This document provides an overview of a presentation on the role of genetics in osteoporosis. It discusses:
- The complex genetics of osteoporosis, with multiple genetic and environmental factors contributing to risk.
- Studies using genome-wide association, exome sequencing, and other approaches to identify genetic variants associated with osteoporosis and bone mineral density.
- The Rotterdam Study, a large longitudinal cohort study that has collected extensive genetic and phenotypic data on bone health over 25 years to help uncover the genetic architecture of osteoporosis.
This document summarizes the qualifications and experience of Shumei Ren, a biomedical research investigator specializing in oncological diseases. Ren has over 15 years of experience in molecular biology, pharmacology, and various techniques including flow cytometry, in vitro assays, and high throughput methods. Ren's professional experience includes positions at Thomas Jefferson University, Albany Medical College, and Hokkaido University investigating topics such as gastric cancer, prostate cancer, fibrosis, and hematopoietic malignancies.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
This document summarizes a research article that studied the role of p53 in daunorubicin (DNR)-induced lesions in the spleen. The key findings were:
1) DNR treatment caused more rapid cell death and weight loss in the spleens of wild type mice compared to p53-null mice.
2) While wild type mouse spleens recovered normal morphology 8 days after DNR treatment, p53-null mouse spleens still had large necrotic lesions.
3) DNR treatment increased p21 levels in wild type mice but not p53-null mice, indicating p53 is required for p21 induction.
4) The results suggest p53
This document provides a partial bibliography for a lecture on May 26, 2021 about a genetic experiment on how children respond. It includes 18 references to articles mentioned in the lecture on topics like: anatomical and physiological differences between children and adults relevant to brain injuries; differences in blood flow in the brain and heart depending on age; toxicity and immunogenicity of lipid nanoparticles and PEGylated systems; factors that predict the severity of COVID-19 infections; and the relationship between GGT enzyme levels and conditions like diabetes and heart disease.
Deep phenotyping to aid identification of coding & non-coding rare disease v...mhaendel
Whole-exome sequencing has revolutionized disease research, but many cases remain unsolved because ~100-1000 candidates remain after removing common or non-pathogenic variants. We present Genomiser to prioritize coding and non-coding variants by leveraging phenotype data encoded with the Human Phenotype Ontology and a curated database of non-coding Mendelian variants. Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes.
This document discusses monogenic and polygenic diseases like cystic fibrosis and autism. It summarizes recent research that found fat-soluble vitamins may help antibiotics treat cystic fibrosis by preventing antibiotics from binding to proteins. A separate study identified 18 new autism-linked genes by analyzing the entire genomes of individuals, providing insight into autism's genetic causes and variability between patients. The research aims to improve treatment and quality of life for patients suffering from these hereditary conditions.
This document discusses several studies on monogenic disorders and their potential medical applications. It first introduces monogenic disorders as involving mutations in a single gene, which can be inherited or spontaneous. Two studies are then summarized: one finding that brain stimulation may help restore breathing capacity in Duchenne muscular dystrophy patients by activating the diaphragm muscle, and another observing changes in mucus protein structure in cystic fibrosis patients that could provide insight into treatment. The document concludes that these studies bring researchers closer to potential treatments for currently incurable genetic diseases and improve patients' quality of life.
Evolutionary medical genomics, whether we realize it or not, is the foundation of genetics of predispositions whose main goal should not be personalized prediction of disease risk, but to develop strategies for its treatment and prevention on the basis of the knowledge of its genetic, evolutionary history and molecular mechanisms.
The Monarch Initiative aims to improve disease diagnostics and analysis by utilizing deep phenotyping data. It has developed ontologies like the Human Phenotype Ontology with over 13,000 phenotype terms to help machines understand human phenotypes. It uses "fuzzy" phenotypic profile matching across species to match patient data to known genetic disorders, as demonstrated by a case solved linking a patient's profile to a STIM1 variant. The Initiative is working to develop lay-friendly phenotyping tools and connect data sources through the Matchmaker Exchange to aid in diagnosis and research.
This document summarizes the qualifications and experience of Shumei Ren, a biomedical research investigator specializing in oncological diseases. Ren has over 15 years of experience in molecular biology, pharmacology, and various techniques including flow cytometry, in vitro assays, and high throughput methods. Ren's professional experience includes positions at Thomas Jefferson University, Albany Medical College, and Hokkaido University investigating topics such as gastric cancer, prostate cancer, fibrosis, and hematopoietic malignancies.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
This document summarizes a research article that studied the role of p53 in daunorubicin (DNR)-induced lesions in the spleen. The key findings were:
1) DNR treatment caused more rapid cell death and weight loss in the spleens of wild type mice compared to p53-null mice.
2) While wild type mouse spleens recovered normal morphology 8 days after DNR treatment, p53-null mouse spleens still had large necrotic lesions.
3) DNR treatment increased p21 levels in wild type mice but not p53-null mice, indicating p53 is required for p21 induction.
4) The results suggest p53
This document provides a partial bibliography for a lecture on May 26, 2021 about a genetic experiment on how children respond. It includes 18 references to articles mentioned in the lecture on topics like: anatomical and physiological differences between children and adults relevant to brain injuries; differences in blood flow in the brain and heart depending on age; toxicity and immunogenicity of lipid nanoparticles and PEGylated systems; factors that predict the severity of COVID-19 infections; and the relationship between GGT enzyme levels and conditions like diabetes and heart disease.
Deep phenotyping to aid identification of coding & non-coding rare disease v...mhaendel
Whole-exome sequencing has revolutionized disease research, but many cases remain unsolved because ~100-1000 candidates remain after removing common or non-pathogenic variants. We present Genomiser to prioritize coding and non-coding variants by leveraging phenotype data encoded with the Human Phenotype Ontology and a curated database of non-coding Mendelian variants. Genomiser is able to identify causal regulatory variants as the top candidate in 77% of simulated whole genomes.
This document discusses monogenic and polygenic diseases like cystic fibrosis and autism. It summarizes recent research that found fat-soluble vitamins may help antibiotics treat cystic fibrosis by preventing antibiotics from binding to proteins. A separate study identified 18 new autism-linked genes by analyzing the entire genomes of individuals, providing insight into autism's genetic causes and variability between patients. The research aims to improve treatment and quality of life for patients suffering from these hereditary conditions.
This document discusses several studies on monogenic disorders and their potential medical applications. It first introduces monogenic disorders as involving mutations in a single gene, which can be inherited or spontaneous. Two studies are then summarized: one finding that brain stimulation may help restore breathing capacity in Duchenne muscular dystrophy patients by activating the diaphragm muscle, and another observing changes in mucus protein structure in cystic fibrosis patients that could provide insight into treatment. The document concludes that these studies bring researchers closer to potential treatments for currently incurable genetic diseases and improve patients' quality of life.
Evolutionary medical genomics, whether we realize it or not, is the foundation of genetics of predispositions whose main goal should not be personalized prediction of disease risk, but to develop strategies for its treatment and prevention on the basis of the knowledge of its genetic, evolutionary history and molecular mechanisms.
The Monarch Initiative aims to improve disease diagnostics and analysis by utilizing deep phenotyping data. It has developed ontologies like the Human Phenotype Ontology with over 13,000 phenotype terms to help machines understand human phenotypes. It uses "fuzzy" phenotypic profile matching across species to match patient data to known genetic disorders, as demonstrated by a case solved linking a patient's profile to a STIM1 variant. The Initiative is working to develop lay-friendly phenotyping tools and connect data sources through the Matchmaker Exchange to aid in diagnosis and research.
