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DOI: 10.1002/sim.2132

**Single patient (n-of-1) trials with binary treatment preference
**

P. J. Schluter∗; †; ‡ and R. S. Ware

Longitudinal Studies Unit; School of Population Health; The University of Queensland; Herston Road; Herston; Qld 4006; Australia

SUMMARY The use of a fully parametric Bayesian method for analysing single patient trials based on the notion of treatment ‘preference’ is described. This Bayesian hierarchical modelling approach allows for full parameter uncertainty, use of prior information and the modelling of individual and patient sub-group structures. It provides updated probabilistic results for individual patients, and groups of patients with the same medical condition, as they are sequentially enrolled into individualized trials using the same medication alternatives. Two clinically interpretable criteria for determining a patient’s response are detailed and illustrated using data from a previously published paper under two di erent prior information scenarios. Copyright ? 2005 John Wiley & Sons, Ltd.

KEY WORDS:

N -of-1; single patient trials; hierarchical Bayesian methods; informative priors; binomial; treatment responder; treatment preference

1. INTRODUCTION First systematically expounded in the psychological literature by Sidman in 1960 [1], the single patient trial (SPT) study design is increasingly being utilized for medical investigation [2, 3]. A typical SPT consists of experimental= control treatment periods repeated a number of times. The order of treatments are randomly assigned within each treatment period pair. Formally, this design is known as a structured within-patient randomized controlled multi-crossover study design [2]. The primary objective of a SPT is to determine treatment preference for the individual patient. The appeal of the SPT method stems from the increased popularity of evidence-based medicine, which relies upon controlled clinical trials, in particular randomized controlled trials (RCT) and systematic reviews of the literature, for clinical decision making [4]. However the cost, complexity, and limited availability of RCT evidence for some treatments and clinical disorders compromises this best practice [5, 6]. Frequently, the RCT evidence that does exist is

∗ Correspondence to: Philip J. Schluter, † E-mail: philip schluter@hotmail.com ‡ Associate Professor.

168 Easterbrook Road, Kaiapoi R.D. 1, North Canterbury, New Zealand.

Copyright ? 2005 John Wiley & Sons, Ltd.

Received April 2004 Accepted October 2004

16]. Statist. depending on the particular characteristics of the trial. Within this paper we provide two selection Copyright ? 2005 John Wiley & Sons. the updated posterior is then used as the prior distribution for the next patients STP [26]. Accordingly. it might be opined that di culties associated with the statistical analysis of SPTs could be one reason. 14]. Ltd. Another approach uses a preference trial where clinical conditions determine when patients change treatment in a prescribed order [25]. The SPT study design has been advocated and adopted by some of its proponents to introduce more rigor into these individual patient investigations [13. SPTs typically occur in a sequential fashion. Based upon the resultant posterior distribution for each patient. the assumption of normality is strong given that many SPTs have only 2–4 period pairs and outcome measurements are commonly measured on discrete visual analogue scales. WARE derived from a contrived study population. 20] to deÿne statistical signiÿcance. Routinely used graphical methods (plotting patient responses over time and determining e cacy by visual inspection) may produce erroneous or misleading results [17]. embodying prior information. in some instances. Preference could be as simple a measure as asking the patient which treatment was preferred in the last experimental= control treatment pair. Practitioners and patients frequently seek a more pragmatic solution and perform their own experiments to assess individual response to the particular medications of interest [11. the assumptions of normality are potentially inappropriate. encapsulating this notion of treatment preference. 8]. a more appropriate likelihood function might embody the notion of categorical improvement or treatment preference. These deÿciencies can be particularly problematic when data from only a small number of SPTs are available. The apparent suitability of the SPT method to many routine clinical problems has led some to question why such trials are not more widely used [15]. Moreover. Others have used 90 per cent conÿdence intervals excluding the null value [12] or one-sided paired Student’s t -tests with p¡0:05 [19. While useful and generally easy to implement. and results are generally reported at the level of the group. decisions about treatment preference can be made. as well as providing probabilistic results for each individual patient and the group of patients as a whole [26]. these approaches can yield parameter estimates or conÿdence intervals that fall outside their deÿned parameter space and they fail to utilize information that may exist about a treatments e ectiveness through previously conducted clinical trials or SPTs. with important and relevant exclusion criteria [7. S. SCHLUTER AND R. Likert scales or using dichotomous responses. or be determined by comparing scores within treatment period pairs and deÿned through recording an improvement over some minimally clinically important threshold. and time series analyses are of limited value [18]. J. The hierarchical Bayesian framework naturally accommodates such sequential acquisition of information through updating the posterior distribution. Parallel to the normal likelihood distribution case [22]. and they do not account for heterogeneity between patients [21]. Instead. However. in these circumstances.2626 P. 12]. an alternative hierarchical Bayesian method founded on a binomial likelihood distribution is proposed in this paper. Appealing to the notion of preposterior analysis. 2005. 24:2625–2636 . allowing covariates and patient sub-group structures to be modelled. This method has the advantage of ensuring sensible parameter estimates and intervals. which can be problematic when individuals exhibit considerable variability in their response to the treatment [9. To overcome these di culties. These methods su er from small statistical power. random e ects logistic models for binary [23] and ordinal [24] data have been proposed and applied to SPTs [2]. 10]. Aside from the usual limitations associated with centre-based cross-over trials [2. a random e ects model [21] and a hierarchical Bayesian method using a normal likelihood distribution [22] have been proposed. Med.

