About%20OMICS%20Group

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About OMICS Group

• OMICS Group International is an
  amalgamation of Open Access publications and
  worldwide international science conferences and
  events. Established in the year 2007 with the
  sole aim of making the information on Sciences
  and technology Open Access, OMICS Group
  publishes 400 online open access scholarly
  journals in all aspects of Science, Engineering,
  Management and Technology journals. OMICS Group
  has been instrumental in taking the knowledge on
  Science technology to the doorsteps of ordinary
  men and women. Research Scholars, Students,
  Libraries, Educational Institutions, Research
  centers and the industry are main stakeholders
  that benefitted greatly from this knowledge
  dissemination. OMICS Group also organizes
  300 International conferences annually across the
  globe, where knowledge transfer takes place
  through debates, round table discussions, poster
  presentations, workshops, symposia and
  exhibitions.

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About OMICS Group Conferences

• OMICS Group International is a pioneer and
  leading science event organizer, which publishes
  around 400 open access journals and conducts over
  300 Medical, Clinical, Engineering, Life
  Sciences, Pharma scientific conferences all over
  the globe annually with the support of more than
  1000 scientific associations and 30,000 editorial
  board members and 3.5 million followers to its
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• OMICS Group has organized 500 conferences,
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  Kingdom, Valencia, Dubai, Beijing, Hyderabad,
  Bengaluru and Mumbai.

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Stepped Wedge Design An RCT for Developmental
Growth in Phelan-McDermid Children
October 2014

• Edwin R. van den Heuvel
• Professor of Statistics
• e.r.v.d.heuvel_at_tue.nl
• Department of Mathematics and Computer Science
• Eindhoven University of Technology

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Content

• Introduction
• Type of Trial Designs
• Statistical Model
• Simulation
• Parameter Settings
• Results
• Conclusions

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Introduction

• Children with Phelan-McDermid syndrome develop
  slower (70) than normal children
• The syndrome is caused by a deletion of gene
  22q13.3
• It is a rare disease (50 known children in
  Netherlands)
• A pilot study showed that insuline can enhance
  mental development
• An RCT is needed to investigate a possible effect
  of intranasal insuline versus placebo

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Introduction

• First type of designs that were thought off were
• Cross-over design issues with carry-over?
• Parallel group design possible
• Matched-pairs design possible
• Parents were not cooperative to participate if
  their child would not receive the intervention
• In a stepped wedge design all participants will
  switch during the trial (one-directional
  cross-over)
• We felt it would only be ethical when this design
  would have similar power than other trials
• Expected number of participants was 20

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Introduction

• Stepped wedge designs
• All patients are first treated with the control
• Patients or group of patients are changing at
  different time points
• It uses intra- and inter-individual variation of
  patients to test for treatment effect
• It could take longer than parallel group designs
• Example Three groups with four periods

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Type of Trial Designs

• Prerequisites
• Five time moments 0, 6, 12, 18, and 24 months
• More time moments would be to much of a burden
• Shorter times affect test-retest variability
• Development is measured by Bayley III
• Scores are transformed to developmental age
• Possible types of designs
• Parallel group design (PGD)
• Matched-Pairs design (MPD)
• Stepped Wedge Designs (SWD)
• Delayed Start Design (DSD)

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Type of Trial Designs

• Parallel Group Design
• At time zero patients are randomly allocated to
  either placebo or intranasal insuline
• Ramdomization is balanced (ratio 11)
• Dotted line is placebo
• Solid line is intranasal insuline
• Ratio of total treatment time on both treatments
  is 11

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Type of Trial Designs

• Matched-Pairs Design
• Patients are treated the first six months at
  placebo
• Developmental growth or change is matched
• Per pair placebo or intranasal insuline is
  randomly allocated
• Ratio of total treatment in placebo vs. Insuline
  53

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Type of Trial Designs

• Stepped wedge designs
• Treatment switches coincide with measurements
• Ratio of total treatment in placebo vs. Insuline
• SWD-S2a 11
• SWD-S2b 35
• SWD-S3 11

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Type of Trial Designs

• Delayed start designs
• Trial starts as a parallel group design
• At a specific time point, (part of) the control
  group switches to treatment
• Common trials for Alzheimer and Parkinsons
  disease
• The goal is to
• Investigate treatment effect
• Whether disease progression can be slowed down
• The second goal is less important for our RCT

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Type of Trial Designs

• Delayed start designs
• Ratio of total treatment in placebo vs. Insuline
• DSD-S1a 13
• Others 11

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Type of Trial Design
Ratio 11
Ratio 35
Ratio 11
Ratio 53
Ratio 11
Ratio 13
Ratio 11
Ratio 11
Ratio 11
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Statistical Model

• Linear Mixed Model
• Random coefficients model
• Yij developmental age of child I at time point
  j
• Z0,i developmental age at baseline for child i
• Z1,i developmental growth for child i
• tij moments of measurement for child i
• xij moments of treatment switch for child i
• eij residuals
• g treatment effect

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Statistical Model

• Model for Stepped Wedge Design

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Statistical Model

• Analysis of Model
• Statistical model can be analyzed with standard
  software for mixed models
• Requires two regression time variables
• One for placebo time tij
• One for the new treatment time2 tij-xij when
  tij gt xij
• time2 0 when tij xij
• SAS codes
• PROC MIXED DATASIMULATIONDATA METHODREML
• CLASS INDIVIDUAL
• MODEL Y TIME TIME2/SOLUTION DDFMSAT
• RANDOM INT TIME/SUBJECTINDIVIDUAL TYPEUNR
• RUN

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Simulation

• Parameter Settings
• Settings were selected on the basis of real data
  and on literature on test-retest variation of the
  Bayley III test
• b0 21
• b1 0.3
• s0 ?10
• t0 ?45
• t1 ?0.1
• r 0.25 0.50 0.75
• g 0 0.15 0.30 0.45
• Number of simulations 50000
• Makes it possible to distinguish a difference of
  1 in power

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Simulation

• Type 1 error
• Type 1 error rates are somewhat inflated
• The null-distribution of the Wald test statistic
  is not perfectly chi-squared distributed
• SWD-S2b and DSD-S1a have only limited inflation
  of type 1 error rates

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Simulation

• Power
• SWD-S3 and DSD-S3 seem to perform quite good
• MPD-A1 is best for r0.75
• PGD, SWD-S2b, and DSD-S1a are less powerful
  designs for testing treatment effect

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Conclusions

• Stepped wedge design is competitive with the more
  classical designs and delayed start designs
• Stepped wedge designs are considered ethical
  since not participant is withhold the new
  treatment
• The number of steps does not seem to affect the
  power strongly
• Imbalance in total treatment time seem to reduce
  power
• Power values are not very large with only 20
  participants