Salon b 18 kasim 2011 11.30 11.50 benan bayrakcityfngnc
1. Hemophagocytosis frequently occurs during systemic inflammation and is associated with increased heme oxygenase-1 (HO-1) expression.
2. Within bone marrow of sepsis patients, macrophages constitute the principal source of HO-1 expression, which reflects heme breakdown.
3. Very high serum ferritin levels in pediatric patients with systemic inflammation are associated with increased risk of critical care and death.
The Human Phenotype Ontology (HPO) was developed to describe phenotypic abnormalities, aka, “deep phenotyping”, whereby symptoms and characteristic phenotypic findings (a phenotypic profile) are captured. The HPO has been utilized to great success for assisting computational phenotype comparison against known diseases, other patients, and model organisms to support diagnosis of rare disease patients. Clinicians and geneticists create phenotypic profiles based on clinical evaluation, but this is time consuming and can miss important phenotypic features. Patients are sometimes the best source of information about their symptoms that might otherwise be missed in a clinical encounter. However, HPO primarily use medical terminology, which can be difficult for patients and their families to understand. To make the HPO accessible to patients, we systematically added non-expert terminology (i.e., layperson terms) synonyms. Using semantic similarity, patient-recorded phenotypic profiles can be evaluated against those created clinically for undiagnosed patients to determine the improvement gained from the patient-driven phenotyping, as well as how much the patient phenotyping narrows the diagnosis. This patient-centric HPO can be utilized by all: in patient-centered rare disease websites, in patient community platforms and registries, or even to post one’s hard-to-diagnosed phenotypic profile on the Web.
This document summarizes potential dangers of COVID-19 vaccines for children aged 12-18 based on adverse event reports. It notes that:
1) Reported adverse events following vaccination are atypically high, with over 250,000 reports including 8,500 reports for children aged 12-18, of which 17% experienced cardiovascular issues.
2) The vaccines are likely causing these adverse events as over 80% of cardiovascular, neurological, and immunological issues were reported within 1 day of vaccination.
3) The vaccines may disrupt the renin-angiotensin-aldosterone system, which regulates blood pressure and electrolytes, as the spike protein binds strongly to ACE2, a key enzyme in
The Application of the Human Phenotype Ontology mhaendel
Presented at the II International Summer School for Rare Disease and Orphan Drug Registries, September 15-19, 2014, Organized by the National Centre for Rare Diseases
Istituto Superiore di Sanità (ISS), Rome, Italy.
Note the extensive contribution by many consortium members and partners listed in the acknowledgements slide.
Patient-led deep phenotyping using a lay-friendly version of the Human Phenot...mhaendel
Presented at AMIA TBI CRI 2018.
Rare disease patients are expert in their medical history and these patients not only are some of the most engaged, but also they can themselves provision data for use in clinical evaluation. We therefore created a lay-person version of our clinical deep phenotyping instrument, the Human Phenotype Ontology. Here, we evaluate the diagnostic utility of this lay-HPO, and debut a new software tool for patient-led deep phenotyping.
What's In a Genotype?: An Ontological Characterization for the Integration of...mhb120
This document discusses challenges in integrating genetic variation data and summarizes efforts by the Monarch Initiative to address these challenges. Specifically, it discusses (1) reconciling genetic variation data associated with different levels (e.g. allele, gene), (2) integrating non-genomic forms of variation, and (3) creating semantic links to related biological data. The Monarch Initiative is developing the GENO ontology and using it in their data integration pipeline to standardize genetic variation data and infer new genotype-phenotype associations.
immunohistochemistry is a combined histological , immunological and biochemical technique used for the identification of specific tissue components by means of specific antigen/antibody reactions.
Use of semantic phenotyping to aid disease diagnosismhaendel
This document discusses using semantic phenotyping to aid disease diagnosis. It outlines using ontologies to semantically annotate phenotypes seen in patients, animal models, and genes. This allows computation of semantic similarity between phenotypes to identify potential disease candidates. The document also discusses challenges such as uneven phenotype data distribution and differences in how phenotypes are described across species. It proposes building an integrated cross-species semantic framework called Uberpheno to address these challenges and better leverage animal models for diagnosing rare diseases.
This study investigates autophagy in neurons and its relationship to Alzheimer's disease pathology. The study finds that:
1) In healthy neurons, autophagosomes are rapidly cleared through fusion with lysosomes, keeping autophagic vacuole levels low.
2) Impeding late stage autophagosome clearance, such as by inhibiting lysosomal proteolysis, causes autophagic vacuoles to accumulate in neurons resembling pathology in Alzheimer's disease.
3) The autophagic pathology observed in Alzheimer's disease likely arises from impaired autophagosome clearance rather than strong induction of autophagy alone.
Data Translator: an Open Science Data Platform for Mechanistic Disease Discoverymhaendel
Architecture of language and data translation that underlays the NCATS Biomedical Data Translator. Presented at the Fanconi Anemia Annual Meeting. http://fanconi.org/index.php/research/annual_symposium
Robert Pesich_PAVA_Stanford Resume v. 8_22_16Robert Pesich
Robert Pesich has extensive experience managing laboratory operations and research projects. He has overseen the daily activities of 25 researchers at Stanford University and the Palo Alto VA, including managing budgets, equipment, and regulatory compliance. Pesich has specialized skills in tissue sample processing, gene expression analysis, and bioinformatics. He has authored several publications characterizing gene expression profiles in normal and diseased tissues. Currently, Pesich also serves as President of a poetry non-profit organization.
CONFERENCE
ON
Multiple Hereditary Exostoses
Insights Into Pathogenesis
November 3-5, 2005
Shriners Hospital of Houston
6977 Main Street
Houston, Texas
and the
Houston Marriott Medical Center
6580 Fannin Street
Houston, Texas
Sponsored By:
The Shriners Hospital
The National Institutes of Health
American Association of Enchondroma Diseases
March of Dimes Birth Defects Foundation
The Orthopaedic Research Society
The MHE Coalition
Gene Dx, DNA Diagnostic Services
The Mizutani Foundation for Glycoscience
Organizers: Dan Wells, Ph.D., Jacqueline Hecht, Ph.D., Sarah Ziegler
This document discusses various animal models used for research including invertebrate models like Drosophila and C. elegans, rodent models, rabbit models, and large animal models. These models are used to study processes like genetics, development, and disease due to their similarities to humans. Drosophila and C. elegans have been important for discoveries in development and genetics. Rodent models are widely used due to their similarities to humans and short lifespans. Larger animal models are needed for pre-clinical research due to closer mimicry of human physiology. A variety of animal models at different sizes are essential for advancing biomedical research.
The document discusses various technologies used at the House Ear Institute including genomics, proteomics, and imaging. It describes how researchers are using these tools to study diseases like neurofibromatosis type 2 (NF2) at the molecular level in order to develop personalized treatments and therapies. Maintaining high quality biospecimens is important for enabling various types of research.
This document discusses genetic genealogy and DNA testing. It begins with definitions of genetic genealogy and traditional genealogy research. It then provides details on human genetics such as the number of chromosomes, genes, and single nucleotide polymorphisms (SNPs). The document lists some major DNA testing companies and notes that the consumer genomics market is growing rapidly. It discusses factors to consider when choosing a DNA testing company. The remainder provides information on genetic genealogy projects and the Gene by Gene laboratory.
