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Onco boards 2024 > research principles 10% > Flashcards

research principles 10% Flashcards

1
Q

Circulating free DNA facts

A
  • malignant > healthy controls
  • higher cfDNA levels and lower DAN integrity index LSA/leuk, HSA, distant mets
  • correlated with clinical stage
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2
Q

How does the TRAP assay work?

A

Detects telomerase activity using primer and amplification

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3
Q

How does the TUNEL assay work?

A

DNA fragmentation

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4
Q

Western vs Southern vs North blots detect?

A

W - protein
S - DNA
N - mRNA

Eastern - extension of western for post translational proteins

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5
Q

How can you detect chromosomal aberrations?

A

FISH or karyotyping

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6
Q

List the molecular tests for chromosome #

A
  • Karyotype: visual assessment of metaphase chromosomes, detects balanced chromosomal abnormalities, chromosomes recognized by size and shape via trypsin digestion
  • Chromosomal microarray: high resolution method for detecting copy number changes (gains or losses) across the entire genome I a single assay
  • SNP assay: single nucleotide polymorphism detection via probes to 50 million SNPs such as LOH and amplifications
  • Comparative genomic hybridization: detailed map of differences between chromosomes in different cell by detecting increase (amplifications) or decreases (deletions) in DNA segments. Misses smaller changes that SNP can detect
  • Microsatellite array: detect the relative abundance of specific nucleic acid sequences (genes or genetic variations) within a sample by hybridizing labeled nucleic acids to complementary probes immobilized on a solid surface.
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7
Q

What is the difference between FISH and comparative genomic hybridization?

A

FISH know chr abnormality and make probe, CGH don’t know yet-hard to see small changes so best when combined with microarray

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8
Q

Fluorescene in situ hybridization (FISH) vs Comparative genomic hybridization (CGH)

A

FISH advantages:
- info about positions of probes in relation to chromosome bands
- can be performed on interphase nuclei from paraffin imbedded tissue bx or cultured tumor cells
- visualization of cytogenic aberrations of whole chromosomes without need for quality metaphase populations
- standard for HER2 breast cancer

CGH advantages:
- detects UNKNOWN cytogenic aberrations that FISH cannot detect (FISH needs a specific probe)
- developed to produce map of differences btw chromosomes in different cells by detecting amplifications or detections in DNA
- DNA from both normal and malignant cells labeled with 2 difference fluorochromes and hybridized simultaneously to a normal chromosome metaphase spread
- detects regions of gain or loss
- can only detect large block of over or under expressed chromosomal DNA

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9
Q

What is the molecular diagnostic that can be utilized to detect chromosome aberrations such as Raleigh/Philadelphia chromosome?

A

genomic hybridization in situ FISH mitosis

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10
Q

Define pharmacokinetics

A

study of drug/metabolite levels in different body fluids and tissues including absorption, distribution, metabolism, and elimination

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11
Q

Define pharmacodynamics

A

study of the relationship between drug effect and its concentration

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12
Q

AUC

A

area under the plasma concentration time curve either from 0 to infinity (AUCinf) or from 0 to last point of blood sampling (AUCt)

AUC = dose/CL

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13
Q

C(t)

A

drug [ ] in plasma at time t

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14
Q

CL

A

clearance, the proportionality factor that related the rate of elimination of a drug from the body and its plasma [ ]

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15
Q

C (ss)

A

steady state plasma drug [ ]

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16
Q

t 1/2

A

half life, the time required for the drug [ ] to decrease by 50%

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17
Q

Vd

A

volume of distribution,
how widely the drug is distributed in the body
th apparent volume into which the drug is dissolved. The larger is the Vd, the less it is able to reach the tissues it is expected to reach and exert its pharmacological effect

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18
Q

Rate of elimination =

A

CL x plasma [ ]

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19
Q

Define pharmacogenomics

A
  • study of how genetic features of the patient and their tumor will influence response and toxicity through alterations in pharmacokinetics
  • seeks to explain differences in response on the basis of differences in activity of genes that are involved in drug metabolism and are related to specific mutations or polymorphisms
  • Goal - define a particular phenotype following drug exposure (eg serious toxicity, secondary malignancy) and then assess changes at the genetic level that might account for this phenotype
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20
Q

Example of pharmacogenomics

A

increased 5FU toxicity in p with deficiency in diphydropyrimidine dehydrogenase (DPD) - people

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21
Q

Sensitivity

A

true positive rate: likelihood of a + test in a diseased animal; those with the disease will test +

TP/ (TP+FN)

