Julia Monnin
email: monninjulia@yahoo.fr

Hélène Loevenbruck
email: helene.loevenbruck@gipsa-lab.grenoble-inp.fr

LANGUAGE-SPECIFIC INFLUENCE ON PHONEME DEVELOPMENT: FRENCH AND DREHU DATA

Keywords: Phonological development, lexical frequency, universal, language-specific, French, Drehu language

This study extends a cross-linguistic collaboration on phonological development, which aims at comparing production of word-initial sequences of consonant-vowel (CVs) across sets of languages which have comparable phonemes that differ in overall frequency or in the frequency with which they occur in analogous sound sequences. By comparing across languages, the influence of language-specific distributional patterns on phoneme mastery can be disentangled from the effects of more general phonetic constraints on development. We made word and non-word repetition experiments with Frenchand Drehu-acquiring two-year-old to five-year-old children. We first analysed production in words according to frequency data in French and Drehu. Results show that productions of word-initial consonants are correlated with their frequencies, especially in younger children. Then we compared the non-word production scores of French-and Drehu-acquiring children. French and Drehu learners have similar mean scores but show different patterns for specific phonemes that differ in frequency.

INTRODUCTION

Universal tendencies during phonological development have long been described [1]. Some sounds and sound sequences, considered as « difficult », are acquired later than other sounds which are observed universally in canonical babble, whatever the child's ambient language. For example, sibilant fricatives and affricates are mastered later than stops [START_REF] Hua | The phonological acquisition of Putonghua (Modern Standard Chinese)[END_REF]. Dorsal stops are mastered later when the following vowel is /i/ as compared to /u/ [START_REF] Davis | Acquisition of serial complexity in speech production: A comparison of phonetic and phonological approaches to first word production[END_REF]. Intrasyllabic associations also seem to follow universal tendencies, which have been explained by mandibular oscillations associated with secondary movements of the tongue, velum and lips [START_REF] Davis | Acquisition of serial complexity in speech production: A comparison of phonetic and phonological approaches to first word production[END_REF].

If universal biomechanical constraints seem to shape the child's first productions, language-specific influences have also been observed, however. Some of the "phonetically difficult" sounds are acquired relatively sooner in some languages than in others. For example, /v/ seems to be mastered earlier in Swedish, Estonian, and Bulgarian than it is in English [START_REF] Ingram | The acquisition of word-initial [v][END_REF]. Ingram [4] suggests this is because of the low type frequency of /v/ in English compared to the other cited languages. Therefore some language-specific differences in phonological development might be related to differences in phoneme and phoneme sequence frequency across languages (see also [START_REF] De Boysson-Bardies | Material evidence of infant selection from the target language. A crosslinguistic phonetic study. Phonological development: models, research, implications[END_REF]). The ambient language would influence the child's first productions. A recent French-German comparison has even showed an influence of the surrounding speech prosody on newborns' cry melody [START_REF] Mampe | Newborns' Cry Melody Is Shaped by Their Native Language[END_REF].

This study is framed within the Paidologos Project (http://www.ling.osu.edu/~edwards/), a cross-linguistic investigation of phonological development. The aim is to compare the production of word-initial sequences of obstruent-vowel across many languages which contain sound sequences that differ in frequency. Children aged 2 to 5 were tested in the languages already studied (Cantonese, English, Greek, Japanese). The present study aims at extending the project to French and Drehu. Drehu is an Austronesian language, with around 15 000 speakers, and is mostly spoken on Lifou Island in New Caledonia. Drehu displays a rich consonant inventory. Although French is quite present in the environment of Drehuacquiring children, Drehu is the dominant language at home and at school on Lifou Island [START_REF] Moyse-Faure | Le drehu, Langue de Lifou (Iles Loyauté)[END_REF].

We first analysed children production according to the frequency data in French and Drehu. Then we compared the production scores of French-and Drehu-acquiring children on similar word and non-word repetition tasks.

CORPUS

Monolingual French-acquiring children and Drehuacquiring children in bilingual French-Drehu environment (referred to as "bilingual children" for the sake of brevity) have been recorded in word and non-word repetition tasks. Eight groups of about 20 French-acquiring children from 2 to 5 years old were recorded, as well as 3 groups of about 20 Drehu-acquiring children, aged 3 to 5. The children had to repeat a list of words in their mother tongue (in French for the "monolingual" children and in Drehu for the "bilingual" ones) and a list of typical French non-words. The words and non-words started with one of the consonants studied in the project. The children were seated in front of a computer and saw pictures of the pronounced words and non-words. The words and nonwords had been previously recorded by two female native speakers in a child-directed speech style. The instruction was to repeat the sound. A native speaker of French (first author) and a native speaker of Drehu transcribed the data.