Induced pluripotent stem cells (iPSCs) derived from patients with alpha-1 antitrypsin deficiency (AATD) due to mutations in the SERPINA1 gene were differentiated into hepatic cells. The PiZZ iPSC-derived hepatic cells displayed intracellular accumulation of mutant alpha-1 antitrypsin (AAT) protein compared to controls, resulting from decreased AAT protein flux and secretion. Microarray analysis identified 135 genes that distinguished PiZZ iPSC-hepatic cells from controls, providing insights into AATD liver disease pathogenesis. The disease-specific cells also exhibited increased autophagic flux and responses to drugs that could augment or adversely affect autophagy, supporting the utility of
Transplant Immunology is known as a providential cure in medical sciences. People recommend it to patients for getting rid of many kinds of problems which are related to health. It involves a surgical operation where a body part is removed from one location and transplanted to another.
This document discusses the potential for organ printing as an alternative to organ transplantation. It outlines some of the safety questions that need to be addressed, such as the risk of malignant cell transformation when cells are cultured ex vivo. Specifically, it notes that cells removed from their natural environment and placed in artificial conditions like culture dishes can potentially become immortalized or tumorigenic over time due to factors like prolonged culture or serum exposure. Maintaining patient safety throughout the development of technologies like organ printing will require careful consideration of these types of risks.
1) The Estonian Biobank project has collected genetic and health data from over 200,000 Estonian volunteers, representing 15% of the country's population. Samples include whole genome sequences, exome sequences, and various omics data.
2) The biobank aims to facilitate personalized medicine by identifying individuals at high genetic risk and returning risk scores and other findings to participants. Studies on conditions like familial hypercholesterolemia and breast cancer have found many underdiagnosed cases using biobank data.
3) Secure electronic health records and national registries allow enrichment of biobank data with disease trajectories, treatments, and outcomes. The biobank also aims to use polygenic risk
This document summarizes Horst Spielmann's presentation on implementing alternative methods. It discusses his role as State Animal Welfare Officer in Berlin where he provides expert advice on animal welfare issues. The presentation covered topics like ending cosmetics testing in Europe, developing adverse outcome pathways, and alternative methods like embryonic stem cells, organ-on-chip technology, and using human cells for disease and infection models. It also discussed increasing collaboration between international regulatory agencies and researchers to advance alternative methods through information sharing and establishing performance standards.
Salon b 18 kasim 2011 11.30 11.50 benan bayrakcityfngnc
1. Hemophagocytosis frequently occurs during systemic inflammation and is associated with increased heme oxygenase-1 (HO-1) expression.
2. Within bone marrow of sepsis patients, macrophages constitute the principal source of HO-1 expression, which reflects heme breakdown.
3. Very high serum ferritin levels in pediatric patients with systemic inflammation are associated with increased risk of critical care and death.
The Human Phenotype Ontology (HPO) was developed to describe phenotypic abnormalities, aka, “deep phenotyping”, whereby symptoms and characteristic phenotypic findings (a phenotypic profile) are captured. The HPO has been utilized to great success for assisting computational phenotype comparison against known diseases, other patients, and model organisms to support diagnosis of rare disease patients. Clinicians and geneticists create phenotypic profiles based on clinical evaluation, but this is time consuming and can miss important phenotypic features. Patients are sometimes the best source of information about their symptoms that might otherwise be missed in a clinical encounter. However, HPO primarily use medical terminology, which can be difficult for patients and their families to understand. To make the HPO accessible to patients, we systematically added non-expert terminology (i.e., layperson terms) synonyms. Using semantic similarity, patient-recorded phenotypic profiles can be evaluated against those created clinically for undiagnosed patients to determine the improvement gained from the patient-driven phenotyping, as well as how much the patient phenotyping narrows the diagnosis. This patient-centric HPO can be utilized by all: in patient-centered rare disease websites, in patient community platforms and registries, or even to post one’s hard-to-diagnosed phenotypic profile on the Web.
This document summarizes potential dangers of COVID-19 vaccines for children aged 12-18 based on adverse event reports. It notes that:
1) Reported adverse events following vaccination are atypically high, with over 250,000 reports including 8,500 reports for children aged 12-18, of which 17% experienced cardiovascular issues.
2) The vaccines are likely causing these adverse events as over 80% of cardiovascular, neurological, and immunological issues were reported within 1 day of vaccination.
3) The vaccines may disrupt the renin-angiotensin-aldosterone system, which regulates blood pressure and electrolytes, as the spike protein binds strongly to ACE2, a key enzyme in
The Application of the Human Phenotype Ontology mhaendel
Presented at the II International Summer School for Rare Disease and Orphan Drug Registries, September 15-19, 2014, Organized by the National Centre for Rare Diseases
Istituto Superiore di Sanità (ISS), Rome, Italy.
Note the extensive contribution by many consortium members and partners listed in the acknowledgements slide.
Patient-led deep phenotyping using a lay-friendly version of the Human Phenot...mhaendel
Presented at AMIA TBI CRI 2018.
Rare disease patients are expert in their medical history and these patients not only are some of the most engaged, but also they can themselves provision data for use in clinical evaluation. We therefore created a lay-person version of our clinical deep phenotyping instrument, the Human Phenotype Ontology. Here, we evaluate the diagnostic utility of this lay-HPO, and debut a new software tool for patient-led deep phenotyping.
What's In a Genotype?: An Ontological Characterization for the Integration of...mhb120
This document discusses challenges in integrating genetic variation data and summarizes efforts by the Monarch Initiative to address these challenges. Specifically, it discusses (1) reconciling genetic variation data associated with different levels (e.g. allele, gene), (2) integrating non-genomic forms of variation, and (3) creating semantic links to related biological data. The Monarch Initiative is developing the GENO ontology and using it in their data integration pipeline to standardize genetic variation data and infer new genotype-phenotype associations.
immunohistochemistry is a combined histological , immunological and biochemical technique used for the identification of specific tissue components by means of specific antigen/antibody reactions.
Use of semantic phenotyping to aid disease diagnosismhaendel
This document discusses using semantic phenotyping to aid disease diagnosis. It outlines using ontologies to semantically annotate phenotypes seen in patients, animal models, and genes. This allows computation of semantic similarity between phenotypes to identify potential disease candidates. The document also discusses challenges such as uneven phenotype data distribution and differences in how phenotypes are described across species. It proposes building an integrated cross-species semantic framework called Uberpheno to address these challenges and better leverage animal models for diagnosing rare diseases.
This study investigates autophagy in neurons and its relationship to Alzheimer's disease pathology. The study finds that:
1) In healthy neurons, autophagosomes are rapidly cleared through fusion with lysosomes, keeping autophagic vacuole levels low.
2) Impeding late stage autophagosome clearance, such as by inhibiting lysosomal proteolysis, causes autophagic vacuoles to accumulate in neurons resembling pathology in Alzheimer's disease.
3) The autophagic pathology observed in Alzheimer's disease likely arises from impaired autophagosome clearance rather than strong induction of autophagy alone.
