Pierre-Yohan Michaud
email: michaud@lma.cnrs-mrs.fr

Abine Meunier

Hilippe Herzog

Lavandier

Gérard Drouet D'aubigny

Perceptual Evaluation of Dissimilarity Between AuditoryStimuli: An Alternative to the Paired Comparison

Keywords: no, 43, 66, Lj

In order to examine the perceptual dimensions used by listeners to differentiate sounds, dissimilarity judgments are analyzed with amultidimensional scaling technique. The paired comparison method is often recommended as the standard method for collecting judgments of dissimilarity between audio stimuli. An alternative method is presented here. On each trial, listeners are asked to select which stimulus among three stimuli is the most similar to areference stimulus. The method wastested wuth simulations and an actual listening test. Across trials, every stimulus wasu sed in turn as the reference stimulus. The analysis of simulated data indicated that, the number of stimuli did not influence the estimation of dissimilarity,a nd that 20 simulated listeners were sufficient for recovering continuous dissimilarity values. The listening test conducted to evaluate the musical restitution by 12 loudspeakers led to twoperceptual dimensions similar to those obtained in apaired comparison experiment.

Introduction

The goal of manystudies on sound dissimilarity is to determine the perceptual dimensions used by listeners to differentiate the stimuli. These dimensions are often estimated based on the method of multidimensional scaling (MDS), which yields the estimated dissimilarity between the stimuli in amultidimensional space.

The paired comparison (PC) method is often considered as the method of choice for the study of sound dissimilarity [START_REF] Borg | Modern multidimensional scaling, theory and applications[END_REF][START_REF] Takane | Multidimensional scaling. -I n: Handbook of quantitative methods in psychology[END_REF]. Accordingly,listeners evaluate the overall dissimilarity between paired stimuli, for example by giving an estimate on ascale ranging from "very similar" to "very dissimilar". An individual dissimilarity matrix is filled with listeners estimates. The individual dissimilarity matrices or their average can be analyzed with the MDS technique. The PC method has been used in several experiments, generally to evaluate the underlying dimensions of different perceptual attributes of sound sets (e.g. musical timbre [START_REF] Grey | Multidimensional perceptual scaling of musical timbres[END_REF], sound reproducing systems [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF][START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF], radiating bars and plates [START_REF] Canévet | Auditory perception of sounds radiated by afluid-loaded vibrating plate excited by atransient point force[END_REF][START_REF] Faure | Perceptual assessment of the influence of structural parameters for aradiating plate[END_REF][START_REF] Mcadams | Roussarie: The psychomechanics of simulated sound sources: Material properties of impacted bars[END_REF][START_REF] Mcadams | The psychomechanics of simulated sound sources: Material properties of impacted thin plates[END_REF] and cochlear implants [START_REF] Mckay | The perceptual dimensions of single-electrode and nonsimultaneous dual-electrode stimuli in cochlear implantees[END_REF]).

Received5March 2012, accepted 12 June 2013.

Ad rawback of the paired comparison method is the number of trials which increases with the number of stimuli. Because of this limitation, several previous studies investigated alternativest ot he paired comparison method [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF][START_REF] Subkoviak | Acloser look at the accuracy of alternative data-collection methods for multidimensional scaling[END_REF][START_REF] Tsogo | Multidimensional scaling methods for many-object sets: Ar eview[END_REF][START_REF] Bijmolt | The effects of alternative methods of collecting similarity data for multidimensional scaling[END_REF][START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF]. Manyo ft he alternative methods are based on an indirect estimation of dissimilarity.Theycan be classified in three categories based on the task carried out by participants: sorting, ranking or picking task.

The most commonly used alternative method to paired comparison is free sorting [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF][START_REF] Bonebright | An investigation of data collection methods for auditory stimuli: Paired comparison versus acomputer sorting task[END_REF]. Accordingly,p articipants are instructed to create groups of similar stimuli. The hierarchical sorting method is an alternative sorting method. On each step of this procedure, participants merge stimuli or groups of stimuli until all of the stimuli are merged in one group. The hierarchical sorting can start from the condition where each stimulus is in as eparate group (complete hierarchical sort), from the groups resulting from af ree sorting step [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF], or from the groups resulting from ac onstrained sorting step where the number of groups of stimuli is decided by the experimenter (truncated hierarchical sorting [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF]).

Another type of method is the conditional ranking method, which consists in ranking the stimuli from the most similar to the least similar compared to ar eference stimulus. Each stimulus in turn serves as the reference [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF][START_REF] Tsogo | Multidimensional scaling methods for many-object sets: Ar eview[END_REF].

The method of triadic combinations belongs to the picking task category.Oneach trial three stimuli are presented and participants are asked to pick the twomost similar and the twom ost dissimilar stimuli within the triad [START_REF] Takane | The method of triadic combinations: An ew treatment and its applications[END_REF]. A different picking task is called pick any k/n and consists in choosing those kstimuli among the presented nstimuli that are more similar to agiven reference [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF]. Similarly to the conditional ranking method, each stimulus is, in turn, considered as the reference.

Sorting and ranking methods have been adopted in a number of previous auditory perception experiments. For example, the free sorting task wase mployed and compared to the PC method by Bonebright [START_REF] Bonebright | An investigation of data collection methods for auditory stimuli: Paired comparison versus acomputer sorting task[END_REF], Parizet and Koehl [START_REF] Parizet | Application of free sorting tasks to sound quality experiments[END_REF], Giordano et al. [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF]. The hierarchical sorting task wasalso tested by Giordano et al. [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF] and the triadic combination method wasused by Novello et al. [START_REF] Novello | Perceptual evaluation of inter-song similarity in western popular music[END_REF] in a musical similarity experiment.

To our knowledge, the pick anym ethod presented by Rao and Katz [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF] and Bijmolt and Wedel [START_REF] Bijmolt | The effects of alternative methods of collecting similarity data for multidimensional scaling[END_REF] has never been applied and studied for the evaluation of sounds. Moreover, it has neverb een compared to the standard paired comparison method. The only practical example that we found in the literature of an application of such method is av isual experiment conducted by Rogowitz et al. [START_REF] Rogowitz | Perceptual image similarity experiment[END_REF]. Theyr an an experiment using the pick any k/n method with the parameters k = 1a nd n = 8. The term "pick anyk /n" does not denote twok ey aspects of this method: the forced choice similarity picking task and the comparison of the presented stimuli to ar eference, with each stimulus used in turn as the reference. Forthese reasons, in the following we term this method "Similarity Picking with Permutation of References" (SPPR).