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22
Q

Specificity

A

True negative rate; likelihood of a - test in animals who DO NOT have the disease; those without the disease test -

TN/(TN+FP)

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23
Q

NPV

A

probability that an animal does not have the disease when the test results are negative

TN(TN+FN)

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24
Q

PPV

A

probability that a test result reflects the true disease status; probability that those with + results have disease

TP/(TP+FP)

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25
Q

Accuracy

A

proportion of all tests (+ or -) that are correct; those who have disease or do not

(TP+TN)/ (TP+FP+FN+TN)

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26
Q

Incidence rate

A

rate at which new events occur in a population: (number of new events in a specified period)/(number of individuals at risk during this period) x 10n

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27
Q

False + rate

A

likelihood of a + test in patients disease free

1 - (TN/(TN+FP))
1- (specifcity)

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28
Q

False - rate

A

likelihood of a - test in patients who have disease

1 - (TP/(TP+FN))
1- (sensitivity)

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29
Q

True prevalence

A

amount of + animals in the entire population

(TP+FN)/(TP+FP++FN+TN)

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30
Q

Odds ratio

A

assess association in case control studies (A/C)/(B/D)

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31
Q

Relative risk

A

determines how likely those who are exposed to a risk factor are to get the disease compared to those not exposed

[TP/(TP+FP)]/[FN/(FN+TN)]

32
Q

At which age should cancer screening begin based on epidemiological studies in dogs?

A

7 for most, 4 for breeds with lower median age

33
Q

Prevalence of proteinuria in dogs present to oncology?

A

51% - screening should be performed

34
Q

Incidence vs. prevalence

A
  • Incidence: the number of newly diagnosed cases at a specific time divided by the total population at risk
  • Prevalence: the number of existing cases at a specific time divided by the total population at risk
35
Q

Lead time vs. length time bias

A
  • Lead-time bias: ability to diagnose at an earlier stage gives false impression that survival is longer
  • Length-time bias: error from detecting disease w a long latency period or pre-clinical period
36
Q

Novel screening test for GRD with HSA. Improved ST with use. Example of what?

A

lead-time bias

37
Q

Geographic bias

A

-Result of differences in prevalence of underlying causes or to differences in diagnostic criteria
- Affected by prevalence of chronic infectious w certain viruses in different countries

38
Q

Phases of clinical trials

A
  • Phase I – dose -finding
  • Phase II – activity/efficacy
  • Phase III – pivotal/confirming
39
Q

Dog has stable disease months following the study and was changed to a separate study arm

A

Randomized discontinuation trials

two phases part one enroll - those who have responses are reallocated to new phase - either placebo or drug

40
Q

Why do we have rules of stopping in RCT

A

decreased type II error in analysis, benefit of owner/pet, preserve resources (money and pets)

41
Q

what are the 3 rules that are used to make decisions on D/C clinical trials

A
  • Negative stopping – AE or sig worse results than std or “Investigative therapy is clearly or likely worse than control”
  • Positive stopping – benefits are sig greater than std placebo “Investigative therapy is clearly better than control “
  • Futility – results are unlikely to change

Needed to know why these are stopping rules (what benefit would you give to an owner)

42
Q

Ways to avoid study bias

A

Ways to avoid confounding = multivariate regression analysis

Randomization, blinding

43
Q

How to increase study significance?

A

Lower P value, higher power, multivariate analysis, randomization, blinding

44
Q

Types of clinical trial designs

A

Cohort – follows group over time comparing exposed to a factor that may influence risk or outcome to those not exposed
- Can be retrospective or prospective
- determinedRelative risk

Case-control – recruit newly diagnosed cases and compare to controls who were also exposed but not diseased
- determined odds ratio

Cross-sectional – sampling of individuals from underling population takes place a specific point in time
- Ex. learning prevalence of diabetes in breast cancer patients
- ex. determining number of patients that got SHC when tx w CTX

45
Q

What type of study to use to evaluate fipronil in MCT development with least finances and time?

A

Case Control

46
Q

Type I error

A
  • False positive
  • Level of significance
47
Q

Type II error

A
  • False negative
  • Fails to reject null hypothesis when it was incorrect
48
Q

Kaplan Meier curve interpretation

A
  • Y axis – event, X axis – time; each drop is a death of patient, results are more significant earlier on in the curve bc less patients are being censored
  • Patients are censored if still alive at time of data collection or lost to follow-up
49
Q

Cat study with new ISS treatment- ST not reached on KM. Interpretation?