Data Translator: an Open Science Data Platform for Mechanistic Disease Discoverymhaendel
Architecture of language and data translation that underlays the NCATS Biomedical Data Translator. Presented at the Fanconi Anemia Annual Meeting. http://fanconi.org/index.php/research/annual_symposium
Robert Pesich_PAVA_Stanford Resume v. 8_22_16Robert Pesich
Robert Pesich has extensive experience managing laboratory operations and research projects. He has overseen the daily activities of 25 researchers at Stanford University and the Palo Alto VA, including managing budgets, equipment, and regulatory compliance. Pesich has specialized skills in tissue sample processing, gene expression analysis, and bioinformatics. He has authored several publications characterizing gene expression profiles in normal and diseased tissues. Currently, Pesich also serves as President of a poetry non-profit organization.
CONFERENCE
ON
Multiple Hereditary Exostoses
Insights Into Pathogenesis
November 3-5, 2005
Shriners Hospital of Houston
6977 Main Street
Houston, Texas
and the
Houston Marriott Medical Center
6580 Fannin Street
Houston, Texas
Sponsored By:
The Shriners Hospital
The National Institutes of Health
American Association of Enchondroma Diseases
March of Dimes Birth Defects Foundation
The Orthopaedic Research Society
The MHE Coalition
Gene Dx, DNA Diagnostic Services
The Mizutani Foundation for Glycoscience
Organizers: Dan Wells, Ph.D., Jacqueline Hecht, Ph.D., Sarah Ziegler
This document discusses various animal models used for research including invertebrate models like Drosophila and C. elegans, rodent models, rabbit models, and large animal models. These models are used to study processes like genetics, development, and disease due to their similarities to humans. Drosophila and C. elegans have been important for discoveries in development and genetics. Rodent models are widely used due to their similarities to humans and short lifespans. Larger animal models are needed for pre-clinical research due to closer mimicry of human physiology. A variety of animal models at different sizes are essential for advancing biomedical research.
The document discusses various technologies used at the House Ear Institute including genomics, proteomics, and imaging. It describes how researchers are using these tools to study diseases like neurofibromatosis type 2 (NF2) at the molecular level in order to develop personalized treatments and therapies. Maintaining high quality biospecimens is important for enabling various types of research.
This document discusses genetic genealogy and DNA testing. It begins with definitions of genetic genealogy and traditional genealogy research. It then provides details on human genetics such as the number of chromosomes, genes, and single nucleotide polymorphisms (SNPs). The document lists some major DNA testing companies and notes that the consumer genomics market is growing rapidly. It discusses factors to consider when choosing a DNA testing company. The remainder provides information on genetic genealogy projects and the Gene by Gene laboratory.
Induced pluripotent stem cells (iPSCs) derived from patients with alpha-1 antitrypsin deficiency (AATD) due to mutations in the SERPINA1 gene were differentiated into hepatic cells. The PiZZ iPSC-derived hepatic cells displayed intracellular accumulation of mutant alpha-1 antitrypsin (AAT) protein compared to controls, resulting from decreased AAT protein flux and secretion. Microarray analysis identified 135 genes that distinguished PiZZ iPSC-hepatic cells from controls, providing insights into AATD liver disease pathogenesis. The disease-specific cells also exhibited increased autophagic flux and responses to drugs that could augment or adversely affect autophagy, supporting the utility of
Transplant Immunology is known as a providential cure in medical sciences. People recommend it to patients for getting rid of many kinds of problems which are related to health. It involves a surgical operation where a body part is removed from one location and transplanted to another.
This document discusses the potential for organ printing as an alternative to organ transplantation. It outlines some of the safety questions that need to be addressed, such as the risk of malignant cell transformation when cells are cultured ex vivo. Specifically, it notes that cells removed from their natural environment and placed in artificial conditions like culture dishes can potentially become immortalized or tumorigenic over time due to factors like prolonged culture or serum exposure. Maintaining patient safety throughout the development of technologies like organ printing will require careful consideration of these types of risks.
1) The Estonian Biobank project has collected genetic and health data from over 200,000 Estonian volunteers, representing 15% of the country's population. Samples include whole genome sequences, exome sequences, and various omics data.
2) The biobank aims to facilitate personalized medicine by identifying individuals at high genetic risk and returning risk scores and other findings to participants. Studies on conditions like familial hypercholesterolemia and breast cancer have found many underdiagnosed cases using biobank data.
3) Secure electronic health records and national registries allow enrichment of biobank data with disease trajectories, treatments, and outcomes. The biobank also aims to use polygenic risk
This document summarizes Horst Spielmann's presentation on implementing alternative methods. It discusses his role as State Animal Welfare Officer in Berlin where he provides expert advice on animal welfare issues. The presentation covered topics like ending cosmetics testing in Europe, developing adverse outcome pathways, and alternative methods like embryonic stem cells, organ-on-chip technology, and using human cells for disease and infection models. It also discussed increasing collaboration between international regulatory agencies and researchers to advance alternative methods through information sharing and establishing performance standards.
Search engine for E NEU network science 080817Chirag Patel
The document describes building a search engine to discover environmental factors associated with disease and health outcomes using large epidemiological datasets like the National Health and Nutrition Examination Survey. It outlines how existing genome-wide association studies were used to discover genetic factors but similar approaches are lacking for environmental exposures. The author advocates developing high-throughput environmental exposure assessment methods and conducting environmental-wide association studies to discover environmental influences in a systematic and reproducible way.
The document discusses diagnosis and screening for rare diseases in Romania. It notes that rare diseases affect less than 5 in 10,000 people. Most rare diseases are genetic disorders resulting from mutations. Early detection of genetic disorders in newborns is important to reduce risks. While Romania screens for some disorders, testing is not uniform nationwide. Diagnosis of genetic diseases is possible at some universities but specialized resources are insufficient. The development of new genetic testing techniques has enabled diagnosis of more genetic disorders.
Repurposing large datasets for exposomic discovery in diseaseChirag Patel
This document discusses the need for large-scale studies of environmental exposures (the exposome) analogous to genome-wide association studies (GWAS) to better understand environmental contributions to health and disease. It notes that while genetics research has made great strides with GWAS, understanding of environmental influences lacks comparable methods and data. The author argues that characterizing the exposome through high-throughput methods could discover new environmental factors in phenotypes, as GWAS did for genetics. National Health and Nutrition Examination Survey is presented as a model for collecting comprehensive human exposure data on a large scale.
This document summarizes discussions from the 6th Genomic Medicine Colloquium hosted by the National Human Genome Research Institute. The colloquium brought together 50 international genomic medicine leaders from 25 countries to discuss opportunities for collaboration. Key areas of discussion included establishing standards for genomic data storage, implementing global pharmacogenomic screening programs, developing genomic medicine policy, and creating an international genomic medicine collaborative.
This document provides a summary of Evmorfia Tzagkaraki's resume. She has over 15 years of experience as a molecular biologist and geneticist. Currently, she is the Head of the Molecular Biology Department at Diagnosis Medical Diagnostic Centre in Rethymnon, Greece, where she helped develop the department. Previously, she was Head of Laboratory at Omnigen Biotechnological Applications SA. She holds a PhD in molecular investigation of genetic diseases from the University of Crete and has published papers in peer-reviewed journals. She is proficient in molecular biology techniques and has experience managing medical laboratories.
Supporting Genomics in the Practice of Medicine by Heidi RehmKnome_Inc
View the webinar at http://www.knome.com/webinar-supporting-genomics-practice-medicine. In this presentation, Dr. Heidi Rehm, Chief Laboratory Director of the Laboratory for Molecular Medicine at Partners Healthcare and one of the Principal Investigators on ClinGen, elucidates the challenges of genomics in medicine and outlined the path to integrating large scale sequencing into clinical practice.
