Precision medicine

How old is precision medicine?

• Very old and has been since (460-370 BC)

• Hippocrates was known as “father of medicine” and practitioner of precision medicine

Whats precision medicine?

Prescribed treatments and prognosis informed by the patient’s own measurements

What are some ancient and modern techniques of precision medicine?

• Ancient one is the phlegm and bile

• Modern is temp, blood pressure, hormone level, MRI scan, cognitive test, genetic markers

Why is modern better than ancient medicine?

• More data = greater precision

LOOK AT AND UNDERSTAND INTUITION CHECK

Whats family history?

• An important data point in precision medicine

• Family history serves as indirect genetic information (indirect cuz doesnt measure genotype, as its inferred risk is based on someones relatives

• Can be used to assess disease risk over 3 sectors (high, moderate, average)

Why is family history underused?

• Time pressure model in healthcare, no time

• People might not be informed of their history

• Doctors might not be trained to take family history

Why is using family history alone imprecise?

• Because its an indirect means of assessing genetic contribution

• 2 people may have different risks even if they have same allele or not (de novo mutations would be labelled average risk even though they have disease variant)

Why is precision med better than just family history?

• It directly assesses genetic variation

• It was one of the major goals of the human genome project

What did the human genome project give us?

• A reference genome (normal baseline)

• Sequencing tools and methods

• Opportunity for extensive associations

STUDY THE FOLLWOING SUMMARY OF FAMILY HISTORY DIRECT GENETIC TESTING

Explain early onset familial alzheimers disease (EOFAD) and its characteristics

Autosomal dominant

Numerous atypical phenotypes such as Visual-spatial difficulties, behavioural changes, Parkinsonism

Diagnosed before 65 years-old

Near complete penetrance = An individual with mutation nearly always will get EOFAD

Pathologies are indistinguishable from late onset alzheimers disease so people with this cant get a quick diagnosis and experience a DIAGNOSTIC ODYSSEY 

What can geentic testing do?

1. Identify the cause of disease

2. Enable early diagnosis

• Brings peace of mind

• Gives access to condition-specific resources

• Helps prepare for the future

3. Assists with career planning

• Via carrier testing and newborn screening

Whatre some considerations for rare diseases?

• Your right to know

• Who gets access?

• What traits should be screened?

Explain late onset alzheimers disease (LOAD)

• Progressive, incurable, neurodegenerative disorder

• Strong disease heterogeneity which means every dementia patient is unique

• Complex exposome which is cumulative of all the exposures in a persons life from birth

• Is highly polygenic → has far more key genes than EOFAD

How can risk for late onset alzheimers disease (LOAD) be quantified?

• Via a polygenic score

Whatre the steps of creating a polygenic score?

1. Choose or create GWAS data for generating a PGS

2. Select variants for inclusion in PGS by applying a significance threshold (leniant, strict, middle → shows importance of p-value)

3. Identify number of effect alleles that each individual carrier

4. Use effect sizes to weight each variant (highest ODDS-Ratio = strongest bearing on trait)

Multiply # of effect alleles by effect sizes (odds ratio) to get polygenic score

NEED TO TEST DATA TO SEE IF POLYGENIC SCORE/ DATA IS USEFUL

Whatre polygenic scores?

• Combination of multiple genetic variants which act together to increase and decrease risk of disease

• They have a comparable risk to rare monographic mutations. Greater population impact

Explain the GWAS diversity gap

• Reduced PGS accuracy in those non-european ancestry (4 in 5 people)

• 79% of GWAS participants were european individuals

Whatre some applications of polygenic score?

1. Identify high-risk individuals for early disease screening

2. Personalized medicine based on genetic risk

3. Assess disease risk in prospective parents

4. Control for genetic confounding in research

Whatre the 2 factors used to evaluate whether a genetic test is appropriate given clinical context?

1. Clinical validity = Extent to which a test is predictive of disease

2. Clinical utility = Degree to which a test will result in changes to medical care

Whatre the 4 aspects of clinical validity?

Sensitivity: Fraction of individuals with the disease who carry the risk variant =  a/(a+c)

Specificity: Fraction of individuals without the disease who do not carry the risk variant = d/(b+d)

Positive predictive value: Proportion of individuals who carry the risk variant and develop the disease =  a/(a+b)

Negative predictive value: Proportion of individuals who do not carry the risk variant and do not develop the disease = d/(c+d)

Whats clinical utility?

• Degree to which a test will result in changes to medical care

• Testing of variants may alter medical managements through the identification of improved treatments and preventative measures

Understand case example

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