Dr.Vithal .K.

Dhulkhed Professor and Head Department of Anaesthesiology KIMS (Medical College) KARAD Maharashtra

You have a Research Question

Does the duration of analgesia in laboring patients after intrathecal bupivacaine is more compared with ropivacaine ?

Design a study to prove or disprove

What type of study ? It depends on research question Do you want to test hypothesis ?

State Null Hypothesis: e.g.There is no difference in

the duration analgesia after intrathecal administration of either Bupivacaine or ropivacaine Define the poulation What is the clinically important effect size ? When do you say null hypothesis is rejected ? ( crtical value)

Is the study powerfull enough so that people can really believe the result or apply the the whole population

sample result to

and how much is that power (1- error) ?

Select an adequate sample size for the answers

Why Sample Size Calculation?

Large Sample: Cost, Time and Personnel Unethical

Small Sample: Unable to detect clinically important results. Not very small and not very large

Clinical Significance:

In 1966 Caluson et al had shown 25% reduction in mortality due to proparanolol among MI patients. But that was not significant. 66 cases and 64 controls were studied.

Is 25% important?

Clinical Significance (Contd..):

If 25% reduction in mortality is clinically relevant, then why sample size calculation?. The worry is that the difference in mortality, ie.,25% could have occurred by chance alone. In order to prove that the 25% reduction in mortality is statistically significant, they should have studied 200 patients in each arm.

Types of Problems in Medical Research:

Estimation: (Prevalence/Descriptive Study) - Given proportion or Prevalence - Given mean and standard deviation Testing Hypothesis:(Cohort/Case Control/Clinical Trial) - Given two proportion or incidence rates - Given two group means and standard deviations

The parameters required

to calculate sample size depend upon the type of study Prevalence,Incidence,Rate, Sensitivity, Specificity, Mean, Variance, SD, Odds Ratio (OR), Correlation Coefficient (r) Effect Size Errors

Type I error and Type II error

eality
Null True
Null False

Innocent

ri inal

Null True

Innocent

orrect
Type II error (or) Beta error

Judges decision

Null-False

ri inal Type I error (or) Alpha error

orrect ower = (1-Beta)

Type I error and Type II error

Reality
Null - True Null - False

Null -True
Researchers decision

Correct

Type II error (or) Beta error

Null-False

Type I error (or) Alpha error

Correct Power = (1-Beta)

Type I ( lpha) Error

------------------------------------------------p Zw ------------------------------------------------0.05 0.01 0.001 1.96 2.57 3.29

------------------------------------------------Type II (Beta) Error ------------------------------------------------p ZF ------------------------------------------------0.10 1.282 0.15 1.037 0.20 0.842 0.25 0.675 -------------------------------------------------

Power
TRUTH Ho D Type I Error E Not Reject H o E - level C I Type I Error S I E level Reject Ho O N HA
Power Type II 1 - Error F F Type II Power F Error

Power is probability of rejecting Ho when Ha is true

Power
Power is a measure of doing the right thing when Ha is true! Higher power is better (the closer the power is to 1.0 or 100%) We can calculate power for a given study if we specify a specific Ha

Types of Errors:
After any decision, questions remain to be answered.

1. What is the probability that difference shown, occurred due to chance?.

p is less than 5 in a hundred (p<.05).

Types of Errors (Contd..):

2. What is the probability, that if a true difference of a stated magnitude existed, but the study would not have picked it up as statistically significant?.

This is beta or Type II error.

Po er of the Study:
Po er: Complement of Beta error. The probability that if a true difference of stated magnitude existed then the study would have picked it up as statistically significant.

Serious Error:
Type I: Reject the null hypothesis, in fact O DIFFERENCE. (False rejection) BCG is effective, in fact No Difference between two arms

Type II: Accept the null hypothesis when it is false. BCG is not effective, in fact there is DIFFERENCE between two arms.

Estimation

Formulae & Problems

Descriptive study
Proportion or Prevalence is the parameter of our study

Where

Z pq n= 2 d

Z = Standardized Normal deviate (Z value) p = Proportion or Prevalence of interest. q = 100 - p d = Clinically expected variation.

Example
Previous post operative shivering incidence rate is 30% Treatment and other measures instituted You ould like to find out the present incidence rate ith allo able error 10% or 20%

What should be the sample size?