This study examined the association between estrogen receptor alpha (ERα) gene haplotypes and radiographic osteoarthritis (OA) of the knee in 1,483 elderly men and women. Three haplotypes (px, PX, Px) were identified. Carriage of the PX haplotype was associated with an increased prevalence and severity of radiographic knee OA, with odds ratios of 1.3 for heterozygotes and 2.2 for homozygotes. Separate analyses showed the association was driven by osteophytosis. This study provides evidence that polymorphisms in the ERα gene are risk factors for radiographic knee OA in both men and women.
Screening and Prostate-Cancer Mortality in a Randomized European StudyTeresa Muñoz Migueláñez
This document summarizes the results of a large European randomized controlled trial that evaluated the effect of prostate cancer screening using prostate-specific antigen (PSA) testing on death rates from prostate cancer. Over 160,000 men ages 55-69 were randomly assigned to either a screening group that was offered PSA screening every 4 years or a control group that did not receive screening. After a median follow-up of 9 years, the cumulative incidence of prostate cancer was higher in the screening group (8.2%) than the control group (4.8%). The rate of death from prostate cancer was 20% lower in the screening group compared to the control group. However, screening led to overdiagnosis, with 1410 men needing
Epigenetics and cell fate in JIA and pulmonary fibrosis by Jim HagoodSystemic JIA Foundation
This document discusses the potential role of epigenetic mechanisms in idiopathic pulmonary fibrosis (IPF) and juvenile idiopathic arthritis (JIA). It outlines how epigenetic changes like DNA methylation and histone modifications can alter gene expression and cell phenotypes, contributing to diseases like IPF that involve remodeling of lung tissue. Studies have found differential methylation and expression of genes in IPF lung tissue. Epigenetic therapies targeting mechanisms like DNA methylation and histone acetylation may one day help treat IPF and other diseases. The document also discusses how epigenetics may contribute to autoimmunity and JIA, noting differences in T cell methylation profiles between JIA patients and controls.
THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE OF HOMEOPATHY IN FRANCEhome
PB7 445 THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE
OF HOMEOPATHY IN FRANCE
J. BILLOT* (AP-HP Hôpital Corenton-Celton, Issy-les -Moulineaux, France)
Introduction At least 30% of the French population has recourse to homeopathy, with a large
proportion of elderly persons. Some 25000 practitioners prescribe homeopathic treatments.
Object: Development of a system of reference for the medical practice of homeopathy in
order to meet with the legal obligations of evaluation and training of homeopaths. Method :
1- Creation by the Société Française d’Homéopathie of a working group of expert specialists
representative of the medical practice of homeopathy to determine: - a basic methodology:
self-evaluation according to the method of practice groups; - the subject: « the homeopathic
medical file»; - the aims and requirements of quality; - the standards of evaluation; - the
number and content of items or inquiries 2- Verification of the text’s form by a reader’s
group; 3- Verification of acceptability and feasibility by a group test; 4- New meeting of the
working group to register the modifications shown necessary by the feasibility study; 5-
Presentation of the text to the methodologists approved by the Haute Autorité de la Santé
(Health Department); 6- Finalization of the project and transmission to the Haute Autorité de
la Santé for validation. Results: Elaboration of a system of analysis with reference to the
«homeopathic medical file», according to the method of practice groups. This system of
reference includes a questionnaire concerning the symptoms noted in the patient’s file: in
order to be of homeopathic value, the symptoms must be precisely characterized and
organized according to their relative importance. Conclusion This system of reference was
validated by the Haute Autorité de la Santé in February 2007. Several practice groups have
already used this system of reference to validate the legal obligations of their profesional
practice. The complete text of this system of reference can be downloaded on web-site:
WWW. homeopathie- francaise. fr
This curriculum vitae outlines the educational qualifications and professional experience of Saeed Saeed Alghamdi. He holds a PhD in Toxicology from the University of London and has over 20 years of experience working as a professor of Pharmacology and Toxicology. He has extensive research experience studying the toxic effects of organic solvents and heavy metals. He has published several articles and books on topics related to toxicology.
1) The document discusses the need for large-scale studies of environmental exposures, known as environment-wide association studies (EWAS), to discover environmental factors associated with disease and address issues with past fragmented studies of single exposures.
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Prof. Dr. Vladimir Trajkovski - IMUNOGENETIC ANALYSES IN PERSONS WITH AUTISM ...Vladimir Trajkovski
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This document summarizes a study identifying the genetic cause of Heimler syndrome (HS). Whole exome sequencing was performed on individuals from eight families with HS. Biallelic mutations in the peroxisome biogenesis genes PEX1 or PEX6 were identified in six families. These findings define HS as a mild peroxisome biogenesis disorder caused by hypomorphic PEX1 or PEX6 mutations, expanding the clinical spectrum of these genes.
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The Human Genome Project was a 13-year international scientific research project that mapped and sequenced all of the genes of the human genome. It was completed in 2003 and has provided a foundation for scientific research into human health and disease. Some key outcomes of the project include identifying all of the approximately 20,000-25,000 genes that make up human DNA, determining the sequences of the 3 billion chemical base pairs in human DNA, and making this genomic data freely available online for scientific research. The project involved collaboration between research institutions in six countries and cost $3.8 billion, but it has generated an estimated $796 billion in economic impact by enabling new medical treatments and industries.
1) Genome-wide gene expression analysis identified immune response and lymphangiogenesis pathways as implicated in the pathogenesis of fetal chylothorax (FC). Genes involved in immune response were universally up-regulated, while genes related to lymphangiogenesis were down-regulated in fetal pleural fluids of FC cases.
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3) For one fetus (Ind) carrying an ITGA9 mutation, immune response pathways decreased after successful treatment of FC with OK-432 pleurodesis, while lymphangiogenesis pathways
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1) DXA scanning is a reliable and low-radiation method to measure bone mineral density (BMD) at the lumbar spine, hip, and wrist to diagnose osteoporosis.
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IWO Meeting 16 November 2022 - ASBMR young talent: Silvia Storoni (Amsterdam): Prevalence and Hospital Admissions in Patients With Osteogenesis Imperfecta in The Netherlands: A Nationwide Registry Study
The document appears to be a presentation on highlights from the ASBMR 2021 conference in San Diego. It discusses several topics that were covered at the conference, including fracture risk assessment, the effects of various osteoporosis treatments on bone mineral density, safety issues like osteonecrosis of the jaw and atypical femoral fractures, the role of vitamin D, and applications of artificial intelligence. The entire document is copyrighted by Prof. Dr. Joop van den Bergh.
