ZAMSTAR restricted randomisation CREATE Investigators Meeting 2005

Charalambos (Babis) SismanidisLSHTM

ZAMSTAR overview

Zambia and South Africa tuberculosis and AIDS reduction study

24 communities (16 in Zambia, 8 in SA) are randomised in 4 arms (2x2 factorial).

Primary outcome: culture +ve TB prevalence (survey on 5,000 patients sampled in each cluster) after 3 years of intervention application

Description of interventions

TB/HIV @ clinic Strengthened DOTS VCT TB/HIV at health centre access (offering IPT) Basic HIV care HIV prevention (condoms, STI management)

Enhanced Tuberculosis Case Finding (ECF) Open access to sputum smear at health centre Schools education campaign Community mobilisation and mobile tuberculosis

laboratory Household level TB & HIV combined activities (HH)

Household counsellor visiting all TB households Household members encouraged to test for HIV TB preventive therapy for HIV+ve and children <6

Both ECF & HH

ZAMSTAR primary aims

Does enhanced tuberculosis case finding (ECF) by a strategy of community mobilisation and improved access to sputum microscopy, reduce prevalence of tuberculosis in the community?

Do combined TB/HIV activities at the household level (HH), reduce prevalence of tuberculosis?

Does ECF plus HH (ECF+HH), yield additional benefits for tuberculosis control through additional case detection, improved case holding, treatment/prophylaxis of latent infection and reduction in HIV incidence?

Clinic &VCT Clinic &

VCT

Clinic &VCTClinic &

VCT

6 Control

6 ECF+HH6 HH

6 ECF

ECF Vs.No ECF

Does ECF reduce the prevalence of tuberculosis in the community?

Does HH reduce the prevalence of tuberculosis in the community?

Clinic &VCT Clinic &

VCT

Clinic &VCTClinic &

VCT

6 Control

6 ECF+HH6 HH

6 ECF

HH Vs No HH

Clinic &VCT Clinic &

VCT

Clinic &VCTClinic &

VCT

6 Control

6 ECF+HH6 HH

6 ECF

HH Vs No HH

Stratification

The 24 clusters are stratified by country of cluster origin. 16 from Zambia, 8 in SA

Randomisation will be performed separately for each of the two strata

Zambia – Step I

4 equally numbered groups of As, Bs, Cs & Ds to form from 16 available communities (i.e. 4 communities in each group).

Arm A will include 4 communities out of the 16: 16!/12!4! = 1820 choicesArm B another 4 from the remaining 12 communities: 12!/8!4! = 495 choicesArm C another 4 from the remaining 8: 8!/4!4! = 70 choicesArm D 4 from the remaining 4: 4!/4!0! = 1 choice

This amounts to=1820*495*70*1=63,063,000

Zambia – Step II

BUT since we do not have a fixed sequence by which intervention arms will be picked (sequence ABCD is a generic example) we need to multiply the previous total by 4! (i.e. all possible permutations for an array of 4 elements).

TOTAL: 63,063,000*4! = 1,513,512,000

South Africa – Step I

4 equally numbered groups (= intervention arms) of As, Bs, Cs & Ds to form from 8 available communities (i.e. 2 communities in each group).

Arm A will have 2 communities out of 8 = 8!/6!2! = 28 choicesArm B another 2 from the remaining 6 communities (6!/4!2!) = 15 choicesArm C another 2 from the remaining 4 = 4!/2!2! = 6 choicesArm D 2 from the remaining 2 = 1 choice

Which amounts to = 28*15*6*1=2520

South Africa – Step II

Similarly since we do not have a fixed sequence by which intervention arms will be picked we need to multiply the previous total by 4!

TOTAL: 2520*4! = 2520*24 = 60,480

Computational headaches

Because of the very large number of possible permutations it has not so far been possible to list them all

Single file size not allowed to be >12GB

Current code produces multiple identical observations (which are then dropped)

Restricting randomisation

Possible restrictions: HIV prevalence TB infection (TST in children) Open/Closed communities (Social

Science) Political restrictions (not all clusters in a

community in the control arm-should this be extended to all arms?)

Changing lanes

THRio approach? Instead of listing all possible permutations

to get the exact proportion by which randomisation is restricted, I will now be randomly drawing a set number of permutations to estimate this proportion.

Then randomly draw one permutation from a list of ‘acceptable’ ones