Pass 15 - Mendelian Randomization With a Binary Outcome

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Pass 15 - Mendelian Randomization With a Binary Outcome

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com

Chapter 851

Mendelian

Randomization with a

Binary Outcome

Introduction

This module computes the sample size and power of the causal effect in Mendelian randomization studies with a

binary outcome. This analysis is often used in observational studies where clinical trials are not possible.

Analogous to randomized clinical trials (RCT), Mendelian randomization (MR) divides subjects into two or more

groups. However, MR uses a genetic variable, such as the state of a certain gene, to form the groups. The state of

the gene is assumed to be random. Using two-stage least squares and making several assumptions, the causal

impact of an exposure variable on the outcome variable can be measured.

For further reading, we recommend the book by Burgess and Thompson (2015) which is completely devoted to

this topic. We also recommend the paper by Burgess (2014).

Technical Details

The following details follow closely the results in Burgess and Thompson (2015). Assume that we are interested

in assessing the causal relationship between a dichotomous outcome variable Y and an exposure variable X using

a two-stage procedure. A genetic variable G is available to use as an instrumental variable. A sample of n will be

selected. The basic models are

ln(( = 1)) = 1 +

= +

An estimate of 1 will be obtained using a two-stage procedure. In the first stage, the regression of X on G is fit.

This equation is used to create a predicted value of X for each data row. In the second stage, a logistic regression

is fit in which the response is Y and the independent variable is the predicted value of X.

851-1

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PASS Sample Size Software NCSS.com

Mendelian Randomization with a Binary Outcome

Power Calculation

The power for a two-sided test is given by

2

Power = 1 ( = 1)( = 0) 1/2

where 1/2 is the quantile from the standard normal distribution which has 1 - /2 to the left. Also, (x) is the

cumulative standard normal distribution.

Procedure Options

This section describes the options that are specific to this procedure. These are located on the Design tab. For

more information about the options of other tabs, go to the Procedure Window chapter.

Design Tab

The Design tab contains most of the parameters and options that you will be concerned with. This chapter covers

four procedures, each of which has different effect size options. However, many of the options are common to all

four procedures. These common options will be displayed first, followed by the various effect size options.

Solve For

Solve For

This option specifies the parameter to be solved for from the other parameters. The parameters that may be

selected are Power and Sample Size.

Test

Alternative Hypothesis

Specify whether the statistical test is two-sided or one-sided.

Two-Sided

This option gives the two-sided test.

One-Sided

This option gives the approximate result for a one-sided test by making an appropriate substitution for .

Power

This option specifies one or more values for power. Power is the probability of rejecting a false null hypothesis.

Values must be between zero and one. Historically, the value of 0.80 was used for power. Now, 0.90 is also

commonly used.

A single value may be entered here or a range of values such as 0.8 to 0.95 by 0.05 may be entered.

Alpha

This option specifies one or more values for the probability of a type-I error. A type-I error occurs when you

reject the null hypothesis of equal survival curves when in fact the curves are equal.

851-2

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Mendelian Randomization with a Binary Outcome

Values of alpha must be between zero and one. Historically, the value of 0.05 has been used for a two-sided test

and 0.025 has been used for a one-sided test. You should pick a value for alpha that represents the risk of a type-I

error you are willing to take in your experimental situation.

You may enter a range of values such as 0.01 0.05 0.10 or 0.01 to 0.10 by 0.01.

Sample Size

N (Sample Size)

Enter a value for the sample size, N. This is the number of subjects in the study. You can enter one or more

positive integers greater than or equal to 3. Note that in these type of studies, very large sample sizes (50000+) are

often needed.

You may also enter a range such as 10000 to 50000 by 10000 or a list of values separated by commas or blanks

such as 2000 4000 6000 8000.

Pc (Proportion Y = 1)

Pc is the proportion of subjects in which Y = 1 in the study. If the design calls for an equal number of cases and

controls, Pc is set to 0.5.

In this definition, we adopt the common convention that if an outcome (Y) is binary, the situation in which Y = 1

is called a case and the situation in which Y = 0 is called a control. Therefore, we might have used yes, positive,

or abnormal for cases and no, negative, or normal for controls.

Range

0 < Pc < 1. Often, we plan to have Pc = 0.5.

Effect Size

OR (Odds Ratio of Y per Change in X)

Enter one or more values for the odds ratio, the parameter of interest in the study. This is the odds ratio of the

binary variable Y per a change in X of one (X).

A log-linear regression model is used to relate Y to X. The model is

ln(OR) = 1 (X) + error term

where

OR = Prob(Y = 1|X) / Prob(Y = 0|X).

OR must be a positive number greater than zero. Usually, it will be near one. Typical values are 1.5, 2, 3, 4, etc.

(XG)

Enter one or more value for (XG), the proportion of the variance of X explained by the regression of X on G. In

practice, it is estimated by the R of this regression. It is routinely very small. Values of 0.01 and 0.02 are

common. This value varies between zero and one. For mathematical reasons, it cannot be exactly 0.