A

Use caution, repeat study

50
Q

advantages and limitations of Randomized Controlled Trials

A

Advantages:
- Gold standard: Considered the most reliable for determining causality due to randomization.
- Controlled environment: Researchers can control variables, minimizing bias.
- Generalizability: Results can often be generalized if the sample is representative.

Limitations:
- Cost and time: Can be expensive and time-consuming.
- Ethical concerns: Some interventions may be unethical or impractical to test.
- Sample size: May require large sample sizes to detect effects, which can be challenging.

51
Q

advantages and limitations of Cohort Studies

A

observational study
cohort studies can be hypothesis testing studies and can infer and interpret a causal relationship between an exposure and a proposed outcome, but cannot establish it

Advantages:
- Temporal sequence: Can establish the temporal relationship between exposure and outcome.
- Long-term data: Useful for studying rare exposures and long-term outcomes.
- Multiple outcomes: Can assess multiple outcomes from the same exposure.

Limitations:
- Loss to follow-up: Attrition can affect validity.
- Selection bias: Cohort may not be representative of the population.
- Time and resources: Can be costly and time-consuming, especially for long-term follow-up.

Cohort studies can be classified as prospective and retrospective

52
Q

advantages and limitations of Case-Control Studies

A

observational study
retrospectively reviewed a defined cohort

Advantages:
- Efficiency: Suitable for studying rare diseases or outcomes.
- Quick: Faster and cheaper than cohort studies.
- Multiple exposures: Can study multiple exposures for a single outcome.

Limitations:
- Recall bias: Participants may have difficulty recalling past exposures.
- Selection bias: Cases and controls may not be properly matched, leading to biased results.
- Cannot establish causality: Only provide association, not causation.

used to study risk factors or etiologies for a disease, especially if the disease is rare.

53
Q

advantages and limitations of cross sectional studies

A

observational - evaluate an association between an exposure and outcome at the same time

Advantages:
- Quick and easy: Efficient for collecting data.
- Prevalence data: Useful for understanding prevalence and distribution of diseases.
- Multiple factors: Can study multiple exposures and outcomes simultaneously.

Limitations:
- Temporal relationship: Cannot establish temporal sequence between exposure and outcome.
- Cannot establish causality: Only provide association, not causation.
- Selection bias: Participants may not be representative of the population.

designed to collect information at the same point of time, this provides an opportunity to measure prevalence of the exposure or the outcome

54
Q

advantages and limitations of Prospective Studies:

A

Advantages:
- Temporal sequence: Establish temporal relationship between exposure and outcome.
- Longitudinal data: Can collect data over time, which is useful for studying changes.
- Less susceptible to recall bias: Participants are followed forward in time.

Limitations:
- Cost and time: Can be resource-intensive.
- Loss to follow-up: Attrition can affect validity.
- Selection bias: Participants may not be representative of the population.

55
Q

advantages and limitations of retrospective studies

A

Advantages:
- Quick and cost-effective: Uses existing data, saving time and resources.
- Useful for rare diseases: Can efficiently study rare diseases or outcomes.
- Can study multiple outcomes: Can look at multiple outcomes from the same exposure.

Limitations:
- Validity of data: Relies on the accuracy and completeness of existing records.
- Recall bias: Participants may have difficulty recalling past exposures.
- Cannot establish causality: Only provide association, not causation.

56
Q

Phase 0 Trial

A

Phase 0 trials, also known as exploratory or microdosing trials, involve administering subtherapeutic doses of a drug to a small number of subjects (usually 10-15). These trials aim to gather initial data on how the drug behaves in the human body, such as its pharmacokinetics and pharmacodynamics. does the drug reach cancer cells?

Results from phase 0 trials are primarily focused on the drug’s pharmacokinetics (how the body absorbs, distributes, metabolizes, and excretes the drug) and its pharmacodynamics (how the drug affects the body). These trials are not designed to assess efficacy or safety but rather to inform further development in later phases.

57
Q

Phase I Trial

A

Phase I trials involve a small number of healthy volunteers (usually 20-100) and are primarily focused on assessing the safety and tolerability of the drug. These trials also aim to determine the drug’s pharmacokinetics, optimal dosing, and initial evidence of efficacy.

Interpretation: Results from phase I trials provide information on the drug’s safety profile, including adverse effects and dose-limiting toxicities. Additionally, phase I trials may provide preliminary evidence of the drug’s efficacy, although this is not the primary focus.

58
Q

Phase II Trial

A

Phase II trials involve a larger number of participants (typically a few hundred) and are conducted in patients with the targeted disease or condition. These trials further assess safety, as well as begin to evaluate efficacy and dosing regimens.