The aim of this paper is to present the SPPRm ethod as an alternative method for the evaluation of sound dissimilarity.The first part of this paper details the proposed method and its adaptation to listening tests. The second part is dedicated to the exploration of the method by simulating the judgments of listeners. The simulation principle and the resulting information concerning the effects of the number of stimuli and the number of listeners on the estimation of dissimilarity are presented. The last part of this paper details the comparison between the results of twolistening tests involving the PC method and the SPPR method on the same set of 12 musical excerpts. The specificfeatures of the SPPRmethod are discussed.

Presentation of the method

The data collection process proposed here is based on the method presented by Rao and Katz [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF]. It wasemployed in the experiment conducted by Rogowitz et al. [START_REF] Rogowitz | Perceptual image similarity experiment[END_REF] to quantify with an MDS analysis the dimensions underlying the perceiveddissimilarity of images. This last study was used here as apractical example to design alistening test based on the same method. On each trial of their experiment, 9s timuli were selected randomly from as et of 97 and presented to the participant. One of these nine images wastreated as areference stimulus and the participant had to choose which of the eight remaining comparison images appeared most similar to this reference. The experiment corresponds to ap ick 1/8t ask for each trial. Every image wasu sed once as the reference and compared to the 96 other images randomly distributed into groups of 8 images without replacement. Forat otal of 97 stimuli, 12 presentations of 8i mages were made for each reference. The entire test appears to be incomplete since every combination to draw8out of 96 images for each reference are not presented. This incomplete design seems convenient to reduce the number of trials to be evaluated by each participant. Based on the incomplete pick 1/p experiment design (p corresponding to the number of comparison stimuli on each trial), the method wasadapted to auditory stimuli evaluation.

Test design forauditory stimuli evaluation

When adapting this method to the evaluation of auditory stimuli, some precautions should be taken. In the experiment designed by Rogowitz et al. [START_REF] Rogowitz | Perceptual image similarity experiment[END_REF], the participants could directly see the reference image along with the eight images to be compared. Comparison and reference stimuli could be compared simultaneously.S ounds cannot be compared simultaneously: the stimuli are therefore presented sequentially and participants have to rely more extensively on mnemonic resources in order to carry out the comparison. Forexample, listeners hear the reference first and then aset of other sounds to be compared to the reference, one after another.The strain on mnemonic resources is particularly daunting when relatively long sounds are involved (e.g., musical excerpts). Thus, it seemed mandatory to reduce the number of stimuli used in each trial, in order to adapt the comparison task from visual to auditory evaluation and to reduce the duration of each trial.

When evaluating as et of n sounds, each reference is compared to the other (n -1) comparison sounds. Those (n-1) sounds are randomly distributed in (n-1)/p groups without replacement where p corresponds to the number of comparison sounds evaluated during atrial. Each sound is used as the reference, leading to an entire test of n(n-1)/p trials. The number p has to be carefully chosen in order to have the best compromise between the number of sounds to be compared during one trial and the total number of trials for the entire test.

Table Ip resents the influence of the chosen number p on the number of trials needed for each reference and on the total number of trials, for the evaluation of aset of 40 stimuli. As acomparison, the evaluation of 40 stimuli with the PC method leads to an entire test of 780 trials. Table I shows that the number of trials rapidly decreases with the number of comparison stimuli p presented on each trial.

In order to adapt the task from av isual to an auditory evaluation, we chose to compare each reference sound to three comparison sounds (p = 3).Three comparison stimuli seemed to be the best compromise between the feasibility of the task for each trial and the total duration of the entire test. The design of the SPPRm ethod with 3 comparison sounds is presented in Figure 1. Foreach reference, the (n -1) remaining stimuli are randomly distributed in (n -1)/3triplets without replacement. This incomplete design of the SPPRmethod involves the evaluation of every stimulus as ar eference, leading to an entire test of n(n -1)/3trials. Note that conducting acomplete test would involvethe evaluation of every possible triplets compared to each reference and would lead to av ery demanding experiment.

The dissimilarity evaluation is based on aforced choice task on each trial and does not imply anydirect dissimilarity estimation. The participants have to choose which of the three comparison stimuli seems the most similar to the reference stimulus.

Accessing an average dissimilarity matrix

As wasdone by Rogowitz et al. [START_REF] Rogowitz | Perceptual image similarity experiment[END_REF], each individual matrix is first initialized to one and each diagonal is set to zero since the dissimilarity value between twoi dentical stimuli is assumed to be null. The matrix is then modified depending on the listener judgments. During the experiment, when astimulus j is judged within the triplet of comparison stimuli as the most similar to the reference i, the ij-th element of the individual matrix d ij is decremented by one.

Judgments reported in each individual matrix may differ depending on whether i or j is presented as the reference. As amatter of fact, apair (i, j)m ay appear in three kinds of presentation. Either i and j are comparison stimuli (not the reference)a nd play as imilar role, or one is the reference stimulus and the other is one of the comparison stimuli, or the opposite. These last twoc ases could lead to asymmetries in the dissimilarity matrix since the choice of the comparison sound which is the most similar to the reference depends on the twoo ther comparison sounds presented in the triplet. Forexample, an asymmetric result could occur when j is judged similar to the reference i in atrial, whereas i is not chosen as the most similar to the reference j in another trial. This example leads to different values of the symmetric elements:

d ij = d ji .
The MDS technique employed by Rogowitz et al. [START_REF] Rogowitz | Perceptual image similarity experiment[END_REF] requires asymmetric dissimilarity matrix to analyze the judgments of participants. Therefore it wasproposed to keep the symmetric part of the matrix:

D ij = (d ij + d ji )/2.
All dissimilarity matrices appearing in this document have been processed following the same procedure.

At the end of the experiment and after the symmetrization step, every individual matrix cell can equal 1if, for the pair (i, j), stimulus j is not judged as similar to the reference stimulus i and reciprocally,0.5 if stimulus j is judged the most similar to the reference stimulus i butstimulus i is not judged the most similar to the reference stimulus j, and 0ifstimulus j is judged the most similar to the reference stimulus i and stimulus i is also judged similar to the reference stimulus j.Since the method consists in evaluating the (n -1)/3triplets for each reference stimulus, judgments from each participant lead to asparse matrix filled with 0, 0.5 or 1. Moreover, depending on the random distribution of the triplets for each reference, the test design differs from alistener to another.Aseach individual matrix is partially and differently filled by listeners answers, we chose to consider only the average of these matrices. This average matrix is then analyzed using an adequate MDS technique [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF][START_REF] Rogowitz | Perceptual image similarity experiment[END_REF].