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IWO bijeenkomst - 17 april - Prof. Dr. A.G. Uitterlinden
1. André G Uitterlinden
Genetic Laboratory
Department of Internal Medicine
Department of Epidemiology
Department of Clinical Chemistry
Human Genomics Facility, HuGe-F
Erasmus MC Genomics Core facility
www.glimdna.org
IWO nascholing, Jaarbeurs, Utrecht, 17 April, 2019
Rol van Genetica bij Osteoporose
Copyright Prof. Dr. A.G. Uitterlinden
2. Companies have sponsored my attendance at some meetings:
- Illumina
- Amgen
- Roche
- MSD
- Calico
My research is funded by public funds from NWO, ZonMW, EU, NIH,
University funds, and charity funds
I receive salary only from Erasmus Medical Centre
I do not hold any stock
Disclosure of Speaker’s Interest
IWO nascholing, Jaarbeurs, Utrecht, 17 April, 2019
Copyright Prof. Dr. A.G. Uitterlinden
3. -Complex Genetics and Genomics
-Genetics of osteoporosis
-Mendelian Randomization studies
-GWAS progress and polygenic risk profiling
-GSA consortium
-Replication and collaboration
-Concluding remarks
IWO nascholing, Jaarbeurs, Utrecht, 17 April, 2019
Rol van Genetica bij Osteoporose
Copyright Prof. Dr. A.G. Uitterlinden
4. The Beauty of Bone…
“The Bone Chair”
-Design: Joris Laarman (NL,1979)
-Just auctioned (6 march 2019) at Christies, London for 825.000 euro
-Created using software to design lighter car-parts in industry
Copyright Prof. Dr. A.G. Uitterlinden
5. We differ from each other…
DNA variation causes differences in:
Development
Appearance
Behaviour
Ageing
Diseases
Copyright Prof. Dr. A.G. Uitterlinden
7. This is what happens
when there are NO POLYMORPHISMS
Why is the study of DNA polymorphisms important ?
Evolution Forensics
Disease
Slide stolen from Prof Axel Themmen
DTC fun
Copyright Prof. Dr. A.G. Uitterlinden
8. ! OPTIMAL EPIDEMIOLOGICAL DESIGN:
A single-centre, longitudinal population-based cohort study of normal elderly Dutch,
started in 1990, with 25 years of follow-up
! LARGE:
Total = 20,000 men and women of age 45 yrs
! VERY DEEP PHENOTYPING:
5 Follow-up measurements with ~1,500 per
subject each time : height, bmi, brain MRI,
DXA, cholesterol level, blood pressure,
glucose, etc. etc. etc.
! ETHNICALLY HOMOGENEOUS:
99% White Caucasian
! EXTENSIVE GENOMICS DATA AVAILABLE:
GWAS, RNA expression (array+ NGS), DNA methylation (450K), Whole Exome
Sequencing, 16S microbiome, telomeres, mitochondrial DNA, metabolomics,..
“ERGO: Erasmus Rotterdam Gezondheid Ouderen”
“The Rotterdam Study”Overview of sample numbers with “omics” datasets across the 3 Rotterdam Study (RS) cohorts with the
number and type of measurement for each omic method
Genomics data type Total Datapoints/sample RS I* RS II* RS III*
Number Type
GWAS SNP data 11,502 40,000,000 SNPs 6291 2157 3054
Exome array 3,183 250,000 SNPs 3183 – –
Whole exome sequencing (WES) 3,778 693,000 Variants 3778 – –
Whole genome sequencing (WGS) 96 3,000,000 Variants 96 – –
Genome wide expression (array) 881 25,000 Genes – – 881
Genome wide expression (RNA Seq) 829 18,000,000 Reads – 500 329
Genome wide DNA methylation 1,600 450,000 CpG’s 100 500 1000
Telomere length (PCR) 1,800 1 – 1800 – –
Mitochondrial DNA (PCR) 500 1 – 500 – –
Microbiome 16S rRNA (faeces) 2,000 500 OTU’s – – 2000
Metabolomics (NMR/UPLC MS) 1,826 4000 Metabolites 1826 – –
Metabolomics (NMR “Nightingale”) 5,381 228 Metabolites 2880 663 1838
Serum protein profile** 9,820 35 Proteins 3812 2542 3466
Total ‘omic’ data points in RS: 43,196 × 62,422,765 = 2,696,413,756,940 (2.7 x 1010 )
SNP single nucleotide polymorphism,
CpG a two-nucleotide position (C next to G on the same strand) of which the C can be methylated;
OTU operational taxonomic unit
*RS1, First cohort of the Rotterdam Study; RS2, Second cohort of the Rotterdam Study; RS3, Third cohort of the Rotterdam Study
**Total estradiol, total testosterone, sex hormone-binding globulin, dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, 17-
hydroxyprogesterone, cortisol, corticosterone, 11-desoxycortisol, vitamin D, thyroid stimulating hormone, free T4, interleukins, C-reactive protein, Insulin-like growth
factor 1, insulin, iron, ferritin, transferrin, fibrinogen, homocysteine, folic acid, riboflavine, pyridoxine, SAM/SAH ratio, cobalamine, Lp-PLA2, Fas/Fas-L, abeta42/40
(Samples x Datapoints)
Copyright Prof. Dr. A.G. Uitterlinden
9. Human Genomic Life Course Epidemiology
Rotterdam Study
Age (yr)
Bone
Mineral
Density
Bone
growth
Peak BMD Bone Loss
50 7525 100
EPOSCALEUR AGGO
Osteoporosis:
Low BMD, fractures
men
women
DNA/RNA
collections
for OMICS
studies
Maternal genotype
Paternal genotype
Environmental factors
“Chronological” vs. “Biological” Ageing
bone phenoptyes
B-Proof intervention
Birth Death
Bone as an Example...
Off-spring
GenRCopyright Prof. Dr. A.G. Uitterlinden
10. Clinical Expression:
Risk Factors:
Fracture Risk
Bone Strength Impact Force Fall Risk
“OMICS”: DNA RNA, METHYLATION, MICROBIOME, etc
BMD Quality Geometry
Osteoporotic fracture is a “complex” phenotype:
Environmental factors: diet, exercise, ...
Hip fx
Wrist fx
Vertebral fx
etc.
Age, Sex, Age-at-Menopause, Height, OA, etc.
dynamic genomics data: cause/effect?genetic data: cause
Copyright Prof. Dr. A.G. Uitterlinden
11. The next challenge: Environmental Factors
The field needs: standardization, harmonization, replication
HOLLAND BELGIUM
> 1100 mg/day < 500 mg/day
Dietary Calcium intake
Geographical distance: <100km
Foto: Barbara Obermayer-Pietsch Foto: Stuart Ralston
Copyright Prof. Dr. A.G. Uitterlinden
12. EffectSize
Frequency Genetic Variant
rare, monogenic common, complex
Next-Generation Sequencing
(WES/WGS of reference sets)
+
Arrays/Imputation
rare common
smallbig
Genetics: the architecture of diseases/traits :
study designs to identify “risk” alleles
Genome-Wide
Association
Study (GWAS)
few “big” effects of
common alleles
(ApoE, CFH)
Whole Exome
Sequencing (WES)
Copyright Prof. Dr. A.G. Uitterlinden
13. Per 12 May 2018:
• 3,379 publications
• 61,620 unique SNP-trait
associations.
(www.ebi.ac.uk/GWAS )
GWAS ….drinking from the firehose
Copyright Prof. Dr. A.G. Uitterlinden
14. Regulatory
sequences
GWAS identifies mostly (common) regulatory variants
Efforts with a focus on
genes/coding variants:
-WES/WGS
-exome chip
> new arrays with
enhanced clinical content
(e.g., GSA, PMRA)
Gene
Copyright Prof. Dr. A.G. Uitterlinden
15. GEFOS collaboration has generated many GWAS discoveries for BMD…
Slide by Fernando Rivadeneira
Copyright Prof. Dr. A.G. Uitterlinden
16. Largest BMD GWAS over time…
In 2012, GWAS of DXA-BMD in 30,000
individuals from GEFOS, including
CHARGE, identified 56 loci
Estrada et al. Nat Gen 2012
In 2017, GWAS of eBMD in 140,000
individuals from UK Biobank interim
release identified 203 loci (153 novel)
Kemp et al. Nat Gen 2017
5.6% trait variance explained
12% trait variance explained
Slide by John Morris, McGill University, Canada
Copyright Prof. Dr. A.G. Uitterlinden
17. – 1,103 conditionally independent SNPs from 515 loci (301 novel) – 2x the previous study!