For words, in French, the consonants were: /t/, /d/, /k/, /g/, /s/, //, /t/, /z/, /n/, /tw/ and /kw/. They were followed by: /A/ (/a/, // and / )/, /E/ (/e/, //, /        / and / /), /O/ (/o/, // and / /), /8/ (// and //), /i/ and /y/. The words were as frequent as possible. For some consonants, (like /t/ for instance), the words were sometimes not so frequent. In Drehu, for words, the consonants were /t/, /d/, /k/, /g/, /t/, /dʒ/, //, //, /x/, /s/ and /z/, followed by /a/, /i/ and /u/.

The non-words were built so as to be typical of French. They followed average frequency of syllable sequences in French. The consonants used belonged to the phonological systems of both French and Drehu. Since the frequency of these consonants are not similar in French and Drehu, this allowed us to compare production on phonemes that are rare in French but frequent in Drehu, and reciprocally. Eleven consonants were tested: /d/, /dz/, /dʒ/, /g/, /k/, /kw/, /t/, /t/, /tw/, /z/, /ʒ/.

For the two languages, the transcriptions only concerned the word-initial consonant-vowel sequence. The transcriptions were both phonological (success or failure on the repetition of the consonant and the vowel) and phonetic (detailed coding of the type of error).

ANALYSIS OF CONSONANT PRODUCTIONS ACCORDING TO THE INPUT

Methods

The data obtained in word repetition were first compared with the frequency data. Some studies suggest that frequency data on phonemes can vary according to the register. Typical input to children may differ from adult lexicon. We have therefore used frequency data that were obtained from recordings of adults speaking to 2-year olds in French and in Drehu. More information on these corpora and their analyses is given in [START_REF] Monnin | Influence des fréquences lexicales des langues française et drehu sur l'acquisition des consonnes initiales de mots[END_REF]. Correlation coefficients have been calculated on the 11 pairs of data. Each pair consists of the score of correct consonant production and the consonant frequency in the language.

Results

French -Figure 1 shows the correlation between percent correct repetition of word-initial consonants and consonant frequency in French for the youngest children in this study (20 children aged 2 years to 2 years 5 months). The two variables are highly correlated (Pearson correlation: 0.81, significant). It should be noted that for children aged 3 years to 3 years, 5 months, the correlation falls to 0.77 and to 0.60 for children aged 3 ½ years to 3 years, 11 months. Figure 2 shows that at 5 years (20 children aged 5 ½ years to 5 years, 11 months), the input frequencies do not explain the scores obtained in word repetition in French (correlation .51, non significant).

Drehu -Figure 3 shows the correlation between percent correct repetition of word-initial consonants and consonant frequency in Drehu for 16 children aged 3 years to 3 years 11 months. The correlation is quite high (0.67, significant). Figure 4 shows that at the age of 5, just like in French, the correct productions are less correlated with the input frequencies (correlation 0.63, significant). It can thus be observed that at the ages of 2 and 3, children consonant production is quite correlated with the frequency in the ambient language; later, when children have a good mastery of their mother tongue, ambient language influence is less obvious. The correct production scores are then higher than 70% for French-acquiring children, and 60% for Drehu-acquiring children.

COMPARISON BETWEEN FRENCH AND DREHU NON-WORD REPETITION TASKS

French and Drehu children were tested on the same nonword repetition task. These data are used to compare the two groups of children with identical repetitions.

Methods

To compare the two groups of children, we grouped together all the 3-year old French-acquiring children, and did the same for the 4-and 5-year olds. The 2-year old French children have not been selected for this study because they were not able to do this non-word repetition task. We therefore analysed the productions of 164 children (116 monolinguals and 48 bilinguals.)

Results for the consonants

An ANOVA shows that the age factor is significant (F(2,316)=29.88 p< .001) but not language (F(1, 158) = 3.01, p=.085). As shown in Figure 5, correct production gradually increases from 3 to 5 years and exceeds 50% at 5 years for the 11 consonants tested.

Figure 6 presents the results obtained in non-word repetition for the initial phonemes /k/, /g/, /t/ and /d/.