Simulations

Simulating the judgments of as ample of listeners allows us to study the suitability of the SPPRmethod to estimate dissimilarities, evaluating the influence on the dissimilarity evaluation of the number of stimuli and simulated listeners. More specifically,simulations allowthe reliability of the method and its potential biases to be evaluated.

Rao and Katz [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF] conducted simulations on another adaptation of the "pick any" method. Foras et of n stimuli, each trial included one reference and the n -1c omparison stimuli. The number of comparison stimuli to be picked as the most similar to the reference wasset to 4or 8. The procedure simulated by Rao and Katz [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF] is thus not strictly the same as the procedure we have tested but the simulation presented in this section is based on asimilar principle.

Principle

The dissimilarity judgments of the simulated listeners are computed from pre-determined dissimilarity values. These known dissimilarities were obtained from distance values, as follows: ar andom set of points wasc reated in as pace for which the number of dimensions wasarbitrarily fixed to 3. The space created wasrandomly filled along the three dimensions. Then, the distance between each pair of points wasc onsidered as ad issimilarity value, and stored into a matrix. This resulting matrix wast hen considered as the reference, assumed to be the result of an ideal test. In the rest of the document, this original matrix will be called the true dissimilarity matrix.

These true dissimilarity values were used during the simulated trials to decide which of the comparison sounds would be chosen as most similar to the reference. A, B, C and Dw ere the four stimuli involved in as imulated trial, Ab eing the reference, and B, Ca nd Dt he comparison stimuli. d AB , d AC and d AD measure the true dissimilarity between Aa nd B, Aa nd C, Aa nd D, respectively.T he lowest value between d AB , d AC and d AD corresponds to the highest similarity and indicates which stimulus among B, Ca nd Dw ould be chosen by the simulated listener as the most similar to the reference Ainthis simulated trial.

By simulating the method based on ar andom spatial configuration, Rao and Katz [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF] interested in measuring the correlation between the original space and the estimated space obtained with the MDS analysis of the estimated dissimilarity matrix. By simulating the judgments of listeners, our approach consists in comparing the estimated dissimilarity matrix resulting from the simulated test and the original true dissimilarity matrix, thus allowing the evaluation of the SPPRm ethod. The transformation of the true dissimilarities into the estimated dissimilarities is the central point of the simulation. Twosimulations were conducted to evaluate the influence of the number of stimuli and listeners on this transformation.

Design

Simulation 1: influence of the number of stimuli

Simulation 1consisted in testing every possible set of three stimuli which could be compared to each reference during acomplete experiment. The presentation of every possible triplet is easy to simulate butw ould be very demanding for an actual experiment. This simulation gathers the maximum of the dissimilarity information to fillt he dissimilarity matrix. By presenting every combination of three out of n -1stimuli, that is (n -1)!/(3!((n -1) -3)!) combinations, the method is able to provide all the available information about the dissimilarity,a sw ould do as ingle listener also evaluating every triplet. We used this simulation to assess the reliability of the method for anumber of stimuli ranging from 10 to 50. In each case, for afixed number of stimuli in the test, the correlation between true and estimated dissimilarities wascalculated.

Simulation 2: influence of the number of listeners

Simulation 2a llowed us to simulate listening tests corresponding to more realistic scenarios. As described previously,one out of n stimuli wasused as the reference, and compared to the other (n -1) stimuli randomly distributed in the (n-1)/3triplets. Hence, each listener does not evaluate every possible triplets. To simulate af ull SPPRt est, several listeners are then needed to obtain an average dissimilarity matrix. The aim of Simulation 2w as to determine the number of listeners required to obtain an average dissimilarity matrix equivalent to the one obtained in Simulation 1. Fort his simulation, the number of stimuli wasa rbitrarily fixed at 40. Thus, the entire test consisted of n(n -1)/3t rials which led to 520 trials for Simulation 2compared to the 365560 trials needed for Simulation 1w ith 40 stimuli. Fore ach reference, the 39 comparison stimuli were distributed in 13 triplets.

First Simulation 2w as conducted as described. Then, simulations corresponding to more realistic experiments were also conducted by adding arandom noise to the simulated listener responses. This investigates the robustness of the method with simulated listeners giving less-ideal answers. The listener-specificn oise wasa dded to each trial. In every trial, each of the three true dissimilarity values wasmodified by adding arandomly selected independent number (different for each dissimilarity value). These number wasd rawn from aG aussian random distribution centered on the true dissimilarity to be modified. Three different noisy simulations were conducted with three noise distributions which variance values were set to 0.0016, 0.008 and 0.02. To evaluate the influence of the noise, the ratio of modified responses overt he number of total responses wasmeasured to get asimple figure of howmany responses had been modified due to the added noise. The three distributions led to three modification ratios: 10, 20 and 30%.

Results

To evaluate the suitability of the SPPRm ethod, correlations were calculated between the matrices of true and estimated dissimilarities. In order to employthe appropriate correlation coefficient, the relationship between true and estimated dissimilarities wase valuated. Figure 2s hows the estimated dissimilarity data, resulting from Simulation 1w ith an umber of stimuli arbitrarily set to 40, as af unction of the true dissimilarity data. The histograms representing the distribution between 0a nd 1o ft he true and estimated dissimilarities are presented on the same figure. These histograms will be described later.T he relation between the true and estimated dissimilarity values is clearly non-linear,and so the linear Pearson coefficient is not appropriate to evaluate this relation. Therefore, for both simulations, the Spearman correlation coefficient was preferred to quantify the link between dissimilarities. This coefficient offers the advantage of being robust to nonlinear relationships as it deals with the ranks of each element included in both matrices to evaluate the monotonicity of their relation (the value of the Spearman correlation corresponds to the Pearson coefficient calculated based on the ranks of both data sets). Correlations were calculated on the set of values corresponding to half of each symmetric matrix without taking into account the diagonal which was not modified during the test.

Number of stimuli

Considering the results of Simulation 1, the Spearman correlation coefficient wasmeasured for anumber of stimuli varying between 10 and 50. It remained almost constant with an average value of ρ = 0.96 and as tandard deviation of 0.01 (not plotted as the correlation is constant). Simulation 1t hus shows that the number of stimuli does not influence significantly the correlation between the true and estimated dissimilarity matrices when every possible triplet presented to each reference is simulated. However, the simulation of the method does not allowt he dissimilarity values to be recovered completely.This bias will be discussed later.

Number of listeners

In order to investigate the differences between Simulations 1and 2, the Spearman correlation coefficient between the estimated dissimilarity matrices resulting from each simulation wascalculated, as afunction of the number of listeners involved in Simulation 2, for 40 stimuli. When the number of simulated listeners increased, the dissimilarity value resulting from Simulation 2c onverged to the value obtained in Simulation 1. Forasample size of 20 or more simulated listeners, the method led to the same information that would be obtained if all the possible triplets were presented for each of the reference stimuli. For2 0s imulated listeners, the correlation coefficient between dissimilarity matrices resulting from Simulations 1and 2already reached ρ = 0.98 (although the total number of trials is only 20x520 = 10400, farl ess than the 365560 trials required in Simulation 1).

