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Pharmacogenetics > Lecture 1 - Introduction > Flashcards

Lecture 1 - Introduction Flashcards

1
Q

Define Pharmacogenetics

What does it combine?

A

Pharmacogeneticsis the study of inheritedgeneticdifferences in drugmetabolic pathways,which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.

It combines pharmacology (the science of drugs) and genetics (the study of inherited variation) to develop effective, safe medications and doses that are tailored to variations in genes involved in drug’s metabolism.

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2
Q

Define Pharmacogenomics?

What does it combine?

A

Pharmacogenomics is the study of how the genome can influence responses to drugs through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.

It combines pharmacology and genomics (the study of genes and their functions) to develop effective, safe medications and doses that are tailored to variations in a person’s genes.

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3
Q

What do Pharmacogenetics and Pharmacogenomics play an important role in?

A
  1. Identifying responders and non-responders to medications
  2. Avoiding adverse events
  3. Optimizing drug dose
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4
Q

What is a classic example of Pharmacogenomics?

A

Expression of Her2 receptor on breast cancer cells used to identify cancer patients who may be good candidates for accepting Trastuzumab (commercial term of monoclonal antibody) – only affects patients in which cancer cells overexpress Her2.

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5
Q

What is a classic example of Pharmacogenetics?

A

The majority ofCYP2C9variants impacting warfarin dosing are nonsynonymous single nucleotide polymorphisms (SNPs), that occur in the exonic regions of the gene and lead to reduced enzyme activity againstS-warfarin and consequently lower warfarin dose requirements.

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6
Q

What does Conventional medicine use?

A

The same drug at the same dose for all patients with the same disease - one size fits all approach

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7
Q

What is the aim of Stratified medicine?

What does this require?

A

To tailor the treatment to the patient

Identification of biomarkers predictive of response (aka theranostic biomarker) that distinguish patients according to their response to the drug

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8
Q

For every patient they do help, the ten highest-grossing drugs in the US fail in between 3 and 24 patients

True or false

A

True

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9
Q

2.2 million Americans require hospitalization in one year because of…

A

Serious reactions to medications.

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10
Q

More than 9000 patients die per year because of properly prescribed drugs which nevertheless have serious side effects.

True or false?

A

False

106,000

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11
Q

Personalised medicines uses what approach?

What does this mean?

A

Patient centred rather than disease centred

Medical decisions, practices and treatments are tailored to the patient based on genomic, environmental and lifestyle information

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12
Q

What term is used to contrast conventional medicine in the USA particularly?

A

Precision medicine

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13
Q

What aim does Precision medicine focus upon?

A

Delivery of the right intervention, to the right patient, at the right time

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14
Q

Stratified, personalised and precision medicine represent what?

A

A continuum whereby such methods transfer from one size fits all approach

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15
Q

Personalised medicine leads to?

A

Precision medicine

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16
Q

What features are patients grouped by according to stratified medicine?

Dogs, seemingly, do, count, butts

A

Disease, Subtypes, Demographics, Clinical features and biomarkers

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17
Q

Personalised medicine focuses on what factors of an individual?

Clue- Pirates Can’t Make Every Baby Burp

A

Preferences

Clinical features

Medication history

Environment

Behaviours & habits

Biomarker

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18
Q

3p Medicine focuses upon what?

A

Preventive:Aimed at absence of disease by preventing its occurrence, halting its progression and averting complications afters it onset.

Predictive: Aimed at predict response to treatment in terms of efficacy and adverse events

Personalised: Tailored approach based on patient’s individual characteristics

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19
Q

What does 4P medicine focus upon?

A

Preventive: Aimed at absence of disease by preventing its occurrence, halting its progression and averting complications afters it onset.

Predictive: Aimed at predict response to treatment in terms of efficacy and adverse events

Personalised: Tailored approach based on patient’s individual characteristics

Participatory: Patients are involved and actively participate in their own crew

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20
Q

What is an example of the application of stratified medicine when the clinical question is susceptibility?

A

Drug/indication: Breast cancer

Biomarker: BRCA1/BRCA2

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21
Q

What is an example of the application of stratified medicine when the clinical question is screening?

A

Drug/Indication: Familial Hypercholesterolemia

Biomarker:APOB, LDLR

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22
Q

What is an example of the application of stratified medicine when the clinical question is diagnosis?

A

Drug/Indication: Cystic Fibrosis

Biomarker: CFTR

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23
Q

What is an example of the application of stratified medicine when the clinical question is prognosis?

