Statistics: An introduction to sample size calculations

Rosie Cornish. 2006.

1 Introduction
One crucial aspect of study design is deciding how big your sample should be. If you increase
your sample size you increase the precision of your estimates, which means that, for any given
estimate / size of effect, the greater the sample size the more “statistically significant” the
result will be. In other words, if an investigation is too small then it will not detect results
that are in fact important. Conversely, if a very large sample is used, even tiny deviations from
the null hypothesis will be statistically significant, even if these are not, in fact, practically
important. In practice, this means that before carrying out any investigation you should have
an idea of what kind of change from the null hypothesis would be regarded as practically
important. The smaller the difference you regard as important to detect, the greater the
sample size required.
Factors such as time, cost, and how many subjects are actually available are constraints that
often have to be taken account of when designing a study, but these should not dictate the
sample size — there is no point in carrying out a study that is too small, only to come up with
results that are inconclusive, since you will then need to carry out another study to confirm or
refute your initial results.
There are two approaches to sample size calculations:

• Precision-based
With what precision do you want to estimate the proportion, mean difference . . . (or
whatever it is you are measuring)?

• Power-based
How small a difference is it important to detect and with what degree of certainty?

2 Precision-based sample size calculations

Suppose you want to be able to estimate your unknown parameter with a certain degree of
precision. What you are essentially saying is that you want your confidence interval to be a
certain width. In general a 95% confidence interval is given by the formula:

Estimate ± 2(approx)1 × SE
where SE is the standard error of whatever you are estimating.
1. This is because 95% confidence intervals are usually based on the normal distribution or a t-distribution —
for a normal distribution the value is 1.96; for t-distributions the value is generally just over 2.

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The formula for any standard error always contains n, the sample size. Therefore, if you
specify the width of the 95% confidence interval, you have a formula that you can solve to
find n.

Example 1
Suppose you wish to carry out a trial of a new treatment for hypertension (high blood pressure)
among men aged between 50 and 60. You randomly select 2n subjects. n of these receive
the new treatment and n receive a the standard treatment, then you measure each subject’s
systolic blood pressure. You will analyse your data by comparing the mean blood pressure
in the two groups — i.e. carrying out an unpaired t-test and calculating a 95% confidence
interval for the true difference in means.
You would like your 95% confidence interval to have width 10 mmHg (i.e. you want to be
95% sure that the true difference in means is within ± 5 mmHg of your estimated difference
in means. How many subjects will you need to include in your study?
We know that the 95% confidence interval for a difference in means is given by
s
1 1
(x̄1 − x̄2 ) ± 2(approx) × sp +
n1 n2
r q
to be equal to 5 ⇒ sp n11 + n12 = sp n
2 ≈ 2.5
q
1 1
Hence, we want 2 × sp n1
+ n2
(since we are aiming for groups of the same size).
In order to work out our sample sizes we therefore need to know what sp is likely to be. This is
either known from (a) previous experience (i.e. knowledge of the distribution of systolic blood
pressure among men with hypertension in this age group), (b) using other published papers
on blood pressure studies in a similar group of people or (c) carrying out a pilot study. I have
used option (b) to get a likely value for sp of 20 mmHg.
This gives s
2 n 20 2
 
2.5 = 20 ⇒ = ⇒ n = 128 (in each group)
n 2 2.5
If you wanted your true difference in means to be within ±2.5 mmHg rather than ±5 mmHg
of your estimate, this would become
2
n 20

= ⇒ n = 512
2 1.25
i.e. if you want to increase your precision by a factor of 2, you have to increase your sample
size by a factor of 4. In general, if you want to increase your precision by a factor k, you will
need to increase your sample size by a factor k 2 . This applies across the board — i.e. whether
you are estimating a proportion, a mean, a difference in means, etc. etc.

Example 2
Supposing you are investigating a particular intervention to reduce the risk of malaria mortality
among young children under the age of five in The Gambia, in West Africa. You know that
the risk of dying from malaria in this age group is about 10% and you want the risk difference
to be estimated to within ±2%. A 95% confidence interval for a difference in proportions is

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given by
s s
p1 (1 − p1 ) p2 (1 − p2 ) p1 (1 − p1 ) + p2 (1 − p2 )
(p1 − p2 ) ± 1.96 + = (p1 − p2 ) ± 1.96
n1 n2 n
if the sample size in each group is the same. As stated previously, we normall approximate
1.96 by 2. We therefore want
s
p1 (1 − p1 ) + p2 (1 − p2 )
≈ 0.02/2 = 0.01
n
To work out the required sample size, we usually take p1 = p2 = the value closer to 0.5,
since this would give rise to a larger standard error and therefore a larger sample size (it is
always better to err on the side of caution in sample size calculations because (a) you often
get drop-outs, so it’s better to have too many rather than too few in your sample to start with
and (b) they are never 100% exact anyway, since you base them on estimates of the standard
error, not on known values.
So, in this case we have
s
2(0.1)0.9) 2(0.1)(0.9)
= 0.01 ⇒ n = = 1800 (in each group)
n 0.012

To summarise, in order to carry out any precision-based sample size calculation you need to
decide how wide you want your confidence interval to be and you need to know the formula
for the relevant standard error. Putting these together will give you a formula which can be
rearranged to find n.

