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Spring 2024 (All Classes Except Therapeutics+ Lab) > Pharmacogenomics Quiz 3 (Lec 9-11) > Flashcards

Pharmacogenomics Quiz 3 (Lec 9-11) Flashcards

1
Q

In a contingency table, if we are trying to find the number of T alleles when T/T= 121 and T/C=297, what would the answer be? (T=?)

A

***121 x 2= 242

242 + 297= 539

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2
Q

What is the null hypothesis regarding the relationship between allele and drug resistance?

A

There is NO ASSOCIATION between any allele and drug resistance

(no effect of allele, want to prove this wrong)

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3
Q

What value of X^2 supports the null hypothesis?

A

A small value of X^2 supports the null

*a large value would reject the null (what we want to see)

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4
Q

What is a p value used for?

A

Determines if there is an effect or if the association occurred by chance

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5
Q

What does P > 0.1 mean?

A

No presumption against the null hypothesis

(there is no association, DO NOT REJECT THE NULL)

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6
Q

What does P < 0.05 mean?

A

Strong presumption against the null hypothesis

(significant association, reject the null, GOOD)

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7
Q

What does P < 0.01 mean?

A

Very strong presumption against the null hypothesis

(very significant association, definitely reject the null, VERY GOOD)

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8
Q

Does P measure the strength of an association relationship?

A

NO
-can be affected by other factors like sample size and allele frequency

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9
Q

What is an odds ratio?

A

A statistical measure of association between two events

-There is an increased risk for a phenotype in people who carry a specific genotype/allele compared to patients who do not carry it

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10
Q

How do we calculate an odds ratio?

A

Odds of phenotype in an individual with
the genotype/allele
———————————————————–
Odds of phenotype in an individual
without the genotype/allele

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11
Q

What is a hazards ratio (HR)?

A

Similar concept as odds ratio but mainly discussed in survival data

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12
Q

What does an Odds Ratio = 1 mean?

A

No association

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13
Q

What does an Odds Ratio > 1 mean?

A

Potentially increases risk

(allele is called “risk allele”)

**The greater the OR is, the higher risk the allele will confer to the phenotype

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14
Q

What does an Odds Ratio < 1 mean?

A

Potentially decreases the risk

(allele will be called “protective allele”)

**The smaller the OR is, the lower risk the allele will confer to the phenotype

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15
Q

What is the 95% Confidence Interval used to decipher?

A

Tells us over 95% probability that the association is confident

**is a statistical probability for OR (the standard error of OR)

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16
Q

What does a 95% CI > 1 mean?

A

There is significant Risk Effect

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17
Q

What does a 95% CI that contains 1 mean?

A

No statistical significance

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18
Q

What does a 95% CI < 1 mean?

A

There is significant protective effect

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19
Q

True or False: Due to the large number of tests required for many SNPs vs the single phenotype, there is a high probability that many SNPs will be associated with the phenotype just by chance

A

TRUE

*called a false positive
*results from multiple-testing
*the more SNPs tested, the higher the probability for a false positive

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20
Q

What value is used as a corrected significant GWAS P value?
(to limit false positives)

A

5x10^ (-8)

**used when testing a large number of SNPs such as in GWAS testing

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21
Q

What is the key to help find cause and effect while doing experiments to test a hypothesis?

A

CONTROL
-Positive control
-Negative control

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22
Q

What is negative control?

A

Conditions/media that do not produce a result

Ex: putting a bacteria in a culture media that you know won’t kill it, just want to make sure the bacteria grows

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23
Q

What is positive control?

A

The standard of care drug

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24
Q

In human clinical trials where having a negative control would be unethical, what do we do?

A

Compare to the standard of care

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25
Q

True or False: A large sample size is essential to have reliable results

A

True

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26
Q

Do clinical studies usually use median or mean?

A

Median

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27
Q

Why do clinical studies normally use median over mean?

A

-Faster

-Patient data may not be normally distributed

(only need 50% of patients to die to get median rate, if patients were to live a long time with the drug you would never get the mean)

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28
Q

The majority of data we deal with in genomics follows what distribution?

A

Normal (Gaussian) Distribution

29
Q

Mutations in PCSK9 cause what type of hypercholesterolemia?

A

Autosomal Dominant

30
Q

What gene affects LDL cholesterol levels?

A

PCSK9

31
Q

What is the desirable value of LDL?

A

<130

32
Q

What causes Low LDL cholesterol levels in some individuals of African Descent?

A

Nonsense mutations in PCSK9
(loss of function)

33
Q

What two things are affected by increasing PCSK9?

A

LDLR protein is decreased (degradated)

LDL-C is increased

34
Q

If PCSK9 is blocked (nonsense mutation), how does this affect LDLR protein and LDL-c levels?

A

LDLR protein increases

LDL-c decreases

35
Q

What is the function of the LDL-R (receptor)?

A

Binds LDL particles

LDL and receptor are internalized

Go into lysosome and ONLY LDL is degradated

36
Q

What affect does PCSK9 have on LDL-R and LDL?

A

PCSK9 binds the internalized LDL-R and LDL complex

This complex goes to the lysosome

PCSK9 causes both the LDL and the LDL-R to be degraded!

**This decreases the receptor numbers and results in more LDL accumulating in the blood

37
Q

How does the human monoclonal antibody against PSCK9 work?