: : : . i ) (1) We use a hierarchical model to pool data from di erent SPTs while also accounting for any clustering or multi-level structure. Statist. between physicians within a given practice. Hyperprior distributions It is necessary to specify hyperprior distributions for both ÿ and | ÿ. ∼ I beta i=1 ÿ 1−ÿ . if the nested structure permitted further grouping of patients (such as by physician or medical clinic) then this prior could be extended to describe the variability between patients within a given physician’s practice. This paper focuses on modelling and applying the single patient trial methodology using a fully parametric Bayesian approach. +1 (3) For clarity.1. : : : . 2. (2) for 0¡ÿ¡1 and 0¡ . Concluding remarks are presented in Section 4. SPECIFIC MODEL AND PRIOR DISTRIBUTIONS 2. The basic model Let xi denote the observed frequency that the treatment under investigation was preferred from ni experimental= control treatment periods for the ith (i = 1. 2. I ) are assumed to be exchangeable between patients. ) by 2. 2005. | ÿ. 24:2625–2636 . We represent the population from which i is drawn by a beta probability distribution. Ltd. and between practices.2. it will be convenient to exploit the relationships in (3) and specify a hyperprior distribution for ÿ and 2 | ÿ. I ) patient.SINGLE PATIENT TRIALS WITH BINARY TREATMENT PREFERENCE 2627 criteria for determining this preference. we denote V ( i | ÿ. Although we shall consider a two-stage prior. to aid elicitation. and demonstrates how prior distributions can be obtained in both the non-informative and informative cases. However. and then transform the latter to obtain | ÿ. Med. Note that this parameterization of the beta distribution yields E ( i | ÿ. implying that they arise from some common distribution. the posterior probability and the posterior mean. At the ÿrst level of our hierarchical model the total number of treatment preferences for each patient is represented by xi ∼ Binomial(ni . Both criteria incorporate a term that allows the designation of treatment preference after accounting for any minimum detectable di erence or a minimum clinical important di erence that might be relevant to that SPT. Copyright ? 2005 John Wiley & Sons. We illustrate the use of the proposed models with numerical results in Section 3. where each patient has some underlying probability of treatment preference i . Section 2 describes the statistical model we use. Prior distribution The components of = ( 1 . ) = ÿ(1 − ÿ) hereafter.3. Within this section we also characterize the two selection criteria that can be used to deÿne treatment preference for individual patients. ) = ÿ and 2 V ( i | ÿ.