Interpretation: Results from phase II trials provide more substantial evidence of the drug’s efficacy in the target population. They also continue to evaluate safety, adverse effects, and optimal dosing. Phase II trials help determine whether the drug should proceed to larger, phase III trials.

59
Q

Phase III Trial

A

Design: Phase III trials are large-scale studies involving hundreds to thousands of participants. These trials are designed to confirm the drug’s efficacy, monitor adverse reactions, and compare it to standard treatments or placebo.

Interpretation: Results from phase III trials provide the most robust evidence of the drug’s efficacy and safety. They often form the basis for regulatory approval. The primary endpoints, such as disease progression, survival rates, or symptom improvement, are crucial for interpreting the overall effectiveness of the drug.

60
Q

Phase IV Trial

A

Phase IV trials occur after the drug has been approved and is on the market. These trials monitor the drug’s safety and effectiveness in larger, more diverse patient populations over an extended period.

Interpretation: Results from phase IV trials provide real-world data on the drug’s safety and effectiveness, which may uncover rare adverse effects or long-term benefits or risks that were not apparent in earlier phases.

61
Q

good clinical practice standards

long but just be familiar

A

1) Ethical Principles:
- Informed Consent
- Beneficence and Non-maleficence: Trials must maximize benefits for participants and minimize risks, ensuring their well-being.
- Respect for Participants’ Rights: Participants’ rights to privacy, confidentiality, and dignity
2) Equitable Distribution of Benefits and Burdens: The selection of participants must be fair and equitable, ensuring no group is unfairly burdened.
3) Trial Design and Conduct:
- Protocol Development: Clinical trials must be conducted according to a detailed protocol outlining the objectives, methodology, participant eligibility criteria, treatment interventions, and endpoints.
- Ethics Committee Approval: IACUC
- Qualified Investigators: Investigators conducting the trial must be qualified and experienced in accordance with their respective roles and responsibilities.
4) Data Integrity: Trial data must be accurate, complete, and verifiable, with appropriate documentation and record-keeping procedures.
5) Participant Rights and Safety:
Safety Monitoring: Adequate measures must be in place to monitor participant safety throughout the trial, including reporting and managing adverse events.
Withdrawal: Participants have the right to withdraw from the trial at any time without penalty.
6) Statistical Analysis: Statistical methods must be appropriate for the study design, and the analysis plan must be pre-specified in the protocol.
7) Regulatory Authority Notification: Regulatory authorities must be notified and approvals obtained before initiating the trial.
8) Adverse Event Reporting: Adverse events must be reported promptly to regulatory authorities, ethics committees, and participants as required.
9) Trial Registration and Reporting: Trials must be registered in publicly accessible databases, and trial results must be reported transparently and accurately, regardless of the outcome.

62
Q

Selection Bias:

A
  • Definition: Occurs when there’s a systematic difference between those who are selected for the study and those who are not, leading to an unrepresentative sample.
  • Example: In a hospital-based case-control study on smoking and lung cancer, if cases (lung cancer patients) are more likely to be heavy smokers than controls (non-lung cancer patients), it may lead to an overestimation of the association between smoking and lung cancer.
  • Mitigation: Randomization, careful selection criteria, and matching are strategies to reduce selection bias.
63
Q

Information Bias:

A

Definition: Arises from errors in the measurement or collection of data.

Types:
- Measurement Bias: Systematic errors in measuring exposure or outcome.
- Recall Bias: Differences in the accuracy or completeness of recall of past events between groups.
- Reporting Bias: Differences in how information is reported between groups.

Mitigation: Blinding, standardized data collection methods, and validation of data can help reduce information bias.

64
Q

Confounding Bias

A
  • Definition: Occurs when the association between an exposure and an outcome is distorted by the presence of a third variable (confounder) associated with both the exposure and the outcome.

Example: In a study investigating the association between coffee consumption and heart disease, age may act as a confounder, as older individuals are more likely to drink more coffee and have a higher risk of heart disease.

Mitigation: Matching, stratification, and statistical adjustment are methods used to control for confounding.

65
Q

Publication Bias:

A

Definition: Occurs when the publication of research findings is influenced by the nature and direction of the results.

Example: Studies with statistically significant or positive results are more likely to be published, while those with nonsignificant or negative results may remain unpublished.

Mitigation: Initiatives like prospective trial registration and publication of all study outcomes can help reduce publication bias.

66
Q

Performance Bias:

A

Definition: Arises when there are differences in the care provided to participants in the intervention and control groups of a study, apart from the intervention being evaluated.