The method of similarity picking with permutation of references applied to aset of n stimuli tested only (n-1)/3 out of (n -1) trials for each reference for Simulation 2. The results obtained when comparing Simulation 2w ith Simulation 1showthat the influence of this partial filling of the dissimilarity matrix is efficiently reduced by using about 20 simulated listeners.

In order to evaluate the performance of the SPPR method in Simulation 2, the Spearman correlation coefficient between the estimated and true dissimilarity values wasc omputed for 40 stimuli, as af unction of the number of simulated listeners. Figure 3i llustrates the evolution of the correlation from one listener to 100 listeners, when simulated listeners (without noise)a nd when more "noisy" listeners were simulated (with added noise leading to 10, 20 and 30% of modification of the simulated listeners' responses). Without noise, the plot shows as teep increase in correlation coefficient for samples of up to 20 simulated listeners. Fors amples exceeding 20 listeners, the curvereaches astable value. When adding noise to the responses, the shape of the correlation curves is modified butonly for small numbers of listeners. The more noise is added, the more correlations decrease. Note that for up to 20% of modification the correlation curveisonly slightly reduced. Even for 30% of modified responses, the Spearman correlation is still above 0.90 for 15 simulated listeners. When reaching 100 simulated listeners, the effect of the added noise is marginal.

Bias characterization

Fort he simulations with and without noise, even for 100 simulated listeners, the Spearman correlation coefficient does not exceed ρ = 0.96 (Figure 3).T his correlation value, also obtained in Simulation 1, indicates that the method is nevera ble to recoverc ompletely the dissimilarity information.

To determine the origin of this partial convergence shown by the simulations, the transformation from true to estimated dissimilarity data wasstudied. First, the relation between both data wasshown to be non linear and monotonically increasing (Figure 2).Inorder to understand how the method transforms the true dissimilarity into estimated data, the distributions of true and estimated dissimilarity values are also displayed in Figure 2.

The distribution of the true dissimilarities, resulting from au niform random distribution of the stimuli along the space dimensions, appears to followaG aussian-like shape. The estimated dissimilarity histogram however shows as hift of the values toward larger values. Indeed, in Figure 2most of the points are above the equality line. This shift towards larger dissimilarity values is due to the wayt he similarity information is coded. At each trial, a piece of information is obtained concerning the similarity between the reference stimulus and the chosen stimulus, butthe dissimilarity value is not changed for the comparison stimuli which were not chosen, and therefore keeps its default value. Foranentire test, before the symmetrization step, the dissimilarity matrix is filled with one third of listener responses with anull value and the remaining two thirds keep their initial value of 1.

To test if the true dissimilarity distribution could influence the simulation results, different distributions were tested. The true dissimilarity matrix obtained from the space wasr eplaced by either au niform distribution, an asymmetric Poisson distribution set between 0a nd 1o r aGaussian distribution centered on 0.5 with avariance of 0.17 and truncated between 0a nd 1. Simulation 2c onducted with anyofthese three distributions led to an identical Spearman correlation coefficient of 0.98 between true and estimated dissimilarities for 100 simulated listeners. This correlation is the same for the three distributions and is just above the correlation obtained with the simulation based on the true dissimilarities resulting from an evenly filled space. Even with those three distributions, as mall bias remains. There is still asystematic bias which leads to dissimilarity values that are overestimated compared to the true dissimilarity values for the different tested distributions. The histograms in Figure 2confirms that the method overestimates the higher dissimilarities. However, this bias does not change the ranking of the averaged dissimilarity data, thus leading to ah igh Spearman correlation coefficient.

The possibility to simulate the SPPRm ethod allowed us to estimate this bias which seems to originate from the dissimilarity construction rather than from the properties of the true dissimilarity matrix or from the noise added to the responses of simulated listeners. The bias is intrinsic to the design of the method butisrelatively small. In order to assess its practical importance, the method of similarity picking with permutation of references wasa pplied to an actual listening test.

Listening test: Application to the evaluation of dissimilarity between loudspeakers

The SPPRm ethod wast ested on an actual sound corpus.

Alistening test wasconducted to evaluate the sound reproduction of loudspeaker recordings. The results were compared to those obtained by Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF][START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF], who used paired comparisons, the method mostly employed when evaluating loudspeakers [START_REF] Lipshitz | Va nderkooy: The great debat: subjective evaluation[END_REF][START_REF] Gabrielson | Perceiveds ound quality of high fidelity loudspeakers[END_REF][START_REF]AES recommanded practice for professional audio -subjective evaluation of loudspeakers[END_REF][START_REF]Sound system equipment -Part 13: Listening tests on loudspeakers[END_REF]. Here, the perceptual results obtained by Lavandier et al. and by the SPPR method are directly compared. First of all, the dissimilarity values resulting from the twom ethods are compared. Then, the MDS analysis of the dissimilarity data allows the comparison of the resulting perceptual spaces.

Stimuli

The work conducted by Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF][START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF] aimed at investigating the restitution of musical excerpts by several loudspeakers. The stimuli consisted of the sound radiated by 12 single loudspeakers recorded at as ame position in the same room using the stereophonic technique AB-ORTF.T he recordings were reproduced under headphones during the listening test. The musical excerpt was McCoyT yner "Miss Bea" (3.3 s).A ll details concerning these recordings, loudspeakers, room and signal can be found in Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF][START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF].

Listeners

Twenty-sevennormal-hearing participants took part in our listening test. This corresponds to the number of listeners involved in the PC experiment conducted by Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF]. None of them had been trained in the perceptual evaluation of loudspeakers.

Procedure

For12loudspeakers, each reference sound wascompared to the 11 other sounds, which were randomly distributed in four triplets for each listener.The 11 sounds did not fill the 4triplets completely,therefore the last triplet wascompleted with one sound randomly chosen within the first 3 triplets. The entire test comprised 48 trials for each listener and wasd ivided into twos essions which lasted about 10 minutes each, and were separated by as mall break. As a comparison, the PC experiment conducted by Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF] lasted about 20 minutes.

Listening tests were conducted with agraphical user interface that comprised four square buttons corresponding to the four stimuli. On each trial, the four stimuli (reference + three comparison sounds)w ere initially presented in sequence. After this initial presentation, listeners could listen to anyofthe stimuli, as manytimes as theywanted, by clicking on the corresponding button. In order to conclude the trial, theyhad to choose the stimulus most similar to the reference. Listening tests were carried out in a soundproof booth and the stimuli were reproduced through headphones (Stax SR Lambda Professional; same model as in [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF]).