ÿ ∼ beta(u. First consider ÿ ∼ beta(u. then di erent speciÿcations (or hyperprior distributions) should be employed. m). We elicit a second interval. c] interval. Informative prior speciÿcation To specify the values of u. v). the possibility that the variance could exceed this value is permitted and is modelled by exponential decay on (c. Notice that the mean speciÿcation is simply the mid-point of the (s1 . m¿2 and normalizing constant =1 − 1 c m ÿ(1 − ÿ) m−1 (5) We express a bound c on 2 | ÿ and take this to imply a at distribution on the (0. Ltd. that the practitioner believes is likely to contain the individual experimental treatment preference rate for any patient. Using similar logic to (7). However. For this characterization of the model. Using the relationship in (3) it is easy to transform (4) to the hyperprior density for | ÿ. 2005. we recognize that ÿ and 2 | ÿ measure di erent aspects of uncertainty. m m [ÿ(1 − ÿ)]m−1 c ¡ ÿ(1 − ÿ) − c (6) 2. (s1 . the shoe density can be expressed by m−1 . 2 | ÿ ∼ shoe(c. v). We elicit from the practitioner an interval. J. which he or she believes is likely to contain the group experimental treatment preference rate over all patients. 2 m mc( ) for 0¡c¡ÿ(1 − ÿ). We then equate the mean and variance of ÿ to s1 + t1 2 and t1 − s1 4 2 (7) respectively. v. 2 f ( | ÿ) = mc( + 1) 0¡ 6 c ÿ(1 − ÿ) − c (m − 1)cm−1 ( + 1)m−2 . t1 ) interval and the variance is derived by presuming that the interval width is around 4 standard deviations. If the practitioner has information that is di erent from these assumptions. c and m. 28]. t2 ). Med. WARE The hyperprior for ÿ will be taken as a beta distribution. ÿ(1 − ÿ)).4. S. 24:2625–2636 . f( 2 | ÿ) = mc 0¡ 2 6c (4) c¡ ¡ÿ(1 − ÿ) 2 (m − 1)cm . t1 ).2628 P. Note that by deÿnition s2 6s1 and t2 ¿t1 . (s2 . while the hyperprior for 2 | ÿ will be given by a shoe distribution. Statist. SCHLUTER AND R. Now consider 2 | ÿ ∼ shoe(c. m) [27. so (m − 1)ÿ(1 − ÿ) . we specify c = [(t2 − s2 )= 4]2 and chose m so that P (0¡ 2 6c) describes the conÿdence of the practitioner Copyright ? 2005 John Wiley & Sons.

2 | ÿ ∼ uniform[0. 2005. P ∗ . as 0¡ 2 ¡ÿ(1 − ÿ). The particular selection criterion depends on the requirements of the practitioner. then we set P ∗ = 0:75 and d0 = 2 3. The posterior distribution is proper and deÿned for these choices of non-informative prior because both hyperpriors are proper densities for all xi . pi (d0 ). suppose we consider a responder as someone who has at least a 75 per cent chance of recording no less than two experimental treatment preferences in every three experimental= control treatment pair periods. Similarly.6. is deÿned to be the probability that this patient’s preference rate i exceeds some predetermined level d0 .5. we might specify P ∗ = 0:8 and 1 d0 = 1 2 . If the calculated pi ( 2 )¿0:8 then patient i would be classiÿed as having responded. m−1 m (8) Statist. 2. Observe from (4) that P (0¡ 2 6c) = so an estimate of m is straightforward. 2. ÿ(1 − ÿ)] is a natural non-informative choice. if 0:5¡pi (d0 )60:8 then the patient is considered to be a possible responder. since 0¡ÿ¡1. to be at least 80 per cent conÿdent that a treatment was as least as good as a control.1] interval. or if pi (d0 )60:2 then the patient is deemed to be Copyright ? 2005 John Wiley & Sons. For example. t2 ) contains the individual treatment preference rate for any patient. the threshold value P ∗ can be extended beyond the binary ‘responded’ and ‘non-responded’ conclusion by employing a predetermined gradated scale. otherwise they would be classiÿed as having failed to respond. A experimental treatment preference rate of 50 per cent is represented by d0 = 1 2 . Ltd. this hyperprior does not yield a prior posterior distribution for all xi . It could be suggested that f( | ÿ) ≡ 1 would be an appropriate non-informative choice. so that pi (d0 ) = P ( i ¿d0 | x) We then deÿne patient i to have ‘responded’ if this posterior probability is greater than or equal to some pre-speciÿed threshold value. however. After transformation. To facilitate clinical interpretability.SINGLE PATIENT TRIALS WITH BINARY TREATMENT PREFERENCE 2629 that (s2 . if 0:2¡pi (d0 )60:5 then the patient is said to be an unlikely responder. The posterior probability for patient i. For example. Non-informative prior speciÿcation An intuitive non-informative choice for ÿ is to take a uniform distribution over the [0. the experimental treatment preference outcome decision rule may be: if pi (d0 )¿0:8 then patient i is deemed to be a probable responder. f( | ÿ) ∝ 1= ( + 1)2 . for some d0 . Med. whereas represents an expression for the increased preference rate of the experimental treatment d0 ¿ 1 2 (compared to a control) by some important amount. the posterior probability and the posterior mean. For example. Selection criteria Two criteria for determining whether patients are deemed to have ‘responded’ to a treatment are explored. 24:2625–2636 .