– 20% of the trait variance explained – 1.5x increase!
Slide by John Morris; Morris J, Kemp J et al. Nature Genetics (2019)
UK Biobank: Largest BMD* GWAS so far…
in 426,824 White-British participants
*estimated BMD from heel QUS: gSOS
Copyright Prof. Dr. A.G. Uitterlinden
18. *Morris et al., An atlas of genetic influences on osteoporosis in humans and mice. Nature Genetics, 2019
February 2019 GWAS of BMD (as estimated by heel
quantitative ultrasound; =gSOS)
Many genetic effects: >500
*Several low frequency with relatively large effect size and
*Many high frequency with modest effects size
Copyright Prof. Dr. A.G. Uitterlinden
19. Study short name Country Ncases Ncontrols Ntotal
AGES Iceland 1458 1727 3185
AOGC Australia 685 1113 1798
BPROOF Netherlands 715 1483 2198
CHS US 519 2742 3261
DeCODE Iceland 1836 14560 16396
EGCUT-I Estonia 217 4296 4513
EGCUT-II Estonia 71 1717 1788
EPICNOR UK 2937 17726 20663
ERF Netherlands 260 1342 1602
FHS US 1520 2782 4302
GOOD Sweden 273 597 870
HEALTHABC US 308 1353 1661
HKOS Hong Kong 79 627 706
MROS US 918 3555 4473
PROSPER Netherlands 426 4816 5242
RS-I Netherlands 2163 3574 5737
RS-II Netherlands 932 1220 2152
RS III Netherlands 505 2421 2926
SOF US 1611 1698 3309
TUK123 UK 839 4111 4950
UKBB UK 14492 130563 145055
WGHS US 1832 20498 22330
WHICT US 1058 647 1705
WHIOS US 1603 989 2592
YFS Finland 611 975 1586
Total 37857 227116 254973
Discovery: 37,857 cases and
227,116 controls;
Replication: 147,200 fracture
cases and 150,085 controls
(23andMe)
Largest GWAS of (any-type of) fracture to date
comprising 185K cases and 377K controls
Slide by Fernando Rivadeneira (Trajanoska K, et al., BMJ, 2019)
Copyright Prof. Dr. A.G. Uitterlinden
20. Fracture risk GWAS identified 15 loci all of which
are established BMD loci
2p16.2 3p22.1 6q22.33 6q25.1 7q31.31 7q21.3 7p14.1 7p12.1 9q34.11 10q21.1 11q13.2 14q32.12 17q21.31 18p11.21 21q22.2
SPTBN1 CTNNB1 RSPO3 ESR1 WNT16 CPED1 C7orf76 SHFM1 STARD3NL GRB10 COBL FUBP3 MBL2/DKK1 LRP5 RPS6KA5 SOST DUSP3 MEOX1 FAM210A RNMT ETS2
Slide by Fernando Rivadeneira (Trajanoska K, et al., BMJ, 2019)
Copyright Prof. Dr. A.G. Uitterlinden
22. A coordinated roadmap of Integrated functional
assessments will translate into clinical applications
Slide by Fernando Rivadeneira
Copyright Prof. Dr. A.G. Uitterlinden
23. Mendelian Randomization
SNPs as Instrumental Variables:
• principle: alleles segregate and are randomly
inherited from parents to offspring (Mendelian laws)
approach similar to RCTs
• alleles are distributed independent of confounders,
i.e. socio-economic and life-style factors
• inherited genotypes are not changed by a disease (or time)
no reverse causation
• SNPs can explain modest proportion of variance
large sample sizes needed for MR
Copyright Prof. Dr. A.G. Uitterlinden
24. Effect (OR) of Genetic Variants for Risk Factors, on Fracture Risk by MR
Slide by Fernando Rivadeneira (Trajanoska K, et al., BMJ, 2019)
Copyright Prof. Dr. A.G. Uitterlinden
26. Can environmental factors decrease genetic effect?
The case of Age-related Macula Degeneration (AMD)
Risk of Late AMDRisk/protective factor
30% - 3x increasecurrent smoking
30% increasebody mass index
‘mediterranean’ diet 25-40% decrease
physical exercise 40% decrease
Data from E3 and various other consortia 2017 slide provided by Prof. Caroline Klaver
Copyright Prof. Dr. A.G. Uitterlinden
27. Genetic testing predicts life-time risk of Late Age-
related Macula Degeneration (AMD)
Rotterdam Study; Buitendijk et al. 2014; slide provided by Prof. Caroline Klaver
Copyright Prof. Dr. A.G. Uitterlinden
28. Never smoked Smokers (past and current)
62%
17%
8%
7%
91%
30%
11%
10%
Smoking and genetic risk for AMD
Genetic risk in
Non-Smokers
Genetic risk in
Smokers
Rotterdam Study
slide provided by Prof. Caroline Klaver
Copyright Prof. Dr. A.G. Uitterlinden
29. Ho et al. Arch Ophthalmol. 2011; Rotterdam Study I N=8000
Good news: dietary anti-oxidants decrease genetic risk
for AMD…
slide provided by Prof. Caroline Klaver
Copyright Prof. Dr. A.G. Uitterlinden
30. BMD Variance Explained
0%
5%
10%
15%
20%
25%
30%
35%
40%
Age, Sex,
Weight,
Height
All FRAX
Risk Factors
2,094 30,000 150,000 456,000 h2SNP
Sample Size for Genetic Studies
Richards, Lancet
2008
Zheng, Nature
2015
Kemp, Nature
Genetics
2017
Morris,
Nature Genetics
2018
Slide by Brent Richards, McGill University, Monreal, Canada; abstract to ASBMR/ASHG 2018
Note:
-variance explained is done in UKBB. It does not include family history or ≥3 drinks per day.
