how to find your way through the jungle of statistics... carl-olav stiller, associate professor...

How to find your way through the jungle of statistics ...

Carl-Olav Stiller , associate professorClinical pharmacologyKarolinska University Hospital - Solna17176 Stockholm

Tel: 08-5177 3261Carl-Olav.Stiller@ki.se

Statistikens djungel - grunder

Why do we need statisticsHypothesis testing Hypothesis generating Common pitfallsParametric or non-parametric

statisticsIndependent or dependent

observations Planning of research

Why do we need statistics in research?

To test hypothesis To show similarities or differences To analyse correlations To describe findings / data

Differences or similarities ?

Do I want to show differences? Power analysis -

Which difference do I want to be able to detect?

Sensitivity and specificity

What can go wrong? We find a difference which is not true

Alpha problem We find similarity, but the groups are

different tBeta problem

Hypotes - endpointPrimary hypotesis

The aim of the study. Highest evidence

Secondary hypotesis / endpoint All other tests

Lower evidenceHypotesis generating

Lack of difference is not the same as similarity!

If you compare small groups it is hard to detect any difference.

In order to show similarities the groups have to have a certain size.

Prior to start of the study you have to define the interval for similarity.

Sensitivity or specificity

Sensitivity:May I trust a positive outcome? What is the likelyhood of a positive outcome

being true / correct ?

SpecificityMay I trust a negative outcome?What is the likelyhood of a negative

outcome being true / correct ?

Parametric or non- parametric statistics?

Non-parametric statistics: Rank order: Same, smaller, bigger

Parametric statistics: Based on normal distribution (Gauss curve)

What kind of data do I have?

Normal distribution: Parametric or non-parametric statistics

Normal distribution with cut off: Non-parametric statistics preferred If you use parametric statistics SD gets too low

and your precision seems to be higher than it is.

Rank order scale: Non-parametric statistics should be used (is

it ?) Assement scale:

Non-parametric statistics should be used (is it?)

Rank order scales: examples

Borg scale for excertion: 1-5 No to maximal excertion

Cardiac failure according to NYHA (New York heart association) 1-4

Pain intensity – for example migraine headace: 0 – no pain, 1 – some pain, 2 – moderate pain,

3 – severe pain, 4- very severe pain

Visual analog scalePain intensity

0: No pain 100: Worst imaginable pain

Problem: Subjective assessment, everyone has different

reference frames - 40 for one individual is not the same as 40 for another

Inter individual variation VAS data are often calculated with parametric

statistics - ”appropiate or not? ”

Combined assessment scales

Depressions skala - Montgomery - Åsberg Olika variabler slås ihop till ett värde

Alzheimer skala - ADAS cog, Olika förmågor som påverkas vid

Alzheimer skattas och slås ihopIntelligenskvot

Prestationer i olika test vägs samman

Parametric or non-parametric statistics ?

Common pit falls:Non-parametric data are calculated

with parametric statistics

But parametric data may also be calculated with non-parametric statistics

Control group or test before treatment and after treatment ?

Test before and after may be useful as pilot study to generate a hypothesis ”hypotesgenererande”

Control group is ”gold - standard” – better data and lower risk for false positive outcome.

Treatment of severe headache with opioids or NSAIDs i.m. at the emergency department

Harden RN, Gracely RH, Carter T, Warner G The placebo effect in acute headache management: ketorolac, meperidine,and saline in the emergency department.Headache 1996 Jun;36(6):352-6

Dependent or independent observations

Dependent observations Control before or after treatment Tissue from different regions of the

same individual

Independent observations Observations in separate individuals

Common staticaal tests comparing two or more groups

Parametric statistics Non-parametric statistics

Two groups

Independent obs. Dependent obs Independent obs. Dependent obs. Unpaired t-test Paired t-test Mann-Whitney test Wilcoxons test

Three or more groups

Independent obs. Dependent obs Independent obs. Dependent obs. One-way ANOVA (analys of variance)

Repeated measures ANOVA

Kruskall Wallis Friedman test

+ Tukey – alla par + Newman Keuls – alla par

+ Bonferroni – alla par + Bonferroni – selekterade par

+ Dunett – mot kontroll

+ Dunns test

Standard deviation SD

Standard deviation SD

Control Drug A Drug B0

20

40

60

80

Eff

ect

Standard error of the mean SEM = SD /√ n

SEM

Control Drug A Drug B0

20

40

60

80

Eff

ect

Confidence interval

Correct illustration av effect range

95 % konfidens-intervall

Control Drug A Drug B0

20

40

60

80

Eff

ect

What is a good clinical study?

Relevant patient population Sufficient size / powerClinically relevanta effect outcomeReference treatment using relevant

dosesDouble blind / randomisedSufficient follow up time Few withdrawals

Common pit falls …..

Preliminary data Limited number of participants No control groupOpen trial or single blind trials

Beware …..

... Control group with inadequate treatment.

Second best alternative Gold standard

Dose selection of drug and comparator ?

Beware …..

No randomisation

It is not the treatment, but the group selection which explains the outcome

Beware ..

Selection criteria

Hard selection: Results may not be generalisable.

No selection: The treament effect can be blurred by other aspects.

Beware …..

... Subgroup analysis not planned in advance

Large number of subgroups analysed Risk for difference just by chance

Beware…..

Outcome was analysed with unproven methods

Surrogate outcomeShort follow upDrop out

Beware …..

... Differences in adverse events were not analysed

Rare adverse events are not detected in RCT

Beware …..

... Results are only presented as percent change and not absolute difference

A large relative change – for example 50 % decreased may soud impressive, but may be not important if the risk is low

Summary

Select statistics before you start your experiment

Analyse your data Mind pit falls Good luck