Results and comparison

Perceptual dissimilarities

The dissimilarity data resulting from our experiment were compared to the data obtained by Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF] with the PC method. Forb oth methods, the diamonds on Figure 4r epresent the Pearson correlation coefficients between the average matrix computed from all individual matrices, and the average matrices computed for subsets of individual matrices. The increasing number of listeners (x axis)c orresponds to the size of each subset considered in the comparison. Each diamond represents the average of 100 Pearson correlation coefficients computed from random subsets of individuals of the same size. Results for both PC and SPPRmethods showav ery similar trend. The correlation coefficient asymptotes its maximum value for subsets containing at least 20 individual matrices. Twenty listeners appeared sufficient for recovering a reliable group-average dissimilarity matrix for both the PC and SPPRmethod.

Black dots on Figure 4present the Spearman correlation coefficients between the average matrix resulting from the PC method, and the average matrix computed for subsets of individual matrices resulting from the SPPRm ethod. Again, for each subset size (x axis), Figure 4presents the average and standard deviation for 100 random subsets of listeners. The correlation increases sharply between 0and 10 listeners and remains constant when reaching 20 listeners. This tendencyi sq uite similar to what waso bserved for the simulations.

The maximum Spearman correlation coefficient between the SPPRa nd PC matrices is 0.75 (black dots on figure 4).T his value indicates that the matrices resulting from the twolistening tests are overall quite similar.Note that for this comparison, the mean dissimilarities are obtained from real (i.e. not simulated)l isteners. This might explain whythe correlation between the PC and SPPRresults is lower than for the simulations.

Figure 5s ummarizes an analysis of the reliability of the group-average dissimilarities obtained with the SPPR method based on amethod similar to what used Giordano et al. [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF]. Twog roups of size Nw ere picked randomly (here without replacement)within the 27 individual matrices and the average matrix of each group wasc omputed. As an estimation of reliability,t he correlation coefficient R 2 wasc alculated between the average matrices of each group. The average value over1 0,000 draws wasc omputed and presented for values of Nb etween 1a nd 13. This group-average data reliability analysis wasd one for both SPPRand PC methods. The reliability values obtained for the PC method are close to the ones presented in [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF]. The reliability values obtained with the SPPRm ethod appear to be very close to those obtained with the PC method, even closer than those obtained with the alternative methods tested in [START_REF] Giordano | Comparison of methods for collecting and modeling dissimilarity data: Applications to complex sound stimuli[END_REF]. Note that for small values of N, the reliability might be overestimated because of the initial filling of the individual dissimilarity matrices. Foro ur maximum group size, both methods have areliability value close to 0.80. This is probably related to the experimental noise associated with the judgments by real listeners.

Perceptual MDS spaces

The dissimilarity data were analyzed using ametric MDS technique based on the SMACOF (Scaling by Majorizing aC omplicated Function)a lgorithm [START_REF] Borg | Modern multidimensional scaling, theory and applications[END_REF], which wasu sed by Lavandier et al. [START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF]. Figure 6s hows the stress plot for both methods as af unction of the number of dimensions. Twodimensions were retained for both experiments. Anyspatial configuration resulting from the SMACOF algorithm can be stretched or rotated. In order to compare the twoM DS spaces, aP rocrustes adjustment procedure that rotates aconfiguration to match another configuration wasperformed. As avisual comparison, Figure 7presents the auditory spaces derivedf rom the dissimilarity matrices obtained with the PC and SPPRm ethods. It can be observed that the twomethods provided very similar twodimensional spaces: the positions of the loudspeakers are very similar in the twoperceptual spaces.

To compare the MDS spaces, the Pearson correlation between the coordinates of the points representing the stimuli wasc alculated for each dimension. This correlation coefficient equals 0.99 for the first dimension and 0.91 for the second dimension. During the recording session, Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF] recorded the reproduction of two recordings from twoidentical loudspeakers (loudspeakers 7a nd 8).A se xpected, those twol oudspeakers appeared very close in the MDS space resulting from the PC experiment. This is also true for the SPPRe xperiment. For further information about the dimensions and their interpretation, the reader is referred to Lavandier et al. [START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF].

Discussion

Validity of the SPPR method

The results of the simulations together with the analysis of the actual listening test indicated that the SPPRmethod seems able to recoveranaverage dissimilarity matrix close to the one that can be obtained with the more commonly adopted PC method. Even if the SPPRm ethod is characterized by as ystematic bias (see section 3.4), it does not impact much the perceptual space revealed with an MDS analysis of the data. Conversely,t he SPPRm ethod does not provide individual dissimilarity matrices: their content is only arough estimate of the individual-leveldissimilarity,b ecause of the effects of the structure of the picking task itself. Interestingly,a veraging overal imited number of listeners nonetheless allows to get an estimate of the underlying dissimilarity which seems reliable enough to allowthe modeling of the underlying perceptual dimensions. The need of only alimited number is again confirmed by both our simulations and the listening test: around 20 listeners seemed to be sufficient. Fort he listening test, this number wassimilar for both SPPRand PC method. Moreover, the reliability estimated for both methods wasv ery close, and wasc haracterized by ah ighly similar effect of the number of listeners. As fara st he average dissimilarity matrix is concerned, the SPPRm ethod seems av alid alternative to the PC method.

Duration of SPPR experiments

With the proposed SPPRm ethod, each stimulus is used in turn as the reference, which leads to an entire test of n(n -1)/3t rials, n being the number of stimuli. During each trial, participants have to listen to am inimum of 4 sounds. As ac omparison, n(n -1)/2trials are needed in PC experiments, with am inimum of 2s ound playbacks for each trial. These are strict minima which do not take into account the potential need for listening several times to some excerpts -e .g. when dissimilarities are small or due to listener'sfatigue. The minimum number of sounds to be listened to is 33% higher for the SPPRt han for the PC method.

Assuming that the twom ethods are equally demanding, an experiment should last significantly longer for the SPPRmethod than for the PC method. Conversely,our experiment showed that both tests last about the same time (20m inutes for 12 stimuli). Such an overall duration is only avery coarse estimate, butthis comparison may indicate that the task involved in the SPPRmethod wasexperienced by the listeners as simpler than adirect dissimilarity evaluation. Indeed, even with 4s ounds per trial, the need to listen again to some excerpts or the time needed to make adecision were reduced. This corresponds to some of the listeners comments which were gathered at the end of each test. Unfortunately,w ed id not record event data sustaining this hypothesis when conducting our experiments. It has still to be backed by future work.