Example
For 10% error P=30% q=100-30=70%

Allowable error d=10% 0f 30%=3% n > 4pq/d=4x3070/3 933 For 20% error P=30% q=100-30=70% Allowable error d=20% 0f 30%=6% n > 4pq/d=4x3070/6 234

Mean is the parameter of our study

n = Z
2

 S d 2

Where Z= Standardized Normal deviate (Z value) S = Sample standard deviation d = Clinically expected variation

Example
In a Health Survey of schoolchildren it is found that the mean haemoglobin level of 55 boys is 10.2/100ml with a standard deviation of 2.1. Consider the precision as 0.8.
Mean = 10.2 Standard = 2.1 ZE= 1.96 for E at 0.05 d = 0.8
2 2

(1.96 )  2.1 n = 2 (0.8 )

= 26

Testing Hypothesis
Formulae & Problems

Analytical study
Proportion is the parameter of our study

n=
Where

2 (Z + Z )  p  q d
2

ZE = Z value for E level ZF = Z value for F level p = average percentage between two groups q = 100 - p d = Clinically meaningful difference between two groups

Example (Qualitative)
A postgraduate student in Anaesthesia wants to take up the research project to answer the research question. Is antiemetic metoclopramide effective in reducing the incidence of vomiting after ether anesthesia ? Previous studies indicated that 60% of patients vomit after recovery from ether anaesthesia Reduction to 20% will make it clinically useful What is the sample size for a power of 0.90 % and 95% two sided significance level ?

Sample size
Literature search indicating p1 i.e. proportion of people ho vomit =
60%
20%

p2 Clinically importance reduction proportion =

Clinically importance reduction proportion = 40%

Po er = 0.90

E = 0.05 i.e. (1 0.95)

p=
n=

p 1 + 2

p 2

60 + 20 2

= 40% ; q = 1 p = 60%

2 ( d2

)2  p  q

2  ( 1.96 1.282 ) 2  60  40 = ( 40 ) 2

n = 32 or 35 for each group.

Total approx = 70

Odds Ratio is the parameter of our study Randomised Clinical Trial

\

Incidence of headache among patients

18 - 44 yrs in hospital given spinal anaesthesia

Group A with 25 g Quincke needle

This according to previous experience is 2/100 =0.02

Group B patients with 25 g Whitaker needle Objective to detect a statistically significant less level of
headache incidence among Group B. This level should be 4 times less i.e. OR = 0.25 Calculate the required sample size.

Solution
P1 = 2% or 0.02
p1  OR = {1  p1( OR  1 )}

OR = = 0.25

P2 = The estimation of proportion of Group B patients =0 .005

p =

p1 + p 2 2

= 0.0125

q = 0.9875

E = 0.05
n= 2 ( +

(ZE = 1.65 )

F = 0.10 Po er = 0.90 (ZF = 1.282)

)2  p  q d2

Put all values and get

n = 944 for each group.

Mean is the parameter of our study

n =
Where ZE = Z value for E error ZF = Z value for F error S = Common standard deviation between two groups d = Clinically meaningful difference

(Z

+Z d

) S 2
2

Research Question
Does the duration of analgesia in laboring patients after intrathecal bupivacaine is more compared with ropivacaine ? Design a study to to answer the question

State Null Hypothesis There is no difference in the duration analgesia after intrathecal administration of either Bupivacaine or ropivacaine

Define the population by inclusion and exclusion criteria

Review the literature to know the clinically important difference or effect size Anesth Analg. 2004 Jan;98(1):235-9 A comparison of duration of analgesia of intrathecal 2.5 mg of bupivacaine, ropivacainein combined spinal epidural analgesia for patients in labor. Lim Y, Ocampo CE, Sia AT. Department of Anesthesia, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Republic of Singapore.

Review the literature The duration of labor analgesia by intrathecal (IT) local anesthetics using combined spinal-epidural technique in 40 nulliparous parturients with IT 2.5 mg bupivacaine (group B), ropivacaine (group R). The duration was the longest in group B P < 0.05 (mean +/- SE, 76.3 +/- 5.9 min vs 52.6 +/- 4.0 min ,). IMPLICATIONS: Intrathecal 2.5 mg bupivacaine significantly prolongs the duration of analgesia in laboring patients compared with ropivacaine

Does the duration of analgesia in laboring patients after intrathecal bupivacaine is more compared with ropivacaine ?