A

Drug/Indication: Breast cancer

Biomarker: HER2, ER, PR

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24
Q

What is an example of the application of stratified medicine when the clinical question is drug response?

A

Drug/Indication: Warfarin

Biomarker: CYP2C9, VKORC1

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25
Q

What are 3 factors that make stratified medicine possible?

A
  1. Most recent cutting-edge technologies for the comprehensive, global, assessment of a set of molecules (-omics analysis)
  2. Government-funded initiatives providing the framework for the acquisition of large-scale omics data (e.g. 100.000 Genome)
  3. Statistics and bioinformatics analysis of omics data, including integration of multilayers -omics
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26
Q

The first factor that has made stratified medicine possible involves what?

A

Tremendous advances in high-throughput technologies in the past 20 years.

Sequencing of first human genome costed ~$450 millions

Massive parallel sequencing, or Next Generation Sequencing, allows for easier, cheaper, and quicker DNA sequencing

Since 2015, an entire human genome can be sequenced in ~1 day, at the cost of ~$1500.

27
Q

Why was the 100,000 genome project established?

A

To sequence 100,000 genomes from 85,000 NHS patients affected by a rare disease, or cancer.

28
Q

What were the three aims of the 100,000 genome project

A

To advance diagnosis and personalised treatments

To create a new genomic medicine service for the NHS

To create a powerful research resource by combining genomic sequence data with medical records

29
Q

The 100,000th sequence was completed in December 2019

True or false

A

False

Completed in December 2018

30
Q

The 100,000 genome project has meant that
actionable findings have been found for1 in 4-1 in 5 rare disease patients

True or false?

A

True

31
Q

The 100,000 genome project has meant that ~50%of cancer cases have the potential for a therapy or a clinical trial.

True or false

A

True

32
Q

What is omics data used for?

A

Generating data is only the first step; crucial is the organization, visualization, analysis and interpretation of the biological data

33
Q

What do Biological databases include?

A

Libraries of biological information, collected from scientific high-throughput experiments, published literature, and computational analysis.

34
Q

A multilayer analysis of patient data comprises of what?

A

Exposome

Epigenome

Microbiome

Metabolome

Proteome

Transcriptome

Genome

35
Q

Biomakers/ biological markers are defined as what?

A

A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

36
Q

What are two means by which biomarkers can be classified?

A

Based on their ontology :
genetics, transcriptomic, epigenomic, serological, immune, etc

Based on their clinical value or application:
diagnostic, prognostic, predictive

37
Q

What does a diagnostic biomarker indicate?

A

Existence of a disease

38
Q

Prognostic biomarkers provide information about what?

A

Patient outcome, such as disease

progression or recurrence, regardless of therapy

39
Q

Predictive/theranostic biomarkers are used to estimate what?

A

The response(therapeutic or adverse) to a specific treatment.

40
Q

What is an example of a diagnostic biomarker?

A

Rheumatoid factor (RF) and the anti-cyclic citrullinated peptide (anti-CCP) are diagnostic biomarkers for Rheumatoid Arthritis (RA).

41
Q

What is an example of a prognostic biomarker?

A

Over-expression ofHER2receptor is prognostic of reduced overall survival and earlier relapse after adjuvant chemotherapy in breast cancer (BC)

42
Q

What is an example of a predictive biomarker

A

Over-expression ofHER2predicts response to trastuzumab and pertuzumab and is used for patient stratification in breast and metastatic gastric cancer.

43
Q

What are three characteristics of biomarkers?

A

Sensitivity

Specificity

Accuracy

44
Q

What is biomarker sensitivity?

A

The ability of a test to correctly identify the individuals with the characteristic of interest (e.g. disease, good response to a drug).

45
Q

What is biomarker specificity?

A

The ability of the test to correctly identify those without the characteristic of interest.

46
Q

A diagnostic test with 100% sensitivity will recognise what?

A

All patients with the disease by testing positive.

47
Q

A diagnostic test with 100% specificity will recognize what?

A

All healthy individuals by testing negative.

48
Q

Few biomarkers have 100% Sensitivity and Specificity

True or false

A

False

No biomarker has 100% Sensitivity and Specificity

49
Q

For every biomarker, there is usually a trade-off between what?

A

Sensitivity and specificity

50
Q

What is biomarker accuracy?

A

The ability of a test to correctly classify e.g. patients and healthy and is a trade-off between sensitivity and specificity

51
Q

What is the ultimate goal of a biomarker development pipeline?