3 Power-based sample size calculations

We have seen above that precision-based sample size calculations relate to estimation. Power-
based sample size calculations, on the other hand, relate to hypothesis testing. In this handout,
the formulae for power-based sample size calculations will not be derived, just presented.
Definitions
Type I error (false positive)
Concluding that there is an effect (e.g. that two treatments differ) when they do not
α = P(type I error) = level of statistical significance [= P (reject H0 | H0 true)]
Type II error (false negative)
Concluding that there is NO effect (e.g. that there is no difference between treatments)
when there actually is.
β = P(type II error) [= P (accept H0 | H1 true)]
Power
The (statistical) power of a trial is defined to be 1 − β [= P (reject H0 | H1 true)]

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3.1 Power calculations: quantitative data
Suppose you want to compare the mean in one group to the mean in another (i.e. carry out
an unpaired t-test). The number, n, required in each group is given by

2s2
n = f (α, β) ·
δ2
Where:
α is the significance level (using a two-sided test) — i.e. your cut-off for regarding the result
as statistically significant.
1 − β is the power of your test.
f (α, β) is a value calculated from α and β — see table below.
δ is the smallest difference in means that you regard as being important to be able to detect.
s is the standard deviation of whatever it is we’re measuring — this will need to be estimated
from previous studies.
f (α, β) for the most commonly used values for α and β
β
α 0.05 0.1 0.2 0.5
0.05 13.0 10.5 7.9 3.8
0.01 17.8 14.9 11.7 6.6
Example
Returning to the blood pressure example. Suppose we want to be 90% sure of detecting a
difference in mean blood pressure of 10 mmHg as significant at the 5% level (i.e. power =
0.9, β = 0.1, α = 0.05). We have, from above, s = 20 mmHg. Using the table, we get
f (α, β) = 10.5. This gives
2s2 2(20)2
n = f (α, β) · = 10.5 · = 84
δ2 102
You would need 84 subjects in each group.
Obviously, if you increase the power or want to use a lower value for α as your cut-off for
statistical significance, you will need to increase the sample size.

3.2 Power calculations: categorical data

Suppose we are comparing a binary outcome in two groups of size n. Let
p1 = proportion of events (deaths/responses/recoveries etc.) in one group
p2 = proportion of events in the other group
We need to choose a value for p1 − p2 , the smallest practically important difference in pro-
portions that we would like to detect (as significant). We also need to have some estimate of
the proportion of events expected. This can often be obtained from routinely collected data
or previous studies.
The number of subjects required for each group is given by
p1 (1 − p1 ) + p2 (1 − p2 )
n= · f (α, β)
(p1 − p2 )2

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Example
A new treatment has been developed for patients who’ve had a heart attack. It is known that
10% of people who’ve suffered from a heart attack die within one year. It is thought that a
reduction in deaths from 10% to 5% would be clinically important to detect. Again we will
use α = 0.05 and β = 0.1. We have p1 = proportion of deaths in placebo group = 0.1, p2 =
proportion of deaths in treatment group = 0.05. This gives

0.1(0.9) + 0.05(0.95)
n= · 10.5 = 578
(0.1 − 0.05)2

Thus, 578 patients would be needed in each treatment group to be 90% sure of being able to
detect a reduction in mortality of 5% as significant at the 5% level.
The size of difference regarded as clinically important to be able to detect has a strong effect
on the required sample size. For example, to detect a reduction from 10% to 8% as significant
(using the same α and β as above) 4295 patients would be needed in each treatment group.
This may be clinically reasonable (since any reduction in mortality would probably be regarded
as important) but perhaps too expensive. Conversely, to detect a reduction from 10% to 1%
as significant, 130 patients would be needed in each group. This kind of reduction would
perhaps be over-optimistic and therefore a trial of this size would be unlikely to be conclusive.

4 Further notes
1. Sample size formulae in other situations
In this handout I have only presented sample size calculations for certain types of analysis.
Similar formulae can be obtained for other types of analysis by reference to appropriate
texts.

2. Increasing power or precision without having to increase sample size

As indicated previously, certain constraints (cost etc.) may mean that the required
sample size is impossible to achieve. In these situations it may be possible to increase
precision or power by changing the design of the study. For example, using a paired
design can often be more efficient since you are considering individual (within-subject)
differences rather than between-subject differences; the former are usually less variable
than the latter (i.e. the standard error is lower) and therefore the sample size required
to detect a given difference will be lower.

3. Allowing for non-response / withdrawals

In most studies, particularly those involving humans, there is likely to be a certain amount
of data “lost” (or never gathered) from the original sample. This could be for a variety
of different reasons: non-response (e.g. to a survey); subjects deliberately withdrawing
from a study or getting “lost” in some other way (e.g. cannot be traced); subjects
in a clinical trial not following their allocated treatment; or missing data (e.g. on a
questionnaire). Allowance should be made for this when determining the sample size —
i.e. the sample size should be increased accordingly. The extent to which this is needed
should be guided by previous experience or a pilot study.