Basic Statistical Concepts

Chapter 2 Reading instructions

2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8

Introduction: Not very important

Uncertainty and probability: Read
Bias and variability: Read
Confounding and interaction: Read
Descriptive and inferential statistics: Repetition
Hypothesis testing and p-values: Repetition*
Clinical significance and clinical equivalence: Read
Reproducibility and generalizability: Read

*) Read extra material

Bias and variability

E [ ]
Bias: Systemtic deviation from the true value
Design, Conduct, Analysis, Evaluation
Lots of examples on page 49-51

Bias and variability

Larger study does not decrease bias

n +

Distribution of sample means:

-10

-7

-4

n=40

mm Hg

-10

Population mean
bias

= population mean

Drog X - Placebo

Drog X - Placebo

Drog X - Placebo

-7

-4

n=200

mm Hg

-10

-7

-4

N=2000

mm Hg

Bias and variability

Amount of difference between observations
True biological:

Variation between subject due

to biological factors (covariates)
including the treatment.

Temporal:

Variation over time (and space)

Often within subjects.

Measurement error:

Related to instruments or observers

Design, Conduct, Analysis, Evaluation

Bias and variability

Y = X +
Variation in = Explained + Unexplained
observations
variation
variation

Bias and variability

Is there any difference between drug A and drug B?

Drug A
Drug B

Outcome

Bias and variability

Model: Yij = i + xij + ij

Y=B+x
B

Y=A+x

A
x=age

Confounding
The effect of two or more factors can not be separated
Example: Compare survival for
surgery and drug

Survival

Life long treatment with drug

Surgery at time 0

Looks ok but:

Surgery only if healty enough

Patients in the surgery arm may take drug
Complience in the drug arm May be poor

Time

Confounding
Can be sometimes be handled in the design
Example: Different effects in males and females
Imbalance between genders affects result
Stratify by gender

Gender

R
B
Balance on average

B
A

Always balance

Interaction
The outcome on one variable depends
on the value of another variable.
Example

Interaction between two drugs

A

B
A=AZD1234
Wash
out

R
B

B=AZD1234 +
Clarithromycin
A

Interaction
Plasma concentration (mol/L)
linear scale

Mean
5
4

AZD1234
AZD0865
alone

Combination of clarithromycin
and AZD0865
AZD1234

2
1
0
0

12

16

20

24

Time after dose

AUC AZD1234:

19.75 (mol*h/L)

AUC AZD1234 + Clarithromycin:

Ratio:

36.62 (mol*h/L)
0.55 [0.51, 0.61]

Interaction
Example:

Treatment by center interaction

Treatment difference in diastolic blood pressure
15
10
5
mmHg

0
-5

10

15

20

25

30

-10
-15
-20
-25
Ordered center number

Average treatment effect: -4.39 [-6.3, -2.4] mmHg

Treatment by center: p=0.01
What can be said about the treatment effect?

Descriptive and inferential

statistics
The presentation of the results from a clinical trial
can be split in three categories:

Descriptive statistics
Inferential statistics
Explorative statistics

Descriptive and inferential

statistics
Descriptive statistics aims to describe various
aspects of the data obtained in the study.
Listings.
Summary statistics (Mean, Standard Deviation).
Graphics.

Example?

Descriptive and inferential

statistics
Inferential statistics forms a basis for a conclusion
regarding a prespecified objective addressing the
underlying population.

Confirmatory analysis:
Hypothesis

Results

Conclusion

Descriptive and inferential

statistics
Explorative statistics aims to find ineresting results that
Can be used to formulate new objectives/hypothesis for
further investigation in future studies.

Explorative analysis:
Results

Hypothesis

Hypothesis testing, p-values and

confidence intervals
Objectives
Variable
Design

Estimate
p-value
Confidence interval
Statistical Model
Null hypothesis

Results
Interpretation

Hypothesis testing, p-values

Statistical model: Observations X = ( X 1 , K X n ) R
from a class of distribution functions
n

= {P : }

Hypothesis test: Set up a null hypothesis: H0: 0

and an alternative H1: 1

Reject H0 if

X Sc R n

P(X S c | 0 ) <

Rejection region

Significance level

p-value: The smallest significance level for which the

null hypothesis can be rejected.

Confidence intervals
Let (X, * )

1 if H 0 : = * rejected
=
0 if H 0 : = * not rejected

(critical function)

Confidence set: C (X ) = { : (X, ) = 0}

The set of parameter values correponding to hypotheses
that can not be rejected.
A confidence set is a random subset C (X )
covering the true parameter value with probability at
least 1 .

Example
Objective: To compare sitting diastolic blood pressure (DBP) lowering effect of
hypersartan 16 mg with that of hypersartan 8 mg
Variable: The change from baseline to end of study in sitting DBP
(sitting SBP) will be described with an ANCOVA model,
with treatment as a factor and baseline blood pressure
as a covariate

Model:

yij = + i + (xij - x) + ij

Parameter space: R 4

( 1 + 2 + 3 = 0)

treatment effect
i = 1,2,3
{16 mg, 8 mg, 4 mg}

Null hypoteses (subsets of

H01: 1 = 2 (DBP)
H02: 1 = 2 (SBP)
H03: 2 = 3 (DBP)
H04: 2 = 3 (SBP)

R 4):

Example contined
Hypothesis

Variable

LS Mean

CI (95%)

p-value

1: 16 mg vs 8 mg

Sitting DBP

-3.7 mmHg

[-4.6, -2.8]

<0.001

2: 16 mg vs 8 mg

Sitting SBP

-7.6 mmHg

[-9.2, -6.1]

<0.001

3: 8 mg vs 4 mg

Sitting DBP

-0.9 mmHg

[-1.8, 0.0]

0.055

4 : 8 mg vs 4 mg

Sitting SBP

-2.1 mmHg

[-3.6, -0.6]

0.005

This is a t-test where the test statistic follows a t-distribution

Rejection region:

{X : T (X ) > c}
-c

P-value: The null hypothesis can pre rejected at

-4.6

-2.8

T (X )

< 0.001
1 2

Statistical and clinical

significance
Statistical significance:

Is there any difference between

the evaluated treatments?

Clinical significance:

Does this difference have any

meaning for the patients?

Health ecominical relevance: Is there any economical

benefit for the society in
using the new treatment?

Statistical and clinical

significance
A study comparing gastroprazole 40 mg and mygloprazole 30 mg
with respect to healing of erosived eosophagitis after 8 weeks
treatment.

Drug

Healing rate

gastroprazole 40 mg

87.6%

mygloprazole 30 mg

84.2%

Cochran Mantel Haenszel p-value = 0.0007

Statistically significant!
Clinically significant?
Health economically relevant?