pi (d0 ) = i ¿d0 f ( | x) d 1 ∞ 1 [ d0 0 0 g( i | ai . so patient i is a responder if E ( i | x)¿0:66. bi ). Med. or average experimental treatment preference rate. specifying our primary outcome to be the proportion of subjects for whom the treatment is preferred. E ( i | x). The number of amitriptyline= placebo treatment pair periods ranged from 3 to 6. An expression for E ( i | x) is given by E ( i | x) = i f( | x) d I j =1 1 ∞ 0 0 [ÿ= (1 + ni ) + ni = (1 + ni )(xi =ni )] 1 ∞ 0 0 I j =1 = nj xj B(a. for i = 1. ·) is the beta function. WARE a probable non-responder. with a median of 3. and g( i | ai . bj )f( | ÿ)f(ÿ) d d ÿ (10) nj xj B(a. a gradated rather than a dichotomous speciÿcation of experimental treatment response can easily be made. b) nj f( | ÿ)f(ÿ) d d ÿ xj B(aj . We re-analyse these data. Statist. a = ÿ= . Design A series of 23 SPTs were conducted to examine the e ectiveness of amitriptyline versus placebo in patients with ÿbromyalgia [19]. I . For instance. b)=B(aj . if E ( i | x) = 0:7. Symbolically. where the observed outcome di erence between amitriptyline and placebo for each treatment pair period was assumed to follow a normal distribution [22]. It provides the expected number of experimental treatment preferences over the long term. Designation of treatment responder is made through determining which patients have values of E ( i | x) above a pre-speciÿed threshold value. where preference is deÿned as having a mean score di erence between treatment pairs favoring amitriptyline. S. Ltd. In this case H ∗ = 0:66. Copyright ? 2005 John Wiley & Sons. suppose we consider a patient to be a responder if they are expected to record a experimental treatment preference in no less than 2 of every 3 treatment pair periods. 24:2625–2636 . 2005. For example. bi = b + ni − xi . SCHLUTER AND R. bi ) denotes i ∼ beta(ai . b) f( | ÿ)f(ÿ) d d ÿ B(aj . : : : .2630 P. which is a point estimate of the underlying proportion of treatment preferences. J. say H ∗ . bi ) d i ] 1 ∞ 0 0 I j =1 I j =1 = nj xj B(a. 7 experimental treatment preferences are expected for patient i.1. The second criterion is the posterior mean. EXAMPLE 3. Similar to the posterior probability criterion. bj ) (9) where B(·. then in 10 further experimental= control treatment pair periods. bj )f( | ÿ)f(ÿ) d d ÿ 3. These data have been analysed and reported using a hierarchical Bayesian method. b = (1 − ÿ)= . ai = a + xi . b)=B(aj . bj ) B(a. and most patients were medicated for two-week periods for each treatment regimen.

