The Anatomy and Physiology of Clinical Research (Part 3)

Question 1

Learning objectives part 3

Focus on subjects which are selection criteria and sampling design

Answer 1

At the end of this lecture, you should be able to:
Understand how a study / trial work.
Know how subjects are recruited in a study / trial in terms of the inclusion and exclusion criteria.
Understand the types of control groups in a study / trial.
Understand what is randomization and its importance in a study / trial.
Understand the types of errors encountered in a study / trial.
Know and understand the different types of sampling methods used in a study / trial.
Appreciate and understand how these are applied in real-world situations.

Question 2

the 3 things we need to consider when designing a clinical trial or study

Answer 2

Target population - focus on the target population first and formulate a general concern/question
Research question - after we start from the target population, we will narrow down to formulate the research question
Study plan - a study plan is formulated based on the research question

When designing a clinical trial, we start from the population first, we then narrow down the question to formulate the research question
From the research question, we formulate a study plan
When we carry out the study plan, we have to ensure it has high internal validity. It allows us to draw conclusions about the predictor and outcome variable.
This way, it allow us to apply these conclusions to people and events outside the study or generalize the results back to the population

Question 3

External validity and internal validity of a trial/study

Answer 3

from research question to target population (external validity) - Having high internal validity allows us to apply these conclusions back to the target population.

from study plan to research questions(internal validity) - When conducting a study plan, we need to ensure a high internal validity (i.e. draw correct conclusions on the predictor & outcome variables)., draw correct conclusions on predictor and outcome variables

Question 4

External validity

Answer 4

We need external validity and internal validity for research to work

Choosing of subjects, inclusion and exclusion criteria, to ensure that we can generalize the results back to the target population.

formulate a question based on the population - What is the prevalence of soya milk consumption among Chinese men from 50-60 years old with hypertensions?

narrow down the question to research question - what is the prevalence of soya milk consumption among Chinese men from 50-60 years old with hypertension seen at TTSH in 2014?

formulate a study plan from the research question - consuming 1 serving of soya milk per day is able to reduce blood pressure in Chinese men from 50-60 years old suffering from hypertension?

Question 5

Internal validity

Answer 5

We need internal validity and external validity for research to work

Design of the study such that a correct conclusion is drawn between the study predictor and outcome variable

Question 6

Design of clinical trial

Answer 6

Study of the accessible population (study population) – via internal validity–> accessible population (define geographic and temporal, relating to the location of the study and duration of the study) -> target population (define demographic and clinical, relating to human population, information collected about them, relating to the condition/disease)

Question 7

Inclusion criteria

Answer 7

Demographic, clinical, geographic and temporal
demographic - information collected about the human population
clinical - condition/disease
geographic - the location of the study
temporal - the duration of the study

Question 8

Exclusion criteria

Answer 8

Indicates subsets of individuals who would be suitable for the research question were it not for certain characteristics such as

• success of certain follow up efforts
• data quality
• acceptability of the randomized treatment

Question 9

the 3 Characteristics of exclusion criteria

Answer 9

1. success of follow-up efforts
2. quality of the data
3. acceptability of the randomized treatment

These characteristics will interfere with the research question by affecting the quality of data and randomization of the treatments and success to follow-up

Question 10

What does characteristics of exclusion criteria affects ?

Answer 10

quality of the data
randomization of treatments and success to follow up

e. g quality of data - children might lite about the number of hours they work or cannot remember how many hours they cannot work
e. g follow-up efforts - if the parents of the children migrate, it can be difficult to do follow-ups with the children

Question 11

Vulnerable subjects and exclusion of vulnerable subjects

Answer 11

Children, people with cognitive disabilities etc.

Those who are significantly less able to protect their own interest

Do not recruit vulnerable subjects even if they satisfy all the inclusion criteria listed

Safety of the participant is the most important

Question 12

note about exclusion criteria

Answer 12

exclusion without a good reason may be unfair or discriminatory

Question 13

How to reduce biases and clinical errors?

Answer 13

randomization, ensuring that control and treatment group have similar baselines minimizing confounding variables & blinding

Question 14

Control group

Answer 14

A control group in a scientific experiment is a group separated from the rest of the experiment where the independent variable being tested cannot influence the results. This isolates the independent variable’s effects on the experiment and can help rule out alternate explanations of the experimental results. (To ensure that the results seen is due to the independent variable and not other variables)

This group of scientific control enables the experimental study of one variable at a time and is an essential part of the scientific method

Question 15

study plan

Answer 15

What type of control groups do we want? How do we perform randomization?