A

To establish a clinical test, or companion diagnostic, based on a clinically accessible biomarker which can inform clinical decision-making to improve patient outcomes

52
Q

What are the three phases of a biomarker development pipeline?

Diamonds, veto, cats

A

Discovery

Validation

Clinical adoption

53
Q

What does the first phase of the biomarker development pipeline involve?

A
  1. Acquisition of relevant clinical sample - e.g. blood for genomic biomarker, tissue for epigenetic or transcriptomic analysis
  2. High-throughput technology e.g. NGS
  3. Statistics and Bioinformatics analysis
    e. g. linear regression, use of databases, clustering analysis
  4. Candidate biomarker(s) identification
54
Q

What are three challenges related to biomarker discovery?

A

To have a clearly defined research question and plan which takes in consideration the clinical context of application (e.g. diagnostic biomarkers for an immune-mediated disease such as RA could be present in blood)

To design an appropriate study (sample size and statistical power, well-defined inclusion and exclusion criteria, clinical note and follow-up)

Establish and implement Standard Operating Procedure (SOPs) for sample collection, processing and analysis

55
Q

What are three considerations about specimens for biomarker discovery?

A

Ease of acquiring, processing and storing the biospecimen needed (e.g. blood for DNA vs blood for immune cells quantification)

Ease of acquiring the quantity of the biospecimen needed (e.g. blood for genomic DNA vs tissue for epigenetics analysis)

Ease of acquiring the quality of the biospecimen needed (e.g. DNA more stable than RNA)

56
Q

Biomarker validation based in what cohort type is ideal?

What is this often substituted by and when?

A

An independent patient cohort is ideal

Often substitued by cross-validation-based methods when independent patient sets are unavailable.

57
Q

Biomarker validation involves what?

A
  1. Development and optimization of a suitable assay - Specificity-Sensitivity-Reproducibility-Standardized-Easy to Perform
  2. Analytical Validation - How accurately and reliably does the test measure the analyte(s) of interest in the patient specimen
  3. Clinical Validation - How robustly and reliably is the test result correlated with the clinical phenotype or the outcome of interest
  4. Validation of candidate biomarker
58
Q

What does analytical validation involve?

A

Assaying the same set of samples by both the assay used in the initial discovery and the clinical test in development to determine robustness and reproducibility of the measurements. E.g. altered gene expression identified by RNA-Seq and validated by RT-qPCR.

59
Q

What does clinical validation test involve?

How should this be pursued ideally?

A

The clinical test must be evaluated to confirm its performance in predicting or diagnosing the clinical phenotype or outcome of interest as demonstrated in the discovery and initial validation phase.

Ideally, this should happen in statistically well-powered prospective trialsbut usually a new retrospective cohort may be used

60
Q

What is the key difference between a clinical validation test and an analytical validation test?

A

A clinical validation test only uses the new developed test in an independent cohort, while analytical validation compares original test by which the biomarker was identified in discovery with the newly developed test

61
Q

What are the key issues for biomarker validation?

Clue: Cute, tigers, shower

A

Choice of suitable clinical platform (often different from the research platform used in discovery)

Type of specimen required, ease of acquiring, processing and storing

Study design (use of prospective-retrospective design and/or biobank/biorepository samples

62
Q

What are the characteristics of a clinical biomarker test/ companion diagnostic?

A

Simple

  • to learn and perform
  • Not complicated sample preparation

Rapid
-To perform and to yield results

Safe and ideally minimally invasive

Valid: High sensitivity

Reliable: Relatively high specificity

63
Q

What steps are part of clinical adoption of a biomarker?

Clue: Qawwalis, cure, current, insecurities

A
  1. Qualification - Regulatory review Process: Filing-Approval
  2. Commercialization
  3. Coverage by Health providers- NHS, Insurance companies
  4. Incorporation in clinical practice guidelines
64
Q

What are the challenges to implement stratified medicine?

Clue: Puppies fight ecology

A
  1. Practical challenges
    - Large, accessible biobank/datasets containing patient sample and information with appropriate safeguards are essential but not available for every disease
  2. Financial disincentives
    - There is a financial ‘double disincentive’ for pharmaceutical companies to stratify medicines . They pay more for R&D of a ‘companion’ diagnostic by which candidates for drug treatment can be selected, thus shrinking their market size shrink.

3.Ethical issues
Consent, data access, equal access and representation.

Pharmacogenetics (16 decks)

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