Med. 3. t2 = 0:99).5. 2. Simulations of size N = 20 000 were run in four parallel chains (with over-relaxation) after a burn-in period of 5000 iterations for each chain. c = ÿ(1 − ÿ) and m → ∞ for the hyperprior density f( | ÿ) given in (6). v = 1). t1 = 0:74) and the individual treatment preference rates would lie within (s2 = 0:29. computer simulation undertaken in MATLAB [30] revealed that we could be 95 per cent conÿdent that the overall group treatment preference rate would lie within the interval (s1 = 0:53.3. Copyright ? 2005 John Wiley & Sons.5 per cent percentiles for each parameter of the beta prior distribution used in the binomial likelihood model for each of the two prior information scenarios. Non-informative prior hyperparameter speciÿcation Notice that. although completely speciÿed in Section 2. 3. Results from the re-analysis of these data using hierarchical Bayesian models is also presented in Table I. 3.70 (1. Numerical results Table I includes the mean observed di erences between outcome measures of amitriptyline and placebo (x). 2005.05 (1. Based on these reported changes. Indeed. of the 15 patients who continued the treatment. they report mean (standard deviation) improvement in clinical impressions for ÿbromyalgia of 0.5. Using (7) and the moment of moments. and the clinical decision for the continuance of amitriptyline (CD). Over a two-week period. The hyperprior density f( | ÿ) given in (6) can now be fully speciÿed. we could reduce the informative prior distributions to these non-informative distributions by assigning ÿ ∼ beta(u = 1. we referred to a published clinical trial by Hannonen and colleagues [29] examining the e ect of amitriptyline on ÿbromyalgia. Informative prior hyperparameter speciÿcation To attain informative priors. Table II includes the median. and recalling that we are 95 per cent conÿdence that all i ’s lie within the (s2 . Ltd.5 per cent and 97. Programs for both non-informative and informative prior scenarios appear in the appendix. Computation Numerical results were derived from computer simulation using Markov chain Monte Carlo methods in WinBUGS [31]. the p-value from the one-sided Student’s t -test (p) originally reported for these data [19]. ÿ ∼ beta(u = 52:9. the design of the published 23 SPTs [19] and a binary measure of treatment preference. Assigning c = [(t2 − s2 )= 4]2 = [(0:99 − 0:29)= 4]2 = 0:1752 .4. recognizing the maximum of ÿ(1 − ÿ) = 1= 4 and assigning this value to this term in (5).05) for 39 subjects receiving amitriptyline and 0. It is notable that there is little agreement between the p-value and the resultant clinical decision. The results from the model of Zucker and colleagues [22]. appear beside the results from the binomial likelihood model using the two information scenarios.42) for 39 subjects receiving a placebo. v = 29:1). 8 (53 per cent) had a p-value that was non-signiÿcant at = 0:05. Statist. who assumed a normal likelihood distribution and non-informative hyperprior distributions (hereafter referred to as Zucker’s model).SINGLE PATIENT TRIALS WITH BINARY TREATMENT PREFERENCE 2631 3. Convergence was checked using visual plots of simulation histories and the modiÿed Gelman–Rubin statistic [32]. then from (8) it is easy to calculate m = 20. 24:2625–2636 .2. t2 ) interval.