Question 16

subject

Answer 16

Who do we include into the study? How many should we include into our study

Question 17

variables measured

Answer 17

Precision and accuracy

Question 18

statistical issues

Answer 18

Hypothesis testing and how do we use statistics to determine sample size?

Question 19

How to ensure high internal validity

Answer 19

we would need to reduce both systemic and random error

Question 20

Systematic error

Answer 20

are errors in the study due to bias

is a consistent, repeatable error associated with faulty equipment or a flawed experiment design.

these errors are usually caused by measuring
instruments that are incorrectly calibrated or are used incorrectly. However, they can creep into your experiment from many sources

produceconsistent errors, either a fixed amount (like 1 lb) or a proportion (like 105% of the true value).If you repeat the experiment, you’ll get the same error.

Question 21

Random error

Answer 21

errors in the study that occur due to chance

has no pattern. One minute your readings might be too small. The next they might be too large. You can’t predict random error and these errors are usually unavoidable.

They areunpredictableandunavoidable even if the experiments are repeated

example: the temperature reading of a solution varies within each user or having small sample size increases the uncertainties of conclusions being drawn

Question 22

How to reduce random errors

Answer 22

Using an average measurement from a set of measurements, or Increasing sample size.

Question 23

3 types of systematic errors

Answer 23

Observer bias - incorrect reporting or perception of the measurement of the observer

Instrument bias - results from a faulty instrument or improperly calibrated instrument

Subject bias - distortion of the measurement by the study subject

Question 24

Observer bias

Answer 24

incorrect reporting or perception of the measurement by the observer e.g habit of rounding up/down measurements
e.g habit of rounding up or down measurements

Question 25

Instrument bias

Answer 25

results from a faulty instrument or improperly calibrated instrument
e.g using an improperly calibrated weighing scale

Question 26

Subject bias

Answer 26

distortion of the measurement by the study subject

e.g a lung cancer patient exaggerates the number of cigarettes he smokes each day that causes his conditions

Question 27

Importance of precision

Answer 27

Precision has a very important influence on the power of a study (the ability of a study to detect a difference that is real)

The more precise the measurement, the greater the statistical power at a given sample size to estimate mean values and to test hypothesis (proposed explanation for a phenomenon)

This is a function of random error, the greater the error, the less precise the measurement

Question 28

3 types of random errors

Answer 28

Observer validity - variability in the measurement caused by the observer
Instrument validity - variability in the measurement due to changing environmental factors
Subject validity - intrinsic biology variability in the subjects caused by various factors

Question 29

Observer validity

Answer 29

Variability in the measurement caused by the observer.

E.g. the observer’s skill in operating the instrument or data collection methods such as asking questions

Question 30

Instrument validity

Answer 30

Variability in the measurement due to changing environmental factors.

E.g. temperature, aging mechanical components

Question 31

Subject validity

Answer 31

Intrinsic biology variability in the subjects caused by various factors.

E.g. the subjects’ mood, daily food intake or time of last medication taken

Question 32

Accuracy

Answer 32

Accuracy is a function of systematic error (bias), the greater the error, the less accurate the variable. The three main classes of measurement error noted for precision each have their counterparts here.

The accuracy of a measurement is best assessed by comparing it, when possible to a “gold standard”. This is a reference technique that is considered to be accurate.

Question 33

Observer bias (accuracy)

Answer 33

Observer bias – is a distortion, conscious or unconscious, in the perception or reporting of the measurement by the observer. It may represent systematic errors in the way an instrument is operated e.g. the tendency to round down measurements, or in the way an interview is carried out e.g. the use of leading questions etc.

Question 34

Instrument bias (accuracy)

Answer 34

Instrument bias – this can result from a faulty function of a mechanical instrument. A scale that is not calibrated recently may have drifted downward, producing consistently low BW readings

Question 35

Subject bias (accuracy)

Answer 35

Subject bias – is a distortion of the measurement by the study subject, e.g. reporting an event. Patients with lung cancer who believe that the number of cigarettes smoked per day is the cause of the disease would exaggerate the number of cigarettes they smoke per day

Question 36

Ideal control group

Answer 36

would comprise patients with the same characteristics of those in the experimental group, including age, race, maturation stage, same tendency for the disease

Question 37

2 types of external control group

Answer 37

Defined external control and undefined external control

an external control group is a group of patients that is external to the study, of similar disease severity (at equipoise) but who received a different treatment.