Design Double blind RCT Parameters Effect size: 25 minutes more with ropivacaine SD common for 2 groups = 24 minutes value =0.05 Z =1.65 value =0.10 Power=90% Z = 1.282

Sample Size calculation

2 2

n =

(Z

+ Z d

) S
2

2

n =

( 1 . 96

1 . 28 )  24  2 2 25

= nearly 20 for each two groups

Issues:
Need to differentiate between Descriptive and Testing Hypothesis or analytical studies. Different formulae depending upon the type of study Incorporate drop out rates. Cluster designs should inflate the size based on Design effect.

Difference between two means is the parameter of our study Example 1 The lung function of two groups of men is to be compared. Using forced expiratory volume (FEV). Literature search: SD 0.5l Mean difference of clinical interest: 0.25l Two sided significance level = 0.05 ( Z2w = 1.96 ) Power = 80% ( ZF = 0.842) n > 2 [( Z w + Z F ) SD / D]2 = 2 [ ( 1.96 + 0.842 ) ( 0.5 )/ 0.25 ]2 = 62.8 63 men in each group

Example 2
Duration of ICU study (in hours):
o Dose ean D n i h Dose

5 (

= )  5 = ( 4 5 )   *

n=

n=

Describing Variability
Example: n = 5 systolic blood pressures (mm Hg) X 1= 120 X 2= 80 X 3= 90 X 4= 110 X 5= 95

Describing Variability
Example: n = 5 systolic blood pressures (mm Hg) Recall, from earlier: X = 99 mm HG Now:
X i X = 120 110
2 2 2 2

i=1

= 1020

Describing Variability
Sample Variance
n

i= 1

X i X n 1

1020 = = 255 4

s 2 = 255 Sample standard deviation (SD) s= = 15.97 (mm Hg)

Notes on s
The bigger s is, the more variability there is s measures the spread about the mean s can equal 0 only if there is no spread
All n observations have the same value

The units of s is the same as the units of the data (for example, mm Hg)

Often abbreviated SD s2 is our best estimate of the population variance W2 Interpretation

Most of the population will be within about 2 standard deviations of the mean For a normally (Gaussian) distributed population, most is about 95%

Notes on s

Distributions of Blood Pressure

.4

.3

68%
.2

Mean = 125 mmHG s = 14 mmHG

95%
.

99.7%
0 83 97 25 39 53 67

The 68-95-99.7 rule applied to the distribution of systolic blood pressure in men.

Example
Measure systolic blood pressure on random sample of 100 students Sample size n = 100 Sample mean X = 123.4 mm Hg Sample SD s = 14.0 mm Hg 14 = 1 . 4 mmHg SEM = 100

Relative risk (RR) and Odds ratio (OR)

Cohort study

The director of community Health observes that rural women have a higher rate of miscarriage than urban women since farming is their primary occupation relying heavily on organophosphorous pesticide. He hypothesizes that rate of miscarriage is related to exposure to this pesticide. Test this at alpha = 0.01. Miscarriage-No miscarriage - Total Exposed - 30 - 70 - 100 Not exposed 10 90 - 100 - 40 - 160 - 200

Determine relative risk (RR) and odds ratio (OR) What are confidence intervals of OR. Determine the magnitude of the public health problem posed by such exposure. Calculate attributable risk, population attributable risk Attributable fraction, Total population attributable fraction

Quantifying risk

Relative Risk = Incidence of disease in exposed group Incidence in non exposed group = 30/100 = 3 10/100 Odds Ratio = Odds that exposed individual has disease Odds that non exposed has disease = 30 / 70 = 3.86 10/90

Example 1 From a pilot study it was reported that 28% post operative had Shivering. It was decided to have 95% C.I with 5% variability in the estimated 28%. How many patients are necessary to conduct the study.
P = 28% q = 72% ZE= 1.96 for E at 0.05 d = 5%

(1.96)2 28 72 = 158 n = 2 (5 )

Odds Ratio is the parameter of our study Case Control Study

\

The controls non pregnant women 18 - 44 yrs in hospitals.

5% were using IUDs at last menstrual period.

The cases same age agroup , admitted with a diagnosis of

ectopic pregnancy.

Objective to detect a statistically significant level of ectopic

pregnancy among IUD users. This level should be twice the level for non-IUD users (I.e. OR = 2) if such a relative difference exists. Calculate the required sample size.

Example (Qualitative)
ta lit

ea i L ta l se se ( ( 6 ( ) ) )

liv e

ta l

P = (16.7+4.2)/2=10.4% q = 89.6% ZE= 1.96 for E at 0.05 ZF = 1.282 for F at 0.10

( 1.96 1.282 )2  10.4  89.6  2 = 125 n = 2 ( 12.5 )

in each group