Comparisons between these consonants are interesting because different trends were obtained for them depending on the language (for example /t/ is better produced than /k/ in English but it is the opposite in Japanese). The results of the statistical analysis on our data show that the effect of language is not significant for these phonemes, except for /t/ which is better pronounced by monolinguals (F(1,158) = 6.38; p = .012). Yet /t/ is more frequent in French than Drehu. We can also note that /k/ reaches over 70% success even at an early age, contrary to data in the literature, where it is considered as a "difficult" phoneme [1]. This result is similar to what was observed for Japanese [START_REF] Beckman | Language-specific and language universal aspects of lingual obstruent productions in Japanese-acquiring children[END_REF] and can be explained by the fact that /k/ is very common in both French and Drehu.

Figure 7 provides the results of non-word repetition for /t/ and /dʒ/, frequent in Drehu and rare in French, and /ʒ/ and /z/ quite common in French and rare in Drehu. The effect of language is significant for /t/ (F(1,158) = 4.86 p = .029) and /dʒ/ (F (1,158) = 4.75 p = .031): bilinguals have better scores. The frequency of a phoneme in a language thus seems to have an impact on its production.

Results for vowels

At 3 years, /A/ is better produced by monolinguals than bilinguals (t(42) = 3.042, p <.05); the production of the other vowels is comparable from one group to another (Figure 8). At the age of 4, /A/ and /i/ are better produced by the group of monolinguals (/A/: t (44) = 2.642, p <.05; /i/: t(44) = 3.625, p <.05). Finally, at the age of 5, only /i/ is better produced by the monolinguals (t(45) = 3.716, p <.05). Figure 9 shows vowel frequencies in initial CV sequences in the Drehu input: /i/ is rare. In French (Figure 10), our data show that /i/ has middle range frequency, which may explain the better production scores compared to Drehu. It should be noted that the 4 vowel groups were not produced in similar contexts: some were preceded by frequent consonants in French, others by frequent consonants in Drehu, or other. This may explain the fact that /A/, for instance, yields better production scores in French, although it is quite frequent in both languages.

DISCUSSION AND CONCLUSION

The initial phonological skills in young children (2-3 years) appear to be strongly correlated with the frequency in the input data. For our group of young French children, this correlation is very strong, and it is also quite strong for our group of Drehu-French bilingual children. As expected, these correlations decrease when the children are older (5 years) in the two groups considered. There is some evidence that bilingual children have sometimes a delay in lexicon acquisition. It is also known that phonological skills are associated with increased lexicon size. Still, in our non-word repetition test, children from both groups did not differ in their scores for initial consonants. Monolingual and bilingual children do display some differences, however, when phonemes are compared in detail. The phonemes that are not frequent in French and more frequent in Drehu (/t/ and /dʒ/) are better repeated by the bilinguals. The opposite is found for /d/ and /i/ in French. Thus, Drehu "bilingual" children are influenced by the input in Drehu, even if they probably also receive some input in French. All together, our results suggest that the productions of young children are highly influenced by the ambient language.

Figure 1 :

 1 Figure 1: Correlation between correct score and input frequency in children aged 2 yrs to 2 yrs, 5 mos in French (S: //, tS: /t/).

Figure 2 :

 2 Figure 2: Correlation between correct score and input frequency in 5 ½ to 5 years, 11 months olds in French.

Figure 3 :

 3 Figure 3: Correlation between correct score and input frequency, 3 year olds, in Drehu (tS : /t/, dZ = /dʒ/, T = //, D = //).

Figure 4 :

 4 Figure 4: Correlation between correct production and input frequency in children aged 5 years in Drehu.

Figure 5 :

 5 Figure 5: Repetition of « French » non-words in Drehu-French bilingual children (D, left) and monolingual French (F, right) at 3 years (1), 4 (2) years and 5 years (3): means of correct repetitions +-1 standard deviations.

Figure 8 :

 8 Figure 8: % of correct repetitions of the vowel following the initial consonant in non-words (NW) with a standard deviation. 1: 3 years, 2: 4 years, 3: 5 years. Hatched: Drehu; gray: French.

Figure 9 :

 9 Figure 9: Vowel frequency in word-initial CV context in the Drehu input. /i/ is not frequent.

Figure 10 :

 10 Figure 10: Vowel frequency in word-initial CV context in the French input. /i/ has middle-range frequency.

ACKNOWLEDGEMENTS

We thank F. Wacalie, N. Henesewene for the Drehu transcriptions, and M. Beckman, A. Vilain for their comments.


PhD Sooky Lum
email: s.lum@ich.ucl.ac.uk

PhD Ah-Fong Hoo

MD Georg Hulskamp

PhD Angie Wade

PhD Janet Stocks

POTENTIAL MISINTERPRETATION OF INFANT LUNG FUNCTION UNLESS PROSPECTIVE HEALTHY CONTROLS ARE STUDIED

Keywords: Infant, forced expiratory maneuvers, pulmonary function test, Reference values, equipment Infant, forced expiratory maneuvers, pulmonary function test, Reference values, equipment

Rationale: Reliable interpretation of pulmonary function tests relies on appropriate reference data which remain very limited for infants.