Question 38

Defined external control group

Answer 38

Group of patients treated at an earlier time i.e. historical control
Group of patients treated during the same time period but in another setting

Question 39

Non-defined external control group

Answer 39

A comparator group based on general medical knowledge of outcome without reference to specific control population

Question 40

Why it is not desirable to have an external control group?

Answer 40

1. This group is not part of the same randomized study, and also not derived from the same population as the concurrently controlled group
2. Since it is not from the same population, blinding and randomization are not possible. Thus, the risk of bias of the study is high.
3. Furthermore, the groups may not be similar with respect to other factors than the study treatment, which greatly affects the study outcome

Question 41

Not concurrently controlled

Answer 41

external

Question 42

Concurrently controlled

Answer 42

different active treatment, different dose/religion, no treatment and placebo

Question 43

Dose related concurrent control

Answer 43

Subjects are randomized to one of several fixed dose groups with or without a placebo group

Question 44

Advantages to include a placebo group

Answer 44

It avoids studies that are uninterpretable because all doses produces similar effects so that one cannot assess whether all doses are equally ineffective or effective

It permits an estimate of the total pharmacologically mediated effect of treatment although the estimate may not be precise if the dosing groups are small

As the drug placebo difference is generally larger than inter dose difference, use of a placebo may permit smaller sample size

Question 45

Placebo concurrent control

Answer 45

The name of the control suggests that its purpose is to control for “placebo” effect i.e. improvement in a subject resulting from thinking that he or she is taking a drug

Subjects are RANDOMLY assigned to a test treatment or to an identical – appearing treatment that DOES NOT contain the test drug

They seek to show a difference between
Treatments when they are studying effectiveness OR
Lack of difference in evaluating safety measurement

Question 46

Active concurrent control

Answer 46

Subjects are randomly assigned to the test treatment or to an active control treatment
Such trials are usually double blinded, but this is not always possible

Objectives
To show efficacy of the test treatment by showing it is as good as a known effective treatment
To show efficacy by showing superiority of the test treatment to the active control
Used to compare safety of two treatment

When comparing the test drug with an active control, it is important to choose an appropriate dose and dose regimen of control and test drugs

Question 47

Randomization

Answer 47

Randomization is a process where people are assigned to groups by chance (i.e. randomly assigned).

This helps prevent bias.
Ensures that each patient has an equal chance of receiving any of the treatments under study, generate comparable intervention groups, which are alike in all the important aspects except for the intervention each groups receives

Bias occurs when a trial’s results are affected by human choices or other factors not related to the treatment being tested. For example, if doctors could choose which patients to assign to which groups, some might assign healthier patients to the treatment group and sicker patients to the control group, without meaning to. This might affect trial results. Randomization helps ensure that this does not happen.

Question 48

What is a external control group

Answer 48

An externally controlled trial is one in which the control group consists of patients who are not part of the same randomized study as the group receiving the investigational agent; i.e., there is no concurrently randomized control group. The control group is thus not derived from exactly the same population as the treated population. Usually, the control group is a well documented population of patients observed at an earlier time (historical control), but it could be a group at another institution observed contemporaneously, or even a group at the same institution but outside the study.

Limited by its ability to minimize bias (Patient, observer and analyst) and in many cases make the design unsuitable

Groups may be dissimilar with respect to a wide range of factors other than the study treatment that could affect outcome (many confounding variables)

Blinding & Randomization are NOT possible

Question 49

Benefits of randomization

Answer 49

1) eliminates the selection bias

2) balances the groups with respect to many known and unknown confounding or prognostic variables

Question 50

Bias

Answer 50

Biasis a prejudice in favor of or against one thing, person, or group compared with another usually in a way that’s considered to be unfair. Biases may be held by an individual, group, or institution and can have negative or positive consequences.

One’s age, gender, gender identity physical abilities, religion, sexual orientation, weight, and many other characteristics are subject to bias.

Question 51

Conscious bias

Answer 51

Explicit bias

Question 52

Unconscious bias

Answer 52

implicit bias

Social stereotypes about certain groups of people that individuals form outside their own conscious awareness. Everyone holds unconscious beliefs about various social and identity groups, and these biases stem from one’s tendency to organize social worlds by categorizing.

Unconscious bias is far more prevalent than conscious prejudice and often incompatible with one’s conscious values. Certain scenarios can activate unconscious attitudes and beliefs. For example, biases may be more prevalent when multi-tasking or working under time pressure.