A

Binds to PCSK9 so it is not able to bind to LDL-R anymore

*ultimately prevents LDL-R degradation and allows it to continue to bind LDL (LDL-R is recycled while LDL is degraded)

38
Q

What are the 2 monoclonal antibody drugs approved to target PCSK9?

A

Praluent

Repatha

39
Q

In hypercholesterolemia, when would we consider adding PCSK9 inhibitors?

A

If LDL >= 70, add ezetimibe

If LDL is still >= 70, then can add a PCSK9i

**note, these are basically last line agents

40
Q

How do we determine ICER (Incremental Cost-Effectiveness Ratio)?

A

Through QALY

41
Q

What is the equation of ICER?

A

(Cost2 - Cost1)/(QALY2 - QALY1)

42
Q

Note

A

See Lec 10 slide 14

43
Q

What is the function of antisense oligonucleotides (ASO)?

A

Block the mRNA directly to reduce the protein being made from that particular mRNA

44
Q

What is the idea behind Discounted Cash Flow?

A

Future money is always worth less than current money

45
Q

What discount rate is assumed each year in the idea of Discounted Cash Flow?

A

10%

(this is the value that the cost of money decreases by every year)

46
Q

True or False: The 10% yearly discount rate associated with Discounted Cash Flow represents inflation

A

False
*this is not inflation

47
Q

What is the function of antisense oligonucleotides (ASO)?

A

RNA interference

-reduce mRNA levels (that have a bad gene) so that less protein will be made

**Block mRNA directly

*use this to block a super active protein

*block mRNA by binding to it

48
Q

What is Onpattro (patisiran)?

A

An RNA interferer used in people with a rare and deadly genetic disorder called hereditary transthyretin-mediated amyloidosis

49
Q

What does mRNA medicine do?

A

Introduces exogenous mRNA into the body so that cells can make proteins based on the introduced mRNA

*do not use when a protein is overactive

50
Q

What is an example of an mRNA medicine?

A

COVID-19 vaccine

51
Q

What is the function of a Monoclonal Antibody / Antibody-Drug Conjugate (ADC)?

A

A type of “Y” shape protein that specifically binds to its target (a “target protein”) to block its function

OR helps to recognize a group of cells that express the “target protein”
*can help direct cancer drugs to a specific target

52
Q

What are two examples of monoclonal antibodies?

A

PD1 drugs

PD-L1 drugs

53
Q

What is Luxturna?

A

An FDA-approved adeno-associated (AAV) drug used to treat a rare form of inherited vision loss

***Gene therapy

54
Q

What is a key component of gene therapy?

A

A virus is used as a vehicle to deliver the gene

55
Q

What is the potential role of stem cell (iPSCs) therapy?

A

Potential to generate any cell type in the body to replace damaged tissue

*no FDA approved therapies yet

56
Q

When would we use an antisense oligonucleotide (ASO)?

A

When a patient has a mutation resulting in a disease-causing protein being formed

-degrade mRNA to prevent the protein from being formed

57
Q

What are the steps to creating mRNA medicine?

A

Identify the spike protein domain on a virus, make it into DNA, and then transcribe it into mRNA

Mix the mRNA sequence with lipid nanoparticle (coating)

Inject into body where it is taken up by muscle cells which DO NOT recognize the mRNA as foreign

Cells produce millions of copies of the spike protein and the fragments are recognized by the immune system which builds antibodies against it

These protect the host when a real antibody enters the body in the future

58
Q

What are 2 critical parts of mRNA medicine development?

A

Making the exogenous mRNA stable

Finding the right “coating” to deliver them into the cell (can cause reactions)

59
Q

What cells make antibodies?

A

B cells

60
Q

What is the role of T-helper cells?

A

Activate helper B cells

61
Q

What is the role of cytotoxic T cells?

A

Identify and destroy virus infected cells

62
Q

What are the 2 functions of Monoclonal Antibodies?

A

Neutralize and block foreign invaders from entering and infecting other cells

Tag foreign invaders for destruction

63
Q

What is an Antibody-drug conjugate (ADC) and how does it work?

A

These are the new versions of MABs

-Bind to an antigen (typically on a cancer cell), gets internalized, releases a toxic molecule into the cell which ultimately kills it

64
Q

How is gene therapy created?

A

Transgene is packaged into a virus (vector)

Delivered to patient through one-time infusion

Carried to target organ (such as liver)

Transported to nucleus to enable production of therapeutic protein

65
Q

What is Zolgensma?

A

A gene therapy that is used to treat SMA which is a neuromuscular disorder caused by a mutation in the SMN1 gene

*This mutation leads to a decrease in SMN protein which is needed for motor neuron survival

*Zolgensma contains SMN1 transgenes which are taken up by the muscle to make healthy proteins (supplement healthy genes)

66
Q

What virus is used as the vector for Zolgensma?

A

Adeno-associated virus (AAV)

67
Q

What is a problem with gene therapy administration?

A

If the effects of the therapy wear off, it cannot be reinjected again because the body builds an immune response to the viral packaging after the first injection

68
Q

How does CRISPR-mediated gene-editing and mutation-repair work?

A

*Target DNA

Cuts double stranded DNA into 2 pieces
-used to inhibit/get rid of a gene/mutation but not to fix it

*Causes double-strand DNA breaks (not great for correcting a single-point mutation)

Spring 2024 (All Classes Except Therapeutics+ Lab) (9 decks)

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