851-3

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PASS Sample Size Software NCSS.com

Mendelian Randomization with a Binary Outcome

Researchers are planning an observation study to determine the causal effect of an exposure X on a binary

outcome variable Y using an instrumental variable G. They want to determine the sample sizes necessary to have

80% power and 5% significance using a two-sided test when OR is 1.5 to 3.0 by 0.5, PC is 0.5, and (XG) is 0.01

or 0.02.

Setup

This section presents the values of each of the parameters needed to run this example. First, from the PASS Home

window, load the Mendelian Randomization with a Binary Outcome procedure window by expanding

Regression and then clicking on Mendelian Randomization with a Binary Outcome. You may then make the

appropriate entries as listed below, or open Example 1 by going to the File menu and choosing Open Example

Template.

Option Value

Design Tab

Solve For ................................................ Sample Size

Alternative Hypothesis ............................ Two-Sided

Power ...................................................... 0.80

Alpha ....................................................... 0.05

Pc (Proportion of Y = 1) .......................... 0.50

OR (Odds Ratio of Y per Change in X) .. 1.5 2 2.5 3

(XG) ..................................................... 0.01 0.02

Annotated Output

Click the Calculate button to perform the calculations and generate the following output.

Numeric Results

Numeric Results for the Two-Sided, Mendelian Randomization Test of a Binary Outcome

0.8000 19097 0.500 1.5000 0.0100 0.0500

0.8000 9549 0.500 1.5000 0.0200 0.0500

0.8000 6535 0.500 2.0000 0.0100 0.0500

0.8000 3267 0.500 2.0000 0.0200 0.0500

0.8000 3739 0.500 2.5000 0.0100 0.0500

0.8001 1870 0.500 2.5000 0.0200 0.0500

0.8001 2602 0.500 3.0000 0.0100 0.0500

0.8001 1301 0.500 3.0000 0.0200 0.0500

References

Burgess, S. and Thompson, S.G. 2015. Mendelian Randomization Methods for Using Genetic Variants in Causal

Estimation. Chapman & Hall/CRC Press. New York.

Burgess, Stephen. 2014. 'Sample size and power calculations in Mendelian randomization with a single

instrumental variable and a binary outcome.' International Journal of Epidemiology, 43, pages 922-929.

Brion, M.J.A., Shakhbazov, K., Visscher, P.M. 2013. 'Calculating statistical power in Mendelian randomization

studies.' International Journal of Epidemiology, 42, pages 1497-1501.

851-4

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PASS Sample Size Software NCSS.com

Mendelian Randomization with a Binary Outcome

Report Definitions

Y is the continuous outcome variable.

X is the exposure variable.

G is the genetic variant or instrumental variable used to divide the subjects up into groups.

Power is the probability of rejecting a false null hypothesis.

N is the sample size, the number of subjects in the study.

OR (odds ratio) is the parameter of interest. It is the odds ratio of Y for a one standard deviation change in

X.

Pc(Y=1) is the proportion of subjects in the study for which Y = 1.

(XG) is the proportion of the variance of X explained by the regression of X on G.

Alpha is the probability of rejecting a true null hypothesis.

Summary Statements

A two-sided test in a Mendelian randomization study for a binary outcome variable that was

based on a sample of 19097 subjects achieves 80.0% power at a 0.0500 significance level to

detect a causal effect (odds ratio) of 1.5000 when the proportion of Y = 1 is 0.500. The

proportion of the variance of X explained by its regression on G, the instrumental variable, is

0.0100.

This report presents the calculated sample sizes for each scenario as well as the values of the other parameters.

Plots Section

851-5

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PASS Sample Size Software NCSS.com

Mendelian Randomization with a Binary Outcome

Burgess and Thompson (2015) give an example in their book of a sample size calculation. However, they only

present graphic results. We obtained numeric results using their online tool (https://sb452.shinyapps.io/power/).

The parameter settings for this example where power is 0.80, alpha = 0.05, Pc = 0.50, OR = 1.5, and (XG) is

0.03. They obtain N = 6400 (which was rounded).

Setup

This section presents the values of each of the parameters needed to run this example. First, from the PASS Home

window, load the Mendelian Randomization with a Binary Outcome procedure window by expanding

Regression and then clicking on Mendelian Randomization with a Binary Outcome. You may then make the

appropriate entries as listed below, or open Example 2 by going to the File menu and choosing Open Example

Template.

Option Value

Design Tab

Solve For ................................................ Sample Size

Alternative Hypothesis ............................ Two-Sided

Power ...................................................... 0.80

Alpha ....................................................... 0.05

Pc (Proportion of Y = 1) .......................... 0.50

OR (Odds Ratio of Y per Change in X) .. 1.5

(XG) ..................................................... 0.03

Output

Click the Calculate button to perform the calculations and generate the following output.

Numeric Results

Numeric Results for the Two-Sided, Mendelian Randomization Test of a Binary Outcome

0.8000 6366 0.500 1.5000 0.0300 0.0500

PASS calculated N as 6366 which matches the 6400 (which was rounded).

851-6

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