Objectives: This study aimed to assess the validity of published reference equations for forced expiratory flow-volume (FEFV) data in infants when using current, commercially available equipment, and how this could impact on interpretation of results from infants with lung disease.

Methods:

The Jaeger Masterscreen BabyBody (v4.67) equipment was used to perform partial and raised volume FEFV maneuvers in healthy infants and those with cystic fibrosis (CF). Results were initially expressed as Z-scores using published reference equations. Multilevel modelling was used to calculate differences, if any, from predicted scores in healthy infants.

Results: Data were available from 66 healthy fullterm infants on 89 test occasions; [median (range) postnatal age 49.4(12-101) weeks. All FEFV outcomes were significantly lower than predicted, with mean (SD) Z-score differences of -0.4(1.1) for FVC; -0.6(1.0) for FEV 0.5 ; -1.0(1.0) for FEF 25-75 and -1.4(1.1) for V' maxFRC . After adjustments using multilevel modelling, mean Z-scores were within 0.1(SD~1.0) predicted for all outcomes in healthy infants. Among 50 infants with CF, studied on 85 test occasions, results were 'abnormal' (< -1.96 Z-scores) on 35 (41%) and 37 (45%) test occasions for FEV 0.5 and FEF 25-75 respectively when using published equations. This fell to 24(28%) and 20 (24%) respectively, after adjustment.

Conclusions: Dependence on published equations for interpreting FEFV data in infants may lead to misinterpretation of lung function status, which could impact adversely both in the research setting and on clinical management. Use of a contemporary control group or establishment of equipmentspecific reference data is essential for meaningful interpretation of infant lung function data.

INTRODUCTION

Assessments of forced expiration have been used extensively in older children and adults to assess the nature and severity of airway disease, response to therapeutic intervention and to monitor disease progression or resolution in both the clinical and research environments. While infants cannot be instructed to perform such maneuvers, forced expiratory flow-volume (FEFV) loops can be obtained by substituting voluntary effort with externally applied pressure to the chest and abdomen to force expiration. Measurements of maximal flow at functional residual capacity (V' maxFRC ) from the tidal rapid thoraco-compression technique (RTC) have been used to characterize growth and development of the airways during infancy [1][2][3] and, together with data derived from the raised volume RTC (RVRTC), have been found to discriminate clearly between health and disease within the research setting. [4][5][6][7][8] Nevertheless, if such tests are to be used in clinical management, reliable reference ranges are also required.

While prediction equations have been published for infant FEFV outcomes, 9,10 these were derived from children studied using equipment developed 'in-house' and the extent to which they remain appropriate for current, commercially available equipment that was introduced following recommendations from the ATS-ERS task force on infant lung function [11][12][13] has yet to be determined. The need to assess whether selected prediction equations are appropriate for a given population or specific equipment is well-recognized, [14][15][16] but has rarely been done in infants due to the time-consuming nature of these tests and need for sedation. In addition, increasing difficulty in obtaining ethics committee approval for sedating healthy infants during the past decade has severely limited the extent to which normal growth and development of infant lung function can be assessed in several countries, including the USA.

The aims of this study were to: a) assess whether FEFV results obtained from healthy infants using the current Jaeger equipment differ from predicted values, b) investigate whether, in the event of any significant offset, it would be possible to adjust for any equipment-specific differences in order to facilitate interpretation in infants with lung disease and c) evaluate the impact of applying such a correction factor to a cohort of infants with cystic fibrosis (CF) studied using identical equipment and techniques. Some of the results included in this study have been reported previously. 5

MATERIALS AND METHODS

The study population was comprised of: a) healthy fullterm (>37 gestational weeks) white infants without congenital abnormalities or respiratory compromise (i.e. no current respiratory problems or history of respiratory illness requiring hospitalization) who had been recruited to epidemiological studies or as controls for clinical research 5,17,18 and b) Infants diagnosed with CF without severe congenital, cardiovascular or neuromuscular disorders that could impact on the respiratory system, who had been recruited to clinical research studies. 5 Children with a history of apneic episodes or upper airway pathology were excluded. Local Research Ethics Committee approval was granted and written informed parental consent was obtained for all infants.

