Week 2 Flashcards
What is NIH definition of a biomarker?
A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention
What are the methods biomarkers are detectable by?
- Physical examination
- Laboratory assays
- Medical imaging
What are the 4 key stages when considering a biomarker design?
- Definition of clinical need
- Selection of patients and matched controls
- Selection of analytical platform and biological material
- Statistical study design
Definition of a clinical need
- what is the desired clinical outcome?
2. Identifying a problem and potential solution
Selection of analytic platform and biological material
Is it blood/urine/CSF - how are we going to measure this?
Have proteomics approach (proteins)
Best biological material = blood plasma
Identify biomarkers
Statistical study design
Pinpoint potential biomarkers in AD patients blood and this will give us range of controls
Biomarkers need to be verified and validated
Underlying all of these 4 stages, what does it need?
Large population
Report by medical research council
Maximising the value of UK population cohorts
What does the UK support?
Unparalleled collection of large scale population cohort studies
Provide wealth of longitudinal phenotypic, biological and social data for studying health and well-being throughout life
The ability to link to health and other routine records, collect data and samples from consenting participants and
apply cutting edge imaging and omics technologies, places the UK in an optimal position to fully capitalise on these
major research assets.
What does the studies of cohort studies require?
Diverse range of population cohorts that differ in:
- Age
- Gender
- Ethnicity
- Socio-economic position
- Geographic location
- Length of follow-up
What do the factors of cohort studies contribute to?
More beneficial cohort in terms of addressing experimental need
What are the 2 largest participant number for UK cohort studies?
- Breast cancer
2. UK biobank
How many people in the cohort for UK biobank?
600,000
How many women in the study ?
1 - 1.2 million
What are the participant in the study driven by?
Government funding
Need for pharmaceutical company to investigate in these studies
What are the large number of clinical studies in UK differing in size driven by?
Public and pharmaceutical desire
When we look at age range of these UK cohort studies what do we see?
Concentration at mid-age between 30 and 70
What do we need to address in clinical studies?
Younger ages
What is trend driven by?
Study itself and by life and age
What is there a need to address?
The missing age gap of particular cohorts
What is the length of UK cohort follow up?
4-10 years
Why is difficult to track people for that length of time?
- Expensive process
2. Need a lot of hard work and dedication to track people
What is the role of large-scale population cohort?
Foundation for understanding the role and dynamic interplay of:
- Genetic
- Lifestyle
- Environmental influences on human health and disease
How are resources used?
In ways to realise their scientific potential and increase societal benefit
- Data-linking between different population cohorts
- Cross-cohort collaborations
2 cohort studies have overlapping aims
Collaboration can increase population size and decrease cost of getting valuable data
Data-Linking
Linkage to:
- Routine health record
- Cross-sector administrative and environmental data
What does research data greatly expand?
Scope of a cohort to carry out:
- Clinical
- Public health
- Socio-economic research
What are recent infrastructure initiatives increasing?
Secure access to clinical records for research and administrative datasets
Why is it important to do data-linking?
- Enrich the study data
2. Expand opportunities for new discovery science
Who established the Farr institute?
The MRC in partnership with funders
What is the Farr institute?
UK-wide research collaboration
21 academic institutions and health partners
Ran between 2013 and 2018 (5 year programme)
Range of universities involved
what was the idea of Farr institute?
Advance health care for patients and public
Delivers high quality, cutting-edge research using big days to advance health and care of patients and the public
What did Farr institute act like?
Data-base
Data from all academic institutions deposit data
Allow researchers to use data to address their own clinical needs
What was found when you compared different sources of information?
A number of these studies missed important data
Why is data process important?
Informs future studies
What can cross-cohort collaboration between institutions provide?
- New research opportunities
(Study of rare phenotypes) - Increase sample size (predict risk and validate findings)
What can comparing or combining cohort populations increase?
Statistical power
Enables replication of findings from individual studies
Studies of inter generational and period effects
help validate biomarkers
What are vital for cohort studies?
Integration of;
- Genomics
- Transcriptomics
- Proteomics
- Metabolomics
- Lipidomics
- Neuroimaging
And other emerging technologies
What has integration into cohort studies improve?
Our understanding of aetiology
Risk prediction
Stratification of disease across different populations
What is MRC cognitive function and ageing studies (CFAS I and II) ?
Two population-based studies investigating health and cognitive ageing in adults aged 65 years and older across the UK
What has CFAS I and II reveal?