Further developments

The majority of previous studies on paired comparison of sound stimuli involved am aximum of 20 stimuli. Evaluating more stimuli potentially leads to am ore homogeneous repartition of the stimuli along the perceptual dimensions and provides abetter description of the perceptual space. It might also allowt he experimenter to reveal more dimensions compared to the perceptual results obtained with smaller sets of sounds. However, the number of presentations (pairs)o ft he experiment increases dramatically with the number of stimuli. Direct similarity ratings involving alarge number of stimuli then become too demanding, as previously stated [START_REF] Borg | Modern multidimensional scaling, theory and applications[END_REF]. Such an experiment is time consuming and the fatigue or the loss of attention of listeners becomes significant [START_REF] Scavone | The sonic mapper: An interactive program for obtaining similarity ratings with auditory stimuli[END_REF]. Most of the studies evaluating large sets of sounds point out the fact that the evaluation of large sets with the paired comparison would be "inefficient" [START_REF] Tsogo | Multidimensional scaling methods for many-object sets: Ar eview[END_REF], "cumbersome" [START_REF] Rao | Alternative multidimensional scaling methods for large stimulus sets[END_REF], "undesirable" [START_REF] Spence | Single subject incomplete designs for nonmetric multidimensional scaling[END_REF] or "limited" by the number of pairs to evaluate [START_REF] Bonebright | An investigation of data collection methods for auditory stimuli: Paired comparison versus acomputer sorting task[END_REF]. Formost listening experiments, it is then recommended to have listeners taking breaks between listening sessions in order to avoid the inconvenience of al ong duration test. Am aximum duration of 30 minutes per session is often recommended [START_REF]AES recommanded practice for professional audio -subjective evaluation of loudspeakers[END_REF]. To evaluate alarge set of audio stimuli, the experimenter must then divide apaired comparison experiment into several sessions.

As farasweknow, there are no studies that have compared aPCdissimilarity estimation conducted during one single session and the same experiment run in several sessions. Poulton [START_REF] Poulton | Models of biases in judging sensory magnitude[END_REF] underlined the sequential or "transfer from previous judgments" bias which exists between the judgment made during one trial and the judgments made during previous trials. Poulton [START_REF] Poulton | Biases in quantitative judgements[END_REF] specified that "the sequential contraction bias is likely to affect anyseries of judgments, unless each stimulus is judged deliberately against astandard stimulus". The permuted references and the forced choice task involved in the SPPRmethod might then contribute to reduce such "sequential bias" by limiting the tendencyo fl isteners to change their evaluation scale between trials. Splitting the test into several sessions could then be less concerning. This is the topic of ongoing work concerning the SPPRmethod.

Conclusion

The similarity picking with permutation of references (SPPR)m ethod wasinspired by avisual experiment conducted to evaluate the similarity between images. In this paper,itwas adapted to auditory evaluation in order to propose an alternative method to the paired comparison (PC) method.

Simulations were conducted in order to investigate the effect of the number of stimuli and listeners on the estimation of dissimilarity.I tw as shown that the number of stimuli involved in the simulation did not influence this estimation. The simulations also showed that most of the dissimilarity information wasgathered with about 20 simulated listeners. Asmall bias appeared in the estimation of dissimilarity leading to overestimate the dissimilarity values. This bias wasc haracterized and seemed to originate from the design of the experiment.

Alistening test wasconducted with 12 loudspeakers and compared to the PC method. Comparing dissimilarity data and MDS spaces revealed that the SPPRmethod givesresults very similar to those obtained with the standard PC method. Even if the PC and the SPPRm ethods require a different task from the listener,t he average dissimilarity judgments obtained with the SPPRmethod were well correlated with those obtained by Lavandier et al. [START_REF] Lavandier | Comparative measurements of loudspeakers in al istening situation[END_REF] with the PC method. The analysis of the dissimilarity matrices led to two-dimensional spaces whose dimensions were very similar to the dimensions obtained by Lavandier et al. [START_REF] Lavandier | Identification of some perceptual dimensions underlying loudspeaker dissimilarities[END_REF].

The SPPRmethod seems to involveasimpler task and its embedded reference could help to divide an entire test into several sessions. This is amotivation for further work, aiming at the evaluation of the performance of the SPPR method for larger sets of stimuli.

Figure 1 .

 1 Figure 1. Design of an experiment involving the method of similarity picking with permutation of references. Each rectangle represents asound. The comparison sounds presented with each reference are randomly distributed in triplets for each reference.

Figure 2 .

 2 Figure 2. Non-linear relation between true and estimated dissimilarity values obtained with Simulation 1for 40 stimuli and histograms presenting their distributions between 0and 1.

Figure 3 .

 3 Figure 3. Correlation between true and estimated dissimilarity matrices in Simulation 2a saf unction of the number of listeners for 40 stimuli. The original simulation and the noisy simulations are presented. The percentage of modification equals the proportion of modified responses givenbythe "noisy" simulated listeners overthe total number of responses.

Figure 4 .

 4 Figure 4. Pearson correlation coefficients between subsets of individual matrices and the group-average matrix, for PC method (black diamonds)and SPPRmethod (greydiamonds). Spearman correlation coefficients between subsets of individual SPPRmatrices and the average PC matrix (black dots). Bars represent ± one standard deviation.

Figure 5 .

 5 Figure 5. Group-average correlation coefficient (R 2 )a ssociated with its standard deviation as af unction of the number of listeners in each group for both PC (black diamonds)a nd SPPR method (greydiamonds).

Figure 6 .Figure 7 .

 67 Figure 6. Stress plots for MDS analysis resulting from the PC method (dashed line)and from the SPPRmethod (plain line).

Table I .

 I Number of trials presented for each reference, (n -1)/p, and number of trials in the entire test, n(n -1)/p,asafunction of the number of comparison stimuli p presented during one trial for aset of 40 stimuli.

	p	(n -1)/p			n(n -1)/p
	21 97 80 31 35 20 49 360 57 280 66 240
		Reference stimulus Reference stimulus	Essai Essai
		1	1	1 2 3 (n-1)/3 1 2 (n-1)/3 3 ... ... ...	...	...	...	...	...
		2	2	1 2 3 (n-1)/3 1 2 (n-1)/3 3 ... ... ...	...	...	...	...	...
		...	...			...	...	...	...	...	...
		n	n	1 2 3 ...	1 2 3 ...	...	...	...	...	...	...