68 0.10 0.67 0.70 0.77 0. SCHLUTER AND R.12 0. Median.60 0.14 0.13 0.98 0.67 0.10 0.23 0.12 0.26 0.60 p 0.2632 P.77) (0.66 0.74 0.94 0.32 0.13 0.09 0.31 0.19 0.13 0.002.44 0.14 0.28 0.66 0.67 0.13 0.01.15 0.38 0.36 0. Information scenario Non-informative prior Informative prior ÿ (2.58.67 0. respectively.77 0.79 0.98 0.53 0. observed mean di erence (x).37 0.15 0.01 CD × √ × × × × × × √ × √ √ √ √ √ √ √ √ √ √ √ √ √ Zucker’s model Mean S.53 0.40 0. 2005.77 0.19 0. 0.81 0.38 0.72 0.97 0. 0.66 Median 0. PP −0.74 0.60 0.07 (2. Med.68 0. pi ( 1 ).78 0.93 0.47 0.72 0.95 0.45 0.66 0.97 0.70 0.28 0.00 1.10 0.002.68 0.27 0.67 0.16 0.18 0.68 0. 0.12 0.14 0.12 0.53 0.5 per cent.00 1.05 −0:14 0.13 0.14 0.98 0.02 0.89 0.87 0.51 0.46 0.06 0.40 0.15 0. The remaining columns house the results from the binomal hierarchical Bayesian model using a non-informative prior (columns 8–10) and informative prior (columns 11–13).40 0.78 0.77 0.06 1.17) Median 0.79 0.92 0.78 0.54.68 0. Within each information scenario.51 0.17 0.87 0.81 0.88 0.12 0.015 (2.90 0.97 0.66 0.04 0.89 0.92 0.68 0.) and the posterior probability that the mean score di erence (amitriptylineplacebo) is greater than zero (PP).50 0.56 0.15 0.17 0.90 0.05 −0:33 −1:02 −0:19 0. 0.46 0. 97.02 0.46 0.29 0.92 0.D.97 0. 2.51 0.44 0.66 0.85 0.39 0.72 0.D.17 0.D.13 0.D.98 0.5 per cent) (0.56 0.29 0. Statist.34 0.11 0.94 0.99 1. Ltd.60 0.15 0. The number of treatment preferences= the number of treatment pair periods (xi =ni ).00 1.94 0.63 0.87 0.67 0.98 0.13 0.66 0.99 Informative prior 1 E ( i | x) S.87 0.76 3.92 0.11 0. 2 Table II.97 0.30 0.90 0.94 0.02 0.003.97 0.05 0.67 0.66 0.97 1.77 0.87 0.68 0.032) Copyright ? 2005 John Wiley & Sons.15 0.5 per cent) (0.97 0.92 0.81 0.12 0.06 0.66 0. pi ( 2 ) 0.06 0.04 0.13 0.029 0.5 and 97.28 0.57 0.12 0.56 0. 97.97 0.60 0.46 0.59) (0.57 0.77 0.10 0.11 0. J.78 0.13 0. S.12 0. p-value derived from a one-sided paired Student’s t -test (p) and the clinical decision made at the completion of the SPT as to whether the patient should continue with amitriptyline (CD).56 0.11 0.56 0.44 0. Binomial likelihood xi =ni 0= 3 1= 3 2= 3 2= 3 1= 3 2= 3 1= 3 1= 3 1= 3 1= 3 3= 4 4= 6 2= 3 4= 4 2= 3 3= 4 3= 4 3= 3 4= 4 3= 3 3= 3 3= 3 3= 3 x −0:36 −0:86 0.68 0.77 0.66 0.14 0. 24:2625–2636 .14 0.17 0.33 0.17 0.45 0.75 0.68 0.12 0.01 0.60 0. we reported the posterior mean E ( i | x) its standard deviation (S.97 0.73) 2 Median 0.49 0.68 0.79 0.5 per cent.17 0.17 0.14 0.14 0.90 0.19 0.20 1.01 0.14 0. This includes the posterior mean (Mean) its standard deviation (S.66 0. pi ( 1 ) 2 0.87 0.37 0.37 1.56 0. 0.32 0.15 0. 97.14 0.00 Overall group estimates Note: The next three columns (columns 5–7) include the results from the hierarchical Bayesian model using a normal likelihood distribution reported by Zucker and colleagues [22].5 per cent) (0.78 0.75 1.11 0.56 0.11 0.12 0.72 0.93 0.02 0.37 0.43 0.085) (0.30 0.25 0.11 0. 0.12 0.) and the posterior probability that a treatment preference rate is above 50 per cent.72 0.17 0.77 0.60 0.5 per cent.74 0.5 per cent percentiles for each parameter of the beta prior distribution for the binomial likelihood hierarchical Bayesian model for each of the two prior information scenarios. WARE Table I.77 0.D.48 0.74 0.90 0.78 0.62 0.85 0.00 Non-informative prior E ( i | x) S.70 0.45 0.