Example: In a randomized controlled trial comparing two surgical techniques, if the surgeons providing one technique are more experienced or skilled than those providing the other technique, it may bias the results.

Mitigation: Blinding of participants, caregivers, and outcome assessors can help reduce performance bias.

67
Q

Attrition Bias:

A

Definition: Occurs when participants drop out of a study, and their reasons for dropping out are related to the outcome being measured.

Example: In a longitudinal study on the effects of a weight loss program, if overweight participants are more likely to drop out due to dissatisfaction with the program, it may lead to biased results.

Mitigation: Minimizing loss to follow-up, intention-to-treat analysis, and sensitivity analysis can help address attrition bias.

68
Q

high power study

A

Increased sample size reduces random variability and increases the precision of estimates.

well-defined hypotheses and objectives

Proper statistical methods

69
Q

low power study

A

Small studies may fail to detect true effects or may produce spurious findings due to random variability - less reliable and less generalizable

Not controlling for confounders- Failure to address confounding may lead to erroneous conclusions or inaccurate effect estimates

inadequate follow up time - if you have to censor too many you need to wait and let the data mature

** this was the problem with the melanoma vax trials**

70
Q

ROC Curve

A

a plot of the sensitivity versus 1 − specificity of a diagnostic test. The different points on the curve correspond to the different cut points used to determine whether the test results are positive. can be considered as the average value of the sensitivity for a test over all possible values of specificity or vice versa. A more general interpretation is that given the test results, the probability that for a randomly selected pair of patients with and without the disease/condition, the patient with the disease/condition has a result indicating greater suspicion

represents the range at each point of false positive rate and its corresponding true positive rate

If the test results diagnosed patients as positive or negative for the disease/condition by pure chance, then the ROC curve will fall on the diagonal line

An overall ROC curve is most useful in the early stages of evaluation of a new diagnostic test. Once the diagnostic ability of a test is established, only a portion of the ROC curve is usually of interest, for example, only regions with high specificity

71
Q

how to recognize a low powered study

A
  • small sample size
  • WIDE confidence interval - indicate high uncertainty
  • fails to detect a plausible result
  • low stat sig
  • post hoc power analysis - below 80%
  • inconsistent with prior knowledge
  • insufficient follow up time
  • subgroups typically underpowered
72
Q

AUC of ROC

A

A value of 0.5 for AUC indicates that the ROC curve will fall on the diagonal (i.e., 45-degree line) and hence suggests that the diagnostic test has no discriminatory ability.

AUC is 0.89. This suggests an 89% chance that the test will correctly identify the problem of interest

0.7 to 0.8 is considered acceptable, 0.8 to 0.9 is considered excellent, and more than 0.9 is considered outstanding

73
Q

Confidence Interval?

A

probability that a population parameter will fall between a set of values for a certain proportion of times

Analysts often use confidence intervals that contain either 95% or 99% of expected observations. Thus, if a point estimate is generated from a statistical model of 10.00 with a 95% confidence interval of 9.50 to 10.50, it means one is 95% confident that the true value falls within that range.

74
Q

Cell Death Assays:

A

Methodology: Cell death assays are used to measure the extent of cell death in a culture or tissue sample. Common assays include:
1) Trypan Blue Exclusion Assay: Dye exclusion method where dead cells take up the dye and appear blue.
2) MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) Assay: Measures metabolic activity of cells, reduced by living cells.
3) Annexin V/Propidium Iodide Staining: Distinguishes between apoptotic (Annexin V positive, PI negative) and necrotic (both positive) cells.

Analysis:
Results are typically quantified using spectrophotometry, fluorescence microscopy, or flow cytometry.
Cell death can be expressed as a percentage of dead cells relative to total cells.

Utility:
Assessing cytotoxicity of drugs or environmental agents.

Limitations:
Some assays may not distinguish between different modes of cell death.
Assays may be influenced by factors such as cell density, culture conditions, or assay duration.

75
Q

next Generation Sequencing

A

Methodology: NGS is a high-throughput sequencing technology that sequences millions of DNA fragments in parallel.

Analysis:
Sequence data is aligned to a reference genome or assembled de novo.
Bioinformatics analysis identifies genetic variants, gene expression levels, and other genomic features.

Utility:
Genome sequencing, variant discovery, and association studies.
Transcriptomics (RNA-seq) for gene expression profiling.

Limitations:
High cost, particularly for whole-genome sequencing.
Complexity of data analysis and interpretation.
Short-read sequencing may have limitations in resolving repetitive sequences or structural variations.

76
Q

RT PCR

A

reverse transcriptase of RNA not DNA

Onco boards 2024 (17 decks)

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