Question 53

4 ways of randomization

Answer 53

1. Systematic sampling
2. Simple random sampling
3. Stratified sampling
4. Cluster sampling

Question 54

Simple random sampling

Answer 54

Select a subset of individuals (sample) from a larger set (population).

Each individual is chosen randomly and entirely by chance, such that each individual has the same probability of being chosen at any stage during a sampling process

It is a fair way to select a sample, it will be reasonable to generalize the results from the sample back to the population

Procedure – Use a table of random numbers e.g. a computer random number generator or mechanical device to select the sample

Question 55

Example of random sampling

Answer 55

Establish our sampling frame

• Sampling frame – source material or device from which a sample is drawn, list of all those within a population who can be sampled.
• Go through the clinic’s records to identify every hypertensive patient that visited in the last 6 months

From these patients who had visited the clinic in the last 6 months to seek help for hypertension, we decide to sample 100 patients

To draw the samples, we may use computers to generate a series of random numbers

Question 56

Systematic sampling

Answer 56

Systematic sampling involves selecting members from a larger population based on a random starting point but with a fixed and periodic interval.

System sampling is relatively more straightforward than random sampling but is also MORE likely to lead to bias and errors.

It should only be applied if the given population is homogenous.

Question 57

Equation for systematic sampling

Answer 57

k = N/n
k = 8000 / 1000
k - systematic sampling interval
N = population size
n = sample size

Question 58

Meaning of sampling interval is 8

Answer 58

Hence every 8th, 17th, 25th etc. patient will be chosen.

The starting point is chosen at random (not necessarily need to start from the first patient!!)

Question 59

Appropriate use of systematic sampling

Answer 59

This sampling is more likely to lead to bias as compared to simple random sampling

Errors can be caused by natural periodicities in the population and may allow the PI to predict and perhaps manipulate those who will be in the sample

It should only be applied if the given population is homogenous

Question 60

Stratified sampling

Answer 60

Stratified sampling involves dividing a population into homogenous subgroups also known as strata.

• Each strata is formed based on the shared attributes or characteristics in every individual.

A random sample from each stratum is taken in a number that is proportional to the stratum’s size when compared to the population.

These subsets of the strata are then pooled to form a random sample.

Question 61

Strata

Answer 61

Division of population into homogenous subgroups

• Group them first – strata
• Grouping them according to some characteristics e.g. colour, look etc.

Then use simple random sampling or systemic sampling

Question 62

Subsets of strata

Answer 62

Each strata is formed based on subject’s shared attributes or characteristics.

A random sample from each stratum is taken in a number that is proportional to the stratum’s size when compared to the population.

These subsets of the strata are then pooled to form a random sample

Question 63

Advantage of stratified sampling

Answer 63

An advantage of using stratified sampling is that the not only the strata represents the overall population, but also the key subgroups of the population.

Hence it is the (MOST representative of a population).

The size of the sample in each stratum is taken in proportion to the size of the stratum is called proportion allocation.

Question 64

Example of stratified sampling

Answer 64

The size of each stratum is taken in proportion to the size of the stratum.

5 out of 10 blue stickmen were picked from sub-group 1.

3 out of 6 orange stickmen were picked from sub-group 2.

2 out of 4 green stickmen were picked from sub-group 3.

Therefore, the percentage of:
Blue stickmen = 50%
Orange stickmen = 30%
Green stickmen = 20%

Question 65

Cluster sampling

Answer 65

Random sampling of natural groupings of individuals in the population.

Useful when the population is widely distributed and dispersed, and impractical to list and sample from all its elements

Question 66

4 steps in cluster sampling

Answer 66

1. Divide the population into clusters – using geographical boundaries
2. Clusters are randomly selected to be sampled
3. Clusters to be sampled are visited by field team who will make a list of all the addresses in each cluster
4. From these addresses, the team randomly selects a subsample for the study

Question 67

Appropriate use of cluster sampling

Answer 67

Useful when the population is widely distributed and dispersed and it is impractical to list and sample from all its elements

Question 68

Process of cluster sampling

Answer 68

Divide the population into clusters – using geographical boundaries

Clusters are randomly selected to be sampled

Clusters to be sampled are visited by field team who will make a list of all the addresses in each cluster

From these addresses, the team randomly selects a subsample for the study

Question 69

Blinding

Answer 69

Procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to.

Important aspect of any clinical trial to avoid conscious or unconscious bias in the design and execution of the clinical trial.

Question 70

How to overcome random error

Answer 70

averaging

Question 71

When is systematic sampling appropiate

Answer 71

Appropriate here as you only need a fraction of the total population in XYZ Primary School for the study.