if our threshold values (P ∗ and H ∗ ) were altered. di erent designations might emerge. For example. The notion of treatment preference embedded within this model has considerable appeal and utility. Using the notion of binary treatment preference. Despite the considerable shrinkage in some estimates. However. An examination of the raw data revealed that all three patients in question recorded only one treatment preference from three treatment pair periods and their measured di erences had considerable variability. 2005. Ltd. then for the binomial model with a noninformative prior. yet was estimated to have E ( 1 | x) = 0:53 and pi (d0 = 1 2 ) = 0:62 under the informative prior scenario. With the informative prior. 4. Med. for the 3 patients meeting the threshold for Zucker’s model but not for the binomial model. 24:2625–2636 . shrinkage to the overall group mean estimates was evident. the lowest estimated posterior probability is 0. 6 (66 per cent) from the binomial model and 7 (78 per cent) from Zucker’s model were deÿned as failing to respond. Of the 16 identiÿed by Zucker’s model. thus having di erent deÿnitions Copyright ? 2005 John Wiley & Sons. of the 15 patients who continued with amitriptyline. DISCUSSION Single patient trials are increasingly being utilized as an apposite clinical tool for the determination of appropriate individualised medication or treatment [33]. Observe that for the binomial likelihood model there is some di erence between the estimates derived from each of the two information scenarios investigated. ÿrst using published data to inform our priors [29].77—little di erent from P ∗ . so these values were shrunk relatively more to the group mean by Zucker’s model. this paper provides a fully parametric binomial hierarchical Bayesian model and two selection criteria to determine whether a patient responded or not. nature and objectives of each trial. Preference may be individually negotiated between the patient and practitioner before the commencement of the trial. Conversely. of the 9 who discontinued their treatment. particularly among those patients whose results were more discrepant than expected. then using noninformative priors. Statist.68—some distance below P ∗ . If we pre-specify a threshold P ∗ = 0:8 to deÿne a responder. the lowest estimated posterior probability is 0. However.SINGLE PATIENT TRIALS WITH BINARY TREATMENT PREFERENCE 2633 Observe from Table I that under the non-informative scenario. if we pre-specify a threshold level H ∗ = 0:66. We demonstrate this model using two di erent prior information scenarios. When related back to the actual clinical decision made. Of the 3 patients meeting the threshold for the binomial model but not Zucker’s model. Posterior means cannot be directly compared across di erent models without careful calibration. both Zucker’s model and the binomial likelihood model have reasonable concordance between posterior probability results. The precise deÿnition of preference is exible and will depend on the characteristics. 13 (81 per cent) are also identiÿed by the binomial model as meeting the P ∗ = 0:8 threshold. However. the posterior probability threshold of P ∗ = 0:8 was exceeded by 13 (87 per cent) for the noninformative binomial model and by 14 (93 per cent) using Zucker’s model. patient 1 who recorded 0 successes from 3 treatment pair periods had E ( 1 | x) = 0:46 and pi (d0 = 1 2 ) = 0:47 under the non-informative prior scenario. there was no change in the designation of treatment responders and non-responders using either the posterior mean or probability selection criteria between noninformative and non-informative prior information scenarios for this example. the same 16 patients identiÿed by the posterior probability as being responders also had E ( i | x)¿0:66. in both cases 16 patients have posterior probabilities that exceed this threshold.

a speciÿc patient characteristic (yi ) can be related to the patient mean i by linear regression such that i = b0 + b1 yi + i . provide probabilistic results to be derived for each individual patient. SPTs are not without limitations. results yielded from the two prior information scenarios were moderately di erent for several patients. as with any clinical trials. no di erences in those deÿned as responding to the treatment emerged between the two prior information scenarios. 16]. A perceived disadvantage with the proposed model could be that it makes no allowance for overall period e ects whereas other methods do [2. Nonetheless. The model is easy to implement and produces readily interpretable results. 24:2625–2636 . The primary objective of the SPT is to decide whether a patient has responded to some treatment for their medical condition. Some may see the elicitation of prior information as troublesome. There are many other salient advantages of the hierarchical Bayesian model. Not all of these features can be accomplished using traditional statistical methods. only chronic conditions that rapidly respond to treatment can be investigated. 23–25]. These criteria contrast markedly with the situation where a conventional test of hypothesis is undertaken to determine whether uctuations within patients are due to chance or some underlying di erence. Moreover. for the analysed data and threshold levels. as patients are allocated completely at random. With the facility to easily extend this model to include more hierarchies and covariates. global impressions of the treatment e ectiveness can easily be elicited and modelled using this notion. at least for the simplest two treatment pair period cross-over design [2]. including its ability to: embody frequently available prior information. accommodate unequal experimental= control treatment pair period numbers between patients. S. Statist.2634 P. However. reliable data. 2005. Med. The presented criteria address these deÿciencies and give the practitioner intuitively appealing procedures on which appropriate decisions speciÿc to their practical situation can be made. For example. Like centre-based cross-over trials. and allow covariates and patient sub-group structure to be modelled. further work extending the binomial hierarchical Bayesian model to accommodate such e ects is recommended. WARE for di erent patients. and the resources and energies needed to rigorously execute such trials can be demanding [2. or the computation may be perceived as being di cult. In an e ort to negate these perceptions. we have carefully presented both non-informative and informative prior analyses using the binomial hierarchical Bayesian model and provided WinBUGS computer code. Embodying the notion of binary treatment preference. J. we present a binomial hierarchical Bayesian model and selection criteria that enable practitioners to determine whether patients respond to treatment in a series of experimental= control treatment pair periods. Ltd. insu cient wash-out periods and treatment period interactions can bias the resultant statistical estimates. we believe that this model will provide an important addition to the current n-of-1 analytic suite. completion and compliance rates can be troublesome. SCHLUTER AND R. However. However. quality research needs well-designed and properly conducted trials that yield valid. To explicitly address this goal we propose two selection criteria: the posterior probability and posterior mean. Bayesian methods are not exploited as much as they might be. In the presented example. Copyright ? 2005 John Wiley & Sons. it has been argued as being permissible to ignore any period e ect in the model used for analysis. which often yield statistically inconclusive results and make no statement about the magnitude of treatment di erence. update this prior information with the completion of similar SPTs. Despite this. as well as for the collective patient group [26]. Appropriate statistical methods can then be employed to process this information in a meaningful way to inform clinical decisions.