Reduction in dementia prevalence over past 20 years
2011 - 214,000 new cases
1.8 per cent lower overall prevalence than expected
What was the major changes in health in people aged 65 (CFAS I and II)
- Longer life
- Reduction in risk factors (e.g. smoking)
- Increases in protective factors (e.g. education)
- Better management of some health conditions
What is UK biobank?
Second largest population cohort
Established in 2006
To determine how genes, lifestyle and environmental interact to cause a wide range of diseases
How has UK biobank become a major national resource?
By collecting information and sample on half a million adults aged 40-69
Help our understanding of disease prevention, diagnosis and treatment
Participants followed over next 30 years mostly by linkage to NHS health records and death and cancer registries
What is East London Genes and Health?
One of the worlds largest community based genetics studies aiming to improve health among people of Pakistani and Bangladeshi heritage in East London
What are East London Genes and Health initial aims?
- Study how genes normally vary from person to person in the adult Bangladeshi and Pakistani communities
- Study genes in people with very high and very low cholesterol levels to better understand why heart disease and stroke occur
- Study genes of people with diabetes, aiming to identify rarer types of diabetes for which specific treatment might be asked
- Study how some people respond differently to certain medicines
For biomarkers design, checkpoints exist between what different phases?
- Discovery
- Verification
- Validation
Bio banking is a multi-step process that includes what?
- Sample collection
- Sample barcoding
- Sample storage
- Integration of patients clinical characteristics and demographic data
Sample collection
Collecting blood, urine or tissue
Sample barcoding
It’s assigned a barcode and deposited in the biobank
Allows researchers to acess the correct material for study
What should Biobank retain?
Maximum quality of biological material stored by following standardised protocols of sample handling
Performance of potential biomarkers should not be influenced by?
Pre-analytical factors
What are the 3 phases of proteomics platform applied in a biomarker workflow?
- Discovery phase
- identification of biomarkers
- look at different approaches
- choice of approach depends on material - Verification
- conforming a candidate abundance in a clinical sample
- dependent on mass spec - Validation phase
- evaluation of clinical utility for disease in question
What is a brain bank?
Collect and store post-mortem Human brains (also biopsy material) to foster research into human CNS function and disease.
What is the general protocol for bio bank material?
Split brain in half
Brain bank material is fixed (frozen and formalin fixation)
Can be distributed (e.g. to research groups)
Where can brain bank material come from?
People who have suffered from neurodegenerative, psychiatric or other disorders
What can brain banking be seen in broader perspective of ?
Bio banking
What is Brain bank timeline?
L dopa is a precursor to dopamine
Converted to dopamine
1973: Nick Corsellis establishes the first UK brain collection at Runwell Hospital in Essex
1957: using donated brain tissue, Prod Arvid Carlson demonstrates that dopamine is an important neurotransmitter and that low level cause symptoms of Parkinson disease, leads to the development of L-DOPA treatment
1973: Prof Corsellis studies the brains of former boxers and discovers the presence of amyloid plaques, a sign of dementia plugilistica
1974: Dr Ted Bird and Prof Leslie Iversen show that a loss of GABA-containing neurons in the basal Ganglia is characteristics of Huntington’s chorea
1984: researchers George Glenner and Caine Wong identify B-amyloid in Alzheimer’s disease brain plaques
2005: MRC sudden death brain and tissue bank opens, providing researchers with access to healthy brain tissue required for comparisons with tissue affected by CNS conditions
2006: Research on donated brain tissue shows that TAR-DNA binding protein 43 (TDP43) is the major disease protein In two neurodegenerative conditions - amyotrophic lateral sclerosis and frontotemporal dementia
DNA preservation
Fixation at -80 degrees / suitable method for long term studies (genetics)
Formalin foxes and paraffin embedded material inferior to frozen fixation but can yield adequate results
RNA preservation
RNA quality affected by node of death as well as post modern delay
Immersion in Trizol reagent and HOPE fixation improve RNA preservation
Protein preservation
Preservation method very much related to protein of choice
Requires systematic studies of post-mortem preservation of protein of choice
How can you investigate morphology of brain structure ?
You can implement histochemistry and morphology studies
What is a lot of neurodegenerative disorders associated with?
Differences in metal concentration
Mass spec based method are able to determine metal concentration in brain material
What can be used in brain bank that need a lot of optimisation?
Newly emerging processes
What is Toponomics?
Describes the topology of all protein complexes and network
Which constitute and influence the micro-environment of a given protein
An example is multiple-epitope-ligand-cartography (MELC)
What can human brain bank material offer opportunity to study?
- Human specific function
- Development and evolution of brain
- Changes related to diseases unique to humans
What is one drawback of human brain bank material ?
