, Italy
Roberto Gambari
Erasmus MC, The Netherlands
Sjaak Philipsen
Ίδρυµα Ιατροβιολογικών Ερευνών της
Ακαδημίας Αθηνών, Ελλάδα
Eleni Katsantoni
Weill Cornell Medical College, ΗΠΑ
Stefano Rivella
University of Masaryk, Czech Republic
Petr Holub
University of Cagliari, Italy
Paolo Moi
King’s College London, ΗΒ
Swee Lay Thein
Λαϊκό Γενικό Νοσοκομείο, Ελλάδα
Ersi Voskaridou
Weill Cornell Medical College, ΗΠΑ
Stefano Rivella
NovaMechanics, Cyprus
BioCep Ltd., Israel
Harbour Antibodies BV, The Netherlands
IRBM Science Park, Italy
24