3. 4.1. 4. 4. 3. b) x[i] ∼ dbin(theta[i]. 2. 3. Statist. 3. 4. 6. 3. 4. 3. 3.5) for (i in 1:N){ theta[i] ∼ dbeta(a. 3. Randomized clinical trials in single patients during a 2-year period. c=0. 24:2625–2636 . Evidence-based Medicine: How to Practice and Teach EBM (2nd edn). 3). 3. Qas J. 4. Jaeschke R. 1. 3). Med. 3. 2. Guyatt GH. 3. 3. 2005. 1.c) eta ¡– sigma2= ((beta*(1-beta))-sigma2) a ¡– beta= eta b ¡–(1-beta)= eta PPgrp ¡– step(beta-0. b) x[i] ∼ dbin(theta[i]. Basic Books: New York. 3. n[i]) PP[i] ¡– step(theta[i]-0. N=23) WinBUGS program: informative prior MODEL model{ beta ∼ dbeta(u. 3). 4. 3. 3. 1) c¡–beta*(1-beta) sigma2 ∼ dunif(0. 1. 2. 3. Larson E. 3. 6. n=c(3. m=20. 3. Keller J. 3.m-1)) conÿdence ¡– (m-1)= (p*m) uncertainty ¡– 1-conÿdence rnd1 ∼ dunif(0. 1. 3.SINGLE PATIENT TRIALS WITH BINARY TREATMENT PREFERENCE 2635 APPENDIX A WinBUGS program: non-informative prior MODEL model{beta∼ dunif(0. Wiley: Chichester. 1) I ¡– step(rnd2-uncertainty) sigma2 ¡– (I*sigma21)+((1-I)*sigma22) eta ¡– sigma2= ((beta*(1-beta))-sigma2) a ¡– beta= eta b ¡– (1-beta)= eta PPgrp ¡– step(beta-0. 11:88 –100. 3. uncertainty) sigma22 ¡– c= pow(1-(p*m*rnd1). 3. 2. N of 1 randomized trails for investigating new drugs. 3. 3. 3. 2. 3. 1. 4. v=29.5) for (i in 1:N){ theta[i] ∼ dbeta(a. 3. 4. Ltd. 2. 1. 3. 3)) REFERENCES 1. 4. 4.030625. x=c(0. 2002. Roberts R. Cross-Over Trials in Clinical Research (2nd edn). 4. 2. 4. 1. Controlled Clinical Trials 1990. 2. 1. Sidman M. 3.9. 3. c) p ¡– 1-((1= m)*pow(c= (beta*(1-beta)). n[i]) PP[i] ¡– step(theta[i]-0. Senn S. 3. 4. Journal of the American Medical Association 1993. 1. u=52. 3. 2. 1= (m-1)) rnd2 ∼ dunif(0. 3. 1960. 4. 3. 3. Sackett DL. 3. 3. Tactics of Scientiÿc Research. Adachi AD. 3. Ellsworth A. 5. 2. x=c(0. 3. Copyright ? 2005 John Wiley & Sons. 270:2708 –2712. 3. 3. 1. 2. 4. 4. 3. 1. v) sigma21 ∼ dunif(0. 2000. 3. Heyting A. 3. 3. 1. Churchill Livingstone: New York.5) }} DATA list(n=c(3.5) }} DATA list(N=23.

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