Essai 1 ... ... ... 1 2 3 (n-1)/3 ... Stimuli de comparaison Reference stimulus 2 ... ... ... 1 2 3 (n-1)/3

	Number of listeners
			...
	...	...	...	...	...	...	...	...
			1
			2
		n	3
	Number of stimuli		...	...		...		...

Tr ial 1 ... ... ... 1 2 3 (n-1)/3 ... Comparison stimuli Reference stimulus 2 ... ... ... 1 2 3 (n-1)/3

	...

©S.Hirzel Verlag • EAA

Vol. 99 (2013)

Michaud et al.:D issimilarity between auditorystimuliVol. 99 (2013)

ACTA ACUSTICA UNITED WITH ACUSTICA Vol. 99 (2013)

Acknowledgement

The authors are grateful to the listeners who took part in the listening test. The authors also thank Bruno Giordano and an anonymous reviewer for very constructive remarks and suggestions.


Infant peri-exposure prophylaxis for 12 months to eliminate breastfeeding transmission of HIV-1 in Africa.

The ANRS 12174 cohort

Summary

The efficacy of infant peri-exposure prophylaxis (PreP) to prevent HIV-1 postnatal transmission has never been assessed for the entire recommended period of breastfeeding (12 months).

The ANRS 12174 study is a randomised controlled trial comparing the efficacy and safety of lopinavir/ritonavir versus lamivudine to prevent HIV-1 postnatal transmission in breastfeeding children born to HIV-1-infected mothers not eligible for ART (CD4 count above 350 cells/mL) during breastfeeding (maximum 50 weeks). HIV-uninfected children aged 7 days were randomised for either drug in a 1:1 ratio.

Infant HIV-infection status was assessed at week 6, 14, 26, 38 and 50 using HIV-1 DNA PCR. The study has completed enrolment in April 2012 in Burkina Faso, Uganda, Zambia and South Africa. We report the current postnatal HIV-1 transmission rate and HIV-1 free survival in the cohort among children aged 50 weeks or more in July 2012.

By the end of July 2012, of 1273 children enrolled in the trial, 788 were aged 50 weeks or older. During this period, 8 transmissions occurred representing a cumulative transmission rate of 1.1% (95%CI: 0.6-2.2). Interestingly, 6/8 transmissions occurred after 6 months of breastfeeding. Overall, 188 severe adverse events (grade 3 or more, DAIDS classification) and 22 deaths were identified. None were considered attributable to the study drugs. The overall cumulative mortality was 3.0% (95%CI: 2.0-4.5) and HIV-1-free survival was 96.0% (95%CI: 94.3-97.2).

Infant PreP is an efficacious strategy that could contribute to the elimination of HIV-1 transmission by breastfeeding.

Infant peri-exposure prophylaxis for 12 months to eliminate breastfeeding transmission of HIV-1 in Africa the ANRS 12174 cohort

Rationale

Based on the goals for 2015 and on results of randomised clinical trials and interventional cohorts (1-10), the WHO presently recommends several options for prevention of HIV transmission to breastfed infants of HIV-infected mothers not eligible for antiretroviral therapy (ART) (i.e. CD4 count > 350 cells/µL and WHO clinical stage <3), as follows [START_REF] Who | Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: recommendation for a pulib health approach[END_REF][START_REF] Who | Use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants -Programmatic update[END_REF]:

Option A -infant peri-exposure prophylaxis (PreP): mothers receive daily azidothymidine (AZT) during pregnancy, a single-dose nevirapine at delivery and, lamivudine plus AZT for one week post-partum. Children receive daily nevirapine (NVP) immediately after birth for a minimum of 4 to 6 weeks, until 1 week after all exposure to breast milk has ended.

Option B -maternal triple antiretroviral prophylaxis (ARP): mothers receive ARP as early as 14 weeks of gestation until 1 week after all infant exposure to breast milk has ended.

Option B+ -maternal ART: HIV-infected pregnant women receive lifelong ART, regardless of their clinical or immunological status.

The recommended duration of breastfeeding is 12 months, in order to reduce infant mortality and morbidity due to early weaning [START_REF] Who | Guidelines on HIV and infant feeding[END_REF].

Although option A (using either nevirapine or lamivudine) and B have both proved efficacious in clinical studies, none has administered any of the recommended prophylaxis beyond 6 months, covering only half of the WHO recommended duration of breastfeeding (12 months) for HIV-1-exposed children.

Similarly, the drug of choice for prophylaxis of breastfeeding transmission of HIV relies only on the comparison between different studies, without direct comparison between drugs. Lopinavir/ ritonavir (LPV/r), a protease inhibitor with paediatric formulation, has a greater antiviral activity than nucleosidic reverse transcriptase inhibitors or non nucleosidic reverse transcriptase inhibitors [START_REF] Chadwick | Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results[END_REF], and a good safety profile in young children [START_REF] Chadwick | Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results[END_REF][START_REF] Chadwick | Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy[END_REF][START_REF] Violari | Early antiretroviral therapy and mortality among HIV-infected infants[END_REF], which makes this drug a good candidate for prophylactic purposes, despite its poor palatability.

We report on the postnatal transmission and mortality rates of WHO option A at one year of age using either LPV/r or lamivudine from an unblinded randomised trial conducted in four African countries: Burkina Faso (Ouagadougou), Uganda (Mbale), Zambia (Lusaka) and South Africa (East London).

Material & Methods

Study design

This cohort report is based on the ANRS 12174 randomised controlled trial (ClinicalTrials.gov Identifier: NCT00640263) comparing the efficacy and safety of prolonged infant PreP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus lamivudine (7.5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) to prevent HIV-1 transmission through breast milk in children born to HIV-1-infected mothers not eligible for ART during the full duration of breastfeeding (maximum 50 weeks).

Study population

Inclusion criteria: • breastfed at day 7;

• negative HIV-1 DNA PCR test result at day 7;

• had received any PMTCT;

• the mother: was HIV-1 infected and was not eligible for ART and was not taking ART.

Exclusion criteria: they presented clinical symptoms and/or biological abnormalities equal to or greater than grade II of the ANRS classification for adverse event on the day of enrolment.

Biological assays

Infant HIV-1 infection was diagnosed on DBS by means of real-time PCR detecting HIV-1 DNA (Generic HIV DNA cell, Biocentric, France) [START_REF] Avettand-Fenoel | LTR real-time PCR for HIV-1 DNA quantitation in blood cells for early diagnosis in infants born to seropositive mothers treated in HAART area (ANRS CO 01)[END_REF].

HIV-1 infection was confirmed on a second sample by the same technique [START_REF] Rouet | Impact of HIV-1 genetic diversity on plasma HIV-1 RNA Quantification: usefulness of the Agence Nationale de Recherches sur le SIDA second-generation long terminal repeat-based real-time reverse transcriptase polymerase chain reaction test[END_REF].