Longitudinal studies of individual are impossible to perform with human brain bank material
What is the major disease protein in fronto-temporal dementia and amyotrophic lateral sclerosis?
TAR-DNA binding protein 43 (TDP43)
What does the subsequent detection of TDP43 mutation in familial ALS suggest?
A pathophysiological link between TDP43 and ALS
What are 2 isoforms of Tau?
3R tau and 4R tau are both expressed in the normal adult brain but 4R tau is lacking in foetal brains
3R tau
Pick’s disease
4R tau
Corticobassal degeneration
Progressive supranuclear Palsy
Argyophilic grain disease
What are the challenges facing brain banks?
- Declining autopsy rate in most western countries
- Have there been changes in patients/relatives attitudes towards post-modern investigation
- Is there a decline in clinical interest in post-mortem investigation
What is TDP43?
major component of ubiquitin positive inclusions
What is TAU?
MT binding protein that stabilises MT involved in helping axonal transport
What were researchers able to differentiate using brain bank materials?
Expression pattern of both isoform in both healthy brain and a range of neurodegenerative disorders
What are present in Alzheimer’s disease?
Mixed pathological aggregates of 3R tau and 4R tau
What can lead to a higher success rate of autopsy?
Government information
What are other challenges facing brain banks?
- Quality of diagnosis
- Funding
- Donor programmes
- Public relations
- New technologies
- Organs scandal
What is characterised by complex and overlapping features?
Brain ageing and neurodegeneration
What is very common?
Mixed pathology
e.g. ~77% of patients with vascular dementia may have concomitant Alzheimer’s disease
what requires strict adherence to consensus diagnostic criteria?
Banking in networks
Funding
- Estimated cost of €10-15,000 per brain for the BrainNet Europe Consortium. → huge amount for getting one brain
- Public funding often time-limited and based on research project grants; thus, there is a need for increased funding from government agencies, charitable foundations and the pharmaceutical industry.
Donor Programmes
- Death and post-mortem organ donation are topics that clinicians can find difficult to talk about with patients.
- Requires brain banks to improve the information given to the general public to increase clinical autopsy rate and brain donations.
Public Relations
- Increased public support is required for brain banks continued success.
- Addressing the notion that brain banks prevent the use of experimental animals and common misconceptions regarding brain banks could help in this regard
New Technologies
- In the post-genomic era, new technologies (e.g. expression arrays) will have to be adapted for (or integrated into) brain banking.
- Brain banks will need to adopt more complex protocols for tissue collection, preparation and storage for such new technologies.
Organ scandal
- Organ-retention scandal at Liverpool’s Alder Hey hospital brought issues of consent (of why u should use organ) and organ/tissue use and storage under the spotlight.
- Relates to organ retention
- Organs were stripped without permission from those who died at the hospital between 1988-1996.
- This led to the formation of the Human Tissue Act 2004 and the creation of the Human Tissue Authority.
What is the Legislation and governance?
- Human Tissue Act 1961
- Human Tissue Act 2004
- Human Tissue Authority (HTA)
Human Tissue Act 1961
• Consent for the retention of human tissue could be presumed unless there was an objection from the donor or a surviving spouse and/or relative
Human Tissue Act 2004
• Made consent a fundamental principle underpinning the use and storage of human tissue.
Human Tissue Authority (HTA)
• Regulates organisations that remove, store and use human tissue (e.g. for research, post-mortem examination, teaching…)
What are the other guiding principle for HTA?
- Dignity
- Quality
- Honesty and Openness
Define human tissue
material that has come from a human body and consists of, or includes, human cells
What aren’t relevant material under human tissue act 2004?
Eggs and Gametes
What is sperm cells covered by?
HFEA
What is consent needed for?
removal, storage and use of human tissue
What is consent related to?
Scheduled purposes
e.g. for research, post-mortem examination, teaching…
What must consent be
- Appropriate
2. Valid
Define Appropriate consent
reference to the person who may give consent.
Define valid consent
consent that has been given voluntarily by an appropriately informed person who has the capacity to agree to the activity in question
What does specific consent refer to?
defined project, treatment and/or use
What does generic consent refer to?
broader permission, where consent may, for example, be given to allow the storage and use of tissue for an as yet unknown research project
List the situations in which consent is not required
I. If material is classified as an “existing holding” (pre 1st September 2006).
II. If material is imported.
III. If material is from a living person.
IV. If material is from an unidentifiable donor.
V. If materials use in a research project has approval from a research ethics committee (REC).
what is generally much less valuable to researchers?
• Human tissue without accompanying data
What is research tissue banks?
often as much of a data store as a tissue store.