-DXA BMD in first two papers; eBMD (from heel ultrasound) in last two papers
Estimated total amount
of variance
explained by SNPs
Copyright Prof. Dr. A.G. Uitterlinden
31. UK Biobank
N=502,639
Individuals
Passing
Phenotype and
Genotype QC
N=426,811
UK Biobank
Training Set
N=341,449
UK Biobank
Model Selection
Set
N=5,335
UK Biobank
Test Set
N=4,741
UKB Genotyped
N=488,366
Pass QC
N=486,369
White-British
Ancestry
Subset
N=440,348
SOS Available
& Pass SOS
QC
N=480,521
Phenotype
Quality
Control
Genotype
Quality
Control
Figure 1. Overall Study Design
GWAS and
Training of
PRS Models
Selection of top
PRS Model
Define gSOS
CLSA
N = 6,704
Mr Os USA
N = 4,657
SOF
N = 3,426
PRS: Polygenic Risk Score. QC: Quality Control
Mr Os Sweden
N = 1,880
Test Performance of gSOS in NOGG Screening Program
Slide by Brent Richards, McGill University, Monreal, Canada; unpublished
Copyright Prof. Dr. A.G. Uitterlinden
32. Eligible for NOGG-Based Screening
(>50 years, with at least one risk factor)
CRF Based FRAX to
calculate
10-year probability of major
osteoporotic fracture
Women with prior fragility fracture
CRF Based FRAX: Moderate Risk
CRF Based FRAX: High Risk
BMD Based FRAXBMD Based FRAX: Low Risk BMD Based FRAX: High Risk
Population
Figure 2: NOGG Guidelines
CRF Based FRAX: Low Risk
<50 Years or ≥50 & No risk factors
Discharge from
Screening Program Recommend Treatment
Both CRF and BMD FRAX generate ten year probabilities of major osteoporotic fracture, which are used to designate risk of fracture
Slide by Brent Richards, McGill University, Monreal, Canada; unpublished
Copyright Prof. Dr. A.G. Uitterlinden
33. Eligible for NOGG-Based Screening
(>50 years, with at least one risk factor)
CRF Based FRAX to
calculate
10-year probability of major
osteoporotic fracture
Women with prior fragility fracture
CRF Based FRAX: Moderate Risk
CRF Based FRAX: High Risk
BMD Based FRAXBMD Based FRAX: Low Risk BMD Based FRAX: High Risk
Population
Figure 3: NOGG Guidelines with gSOS Screening Step
CRF Based FRAX: Low Risk
<50 Years or ≥50 & No risk factors
Discharge from
Screening Program Recommend Treatment
Both CRF and BMD FRAX generate ten year probabilities of major osteoporotic fracture, which are used to designate risk of
fracture. gSOS is standardized to have a mean of zero and standard deviation of one
gSOSgSOS > 0
Slide by Brent Richards, McGill University, Monreal, Canada; unpublished
Copyright Prof. Dr. A.G. Uitterlinden
34. 28 euro for GSA array
In 2016 costs of DNA analysis has gone down
Arrays are preferred in large-scale
application (compared to sequencing)
30-100x (!) cheaper
Only relevant DNA variants
Customizable
Very high throughput
Easy data analysis and automation
DTC companies prefer arrays
Less ethical issues
700,000 DNA variants on the GSA array:
GWAS, Clinical, pharmacogenetics, HLA,
forensic, mitochondrial, ancestry, blood
groups, etc.
Copyright Prof. Dr. A.G. Uitterlinden
35. 1 093 522
Europe 1 004 992
Netherlands 168 992
Canada/USA 28 209
Australia 37 219
Asia 21 952
South America 1 150
Africa 0
EU GSA consortium
Coordinating center
HuGe-F Erasmus MC
By end 2018 there will be many SNP array datasets..
Existing:
academic data 1 million samples (global)
UK Biobank 0.5 mio samples (UK)
Millions Veterans Program (MVP) 1 million samples (USA)
FinGen 0.5 mio samples (Finland)
23andme >2 mio samples (USA centric)
Avera, Kaiser Permanente 0.6 mio samples (USA)
New:
GSA sales 2016/2017/2018 >20 million samples (USA centric)
EU-GSA 1.1 million samples (global)
TOTAL ~25 million samples with SNP array data……
Copyright Prof. Dr. A.G. Uitterlinden
36. GOALL! Genotyping On ALL patients at Erasmus MC
Subscription to
GENETIC REPORT
Commercial Partners:
Illumina, BC Platforms
Pilot Projects:
-Eye disease
-Cardiovascular Disease
-Pharmacogenetics
-Breast Cancer
-Type 2 Diabetes/Obesity
-……
DNA Array
Processing:
Erasmus MC
Genomics
Core Facility
Patient’s Home
Erasmus MC
as trusted
Partner
Erasmus MC Partners:
*Interpretation/Counseling:
Internal Medicine : Complex Diseases
Clinical Genetics : Mendelian Diseases
Clinical Chemistry : Pharmacogenetics
*Patient inflow/Reporting:
Clinical departments (per disease)
Costs: < 30 euro per patient
Content: 700.000 selected variants for:
- Pharmacogenetics
- Mendelian Disease Variants
- HLA types
- Clinical (actionable) Variants
- Polygenic Risk Scores Complex Disease
- Ancestry
- etc.
Information and Consent
Regular Updates with
Risk Profile Information
*ALL patients undergo DNA
array genotyping
*Patient DNA Array results are
available BEFORE clinician sees
the patient
Copyright Prof. Dr. A.G. Uitterlinden
37. Grades of Evidence
Level Method Science disciplines
- Large scale collaborative prospective
meta-analysis of individual level data in
consortia
- Meta-analysis of published data
- >2 large studies (n > 1000 each)
- 1-3 smaller studies
- 1 small study (n<500), NO replication
- Expert Opinion…
Very Good
Not so Good
-Complex Genetics
-Physics
-Astronomy
-Sociology
-Psychology
-Medicine
Cell Biology
-The biomedical community publishes 2,5 mio papers per year
-<50% papers describe results that can be replicated (the “reproducibility crisis”)
Copyright Prof. Dr. A.G. Uitterlinden
38. *to convince yourself, colleagues, society that the observation is true and
generalizable
*because methodology in one centre is flawed:
-transformed cell lines
-wrong/mixed cell lines
-bad antibodies
-complicated/outdated genotyping method
-human error, fraud
*because effect sizes are small (e.g., GWAS, omics data)
*because the modelsystem used is not representative for humans, e.g.:
-worm/insect/mouse biology is not similar to human biology
-only one (inbred mouse) strain is used (n=1 human, and a strange one…)
-only one iPS cell line is used (n=1 human)
-a small human sample is used (cases only; an isolated population; etc.)
Replication/validation is needed (a few reasons):
> Provide replication in one and the same paper with colleagues
Copyright Prof. Dr. A.G. Uitterlinden
39. Collaboration doesn’t come easy…..
>> Donald Trump’s view on EUROPE…. ?
(From: Yanko Tsvetkov, alphadesigner.com)
Wall !!
Wall !!
Wall !!
Wall !!
Wall !!
Wall !!
Wall !!
Copyright Prof. Dr. A.G. Uitterlinden
40. A “Culture” Change in doing Research:
GLOBAL COLLABORATIONS IN COMPLEX GENETICS
Example: the “GIANT” consortium:
>2,000,000 participants…
SUNLIGHT consortium
Copyright Prof. Dr. A.G. Uitterlinden
41. - More data is better: Growth of NGS sequencing data is slow due to high
costs and complexity; GWAS by arrays/imputation grows (much) faster
- New Biology: Dozens of novel genes/pathways discovered to be involved
in disease phenotypes and risk factors
- Potential for Prediction: A still increasing part of heritability of phenotypes
is being explained
- Better Epidemiology: Mendelian Randomization is now more feasible to
analyse causality of “classic” epidemiologiccal associations
- High Impact and Exemplary: Large-scale international collaborations
allow for very robust evidence for genetic & genomic discoveries
- Populations are a bunch of individuals: opportunities for studying
“personalized/precision/stratified aspects” of biology and medicine
>> Translational Research based on these discoveries is ongoing
Population Genomics: what have we learned?
Copyright Prof. Dr. A.G. Uitterlinden
42. …..IGNORANCE CAN BE DAUNTING……EDUCATION IS IMPORTANT !!
Annual Courses organized by the Genetic Laboratory:
in 2019:
- 14th edition of “Genomics in Medicine” (Aug; ESP57; NIHES)
- 4th edition of Microbiome course (Sept; MolMed)
- 11th edition of “Genetic for Dummies” (Nov; MolMed)
- 16th edition of “SNP Course” (Nov; MolMed)
www.molmed.nl
www.nihes.nl
Copyright Prof. Dr. A.G. Uitterlinden