Results

In April 2012, the study completed enrolment of 1273 babies in the four African countries.

As of 23 rd of July 2012, 813 infants were aged 50 weeks or more (figure 2). Among them, 25 never came back after enrolment, leaving 788 children included in the cohort analyses: 105 children from South Africa, 143 from Uganda, 166 from Burkina Faso and 374 from Zambia.

PMTCT was provided according to national guidelines during pregnancy and labour for more than 95% of mothers, except in Uganda where PMTCT was given during labour only for 24% of women.

Among these 788 children, no HIV-1 testing was available after enrolment for 19 children, 682 completed the final visit; they provided 695 child-years of follow-up for the mortality outcome, and 679 for the HIV-1 outcome (figure 2).

Discussion

First report of the infant PreP strategy during the recommended 12-months duration of breastfeeding with both the lowest postnatal transmission rate (1.1%, 95%CI: 0.6-2.2) and the highest HIV-1 free survival rate (96.0%, 95%CI: 94.3-97.2) ever published.

Combined with mother MTCT, option A allowed an overall MTCT below 2%, well within the target of elimination.

About three-quarters of transmissions occurred after 6 months of age, the time when all previous studies (using either infant PreP or maternal ARP) had stopped antiretrovirals. This stresses the need to obtain complete and valid efficacy data before issuing policy recommendations and choosing between the infant PreP option (A) or the maternal option (B/B+).

Our study had several limitations:



Although still possible, it is unlikely that some deaths be attributed to undiagnosed HIV-1 infection, given the narrow period since the last HIV-1 negative test. AZT after birth). These transmission rates on maternal ARP are four times higher than the MTCT in our cohort at the same time (0.67% perinatal + 0.3% postnatal transmission at 6 month, i.e. 1.0% overall).

The choice of option A or B/B+ to prevent HIV-1 postnatal transmission should be based on robust scientific grounds. Our findings should encourage maintaining infant PreP among the strategic options offered to prevent breastfeeding transmission of HIV-1. As infant PreP, in contrast to maternal ARP, can prevent cell-associated HIV-1 transmission events, [START_REF] Rouet | Impact of HIV-1 genetic diversity on plasma HIV-1 RNA Quantification: usefulness of the Agence Nationale de Recherches sur le SIDA second-generation long terminal repeat-based real-time reverse transcriptase polymerase chain reaction test[END_REF]19) it could avert more residual transmission cases than maternal ARP. This could explain the large difference in HIV transmission between the Kesho-Bora trial (maternal ARP) and our study.

Conclusion

The ANRS 12174 study, covering the 12 months of recommended breastfeeding, demonstrated that the infant PreP strategy is an efficacious and safe strategy that could contribute to the elimination of HIV-1 transmission. The identification of the best drug to use for this strategy is the next outcome of this trial.

Competing interests

The authors declare that they have no competing interests.

Breastfeeding

The overall median duration of any breastfeeding was 41 weeks (figure 3)

HIV-1 transmission 8 HIV-1 transmissions have been identified: 5 in Zambia, 3 in Uganda, 0 in Burkina Faso, 0 in South Africa;

→ Cumulative postnatal transmission rate: 1.1% (95%CI: 0.6-2.2).

Interestingly, 6 out of 8 (75%) transmissions occurred after 6 months of breastfeeding, and 2 transmissions occurred within the first six weeks.

A 9 th transmission case was detected at 69 weeks after intensive search for a child who never attended any visit since enrolment. Accounting for this case, the HIV-1 transmission rate would become 1.3% (95%CI: 0.7-2.4).

The HIV-1 transmission rate between day 7 and 26 weeks was 0.3% (95%CI: 0.1-1.1).

Among the 1760 mothers potentially eligible in the trial, 1484 of their babies were tested for HIV-1 and 10 were HIV-1 infected (figure 2), giving a perinatal HIV transmission of 0.67%. Therefore, the overall MTCT of full option A was 1.8% using PMTCT during pregnancy and labour as implemented by national programmes followed by our infant PreP regimens. All had a negative HIV-1 DNA PCR test when last tested, on average 7 weeks before death (min: 1 week, max: 35 weeks). No death was deemed attributable to the study drugs.

HIV-1-free survival

Probability for a child to be alive without HIV-1 infection:  98.2% (95%CI: 96.9-98.9) at 26 weeks; At 50 weeks, it was the highest in South Africa (98.9%), and the worst in Uganda (92.7%) (figure 4).

Severe adverse events

Among the 788 children, 188 severe adverse events (88 clinical and 100 biological with no clinical symptoms) had been reported. In April 2012, the Independent DMC recommended continuation of follow-up without unblinding, to the end of the trial (planned in May 2013), considering that these adverse events were not grossly unbalanced between the two arms.

T

  . Tylleskär, N. Nagot, C. Kankasa, N. Meda, J.K. Tumwine, J.G. Hofmeyr, M. Mwiya, C. Siuluta, H. Traore, M. Kwagala, A. Sunday, M. Singata, R. Vallo, V. Maréchal, E. Some, D. Rutagwera, D. Neboua, G. Ndeezi, D. Neveu, D. Jackson, C. Lombard, S. Blanche, H. Sommerfelt, C. Rekacewicz and P. Van de Perre for the ANRS 12174 Trial Group



  All aspects of the infant PreP safety could not be addressed at this stage.  The drug adherence data have not yet been analysed. Comparison with maternal antiretroviral prophylaxis (ARP) trials: In the Kesho-Bora trial, among mothers with CD4 count > 350 cells/µL, the 6-month transmission rate, when exposure to breastfeeding stopped, was 4.1% (2.0-8.3%) among mothers with maternal ARP from 28 weeks of pregnancy vs. 5.8% (3.1-10.5%) in the placebo arm (AZT during pregnancy and NVP during labour, infant single-dose NVP at birth and one week

Mortality

  22 children died: 3 in Burkina Faso, 1 in South Africa, 7 in Uganda and 11 in Zambia; → Overall mortality rate: 3•0% (95%CI: 2.0-4.5).

Figure 2 .Figure 3 .

 23 Figure 2. ANRS 12174 cohort profile of infants aged 50 weeks or more on July 23, 2012

Figure 4 .

 4 Figure 4. Life table of HIV-1 free survival by site and overall in the ANRS 12174 cohort

Figure 1 .

 1 Figure 1. ANRS 12174 Study design

Table 1 .

 1 Baseline (day 7) characteristics of mothers and infants aged 50 weeks or more on the 23 rd of July, 2012 in the ANRS 12174 cohort.

WHO clinical HIV staging