Equipment and study protocol: With the exception of two infants with CF who had had repeated respiratory exacerbations and were therefore tested as soon as asymptomatic for 14 days, lung function tests in all children were undertaken at least 3 weeks after any respiratory illness. Data were collected during quiet sleep, after oral sedation with chloral hydrate (50-100mg/kg depending on age). RTC and RVRTC data were collected using the Jaeger Masterscreen BabyBody System (CareFusion, San Diego). This equipment was designed in adherence with the ATS-ERS recommendations [11][12][13] and uses a low deadspace pneumotachometer with solid-state transducers. Tidal and raised volume maneuvers were performed in accordance with international recommendations 11,12 as previously described, 19,20 with the tidal RTC being performed prior to raised volume maneuvers. 21 The RVRTC was performed from an inflation pressure of 30 cmH 2 O, the maneuver being repeated until a minimum of three acceptable and reproducible FEFV curves was obtained. Forced expiratory volume in 0.5 second (FEV 0.5 ), forced vital capacity (FVC), forced expiratory flow when 75% FVC had been expired (FEF 75 ) and FEF between 25-75% FVC (FEF 25- 75 ) were reported from the "best" raised volume curve. The latter was defined as the technically 11 For RTC, the mean V' maxFRC from at least two (usually three) reproducible FEFV curves was reported. 12

Statistical Analysis

Power calculations demonstrated that FEFV measurements from 65 healthy children would enable differences equivalent to 0.4 SD (or Z-scores) to be detected between the controls and the published reference population with 90% power at the 0.05 significance level. Standard software packages were used for data inspection, distribution and descriptive statistics (SPSS for Windows, v15.0, SPSS Inc.). Results from healthy controls were expressed as Z-scores using published prediction equations. 9,10 To ensure that we would still be able to detect differences between those exposed to maternal smoking during pregnancy compared to those who were not, the calculation of Z-scores for RVRTC data was made with smoking status during pregnancy being set to 0 (zero) . The extent to which these Z-scores differed from zero according to sex, age and body size was inspected and univariable regression analysis was used to establish the association between each FEFV outcome and likely explanatory variables. Where potentially significant associations existed, these were further explored using multivariable, multilevel regression modeling (MLwiN, version 2.12;

Institute of Education, UK). These highly flexible models adjust for the correlated nature of repeated measurements in individuals and allow inclusion of variable numbers of measurements per child to provide the most precise characterization of changes over time. [22][23][24] To quantify the extent to which age or length was independently associated, after adjusting for factors accounted for by the Jones and Hoo equations 9, 10 , a stepwise approach was used in developing the multivariable models: each dependent (FVC, FEV 0.5 etc) was adjusted for potential determinants such as length, age, sex etc. The derived regression equations for the LF variables were then applied to results from children with CF to evaluate the potential impact of applying such an adjustment factor on clinical management. Data management was undertaken using Re-Base software (J7IS Ltd). 1).

F

On multilevel, univariable analysis, FVC, FEV 0.5 , FEV 75 , FEF 25-75 and V' maxFRC were all significantly and negatively associated with length (Table 2a) and age (Table 2b) at test. However after adjusting for length or age, addition of the other variable did not add significantly to the model, and length was chosen in preference to age to prevent any bias due to restricted growth when applying such equations to children with lung disease. Sex had already been taken into account in the original prediction equations, and was not further associated with any of the adjusted FEFV Z-scores.

After adjustment, the mean (SD) Z-scores for all FEFV outcomes in healthy controls approximated 0 (1.0), suggesting that the correction factors derived from these equations were appropriate (Table 1 and Figure 1).

Infants with CF

Data collected using the Jaeger equipment were available from 54 infants and young children with CF on 96 test occasions (mean (SD) age: 53.5 (26.7) w; length 73.9 (8.5) cm; weight 8.8 (2.2) kg).

When results were expressed in relation to published reference equations, an abnormal FEV 0.5 (< -1.96 Z-scores) was detected on 35/85 (41%) test occasions, whereas after applying the adjustment factor, this fell to 24 (28%). Similar results were observed for FEF 25-75 and V' maxFRC (Table 1 and Figure 2).

DISCUSSION

We have shown that, when using the Jaeger Masterscreen, FEFV data from healthy infants are significantly lower than published reference data, which could lead to over-diagnosis of lung disease in children with CF or other respiratory diseases. While published reference data for infant FEFV maneuvers 9,10 are clearly inappropriate for data collected using the Jaeger Masterscreen, application of an appropriate adjustment factor may minimize such errors until sufficient multicentre data are available to construct reliable equipment-specific reference ranges in this age group.

When using our original 'in-house' equipment and software (RASP), published reference data for both partial 9 and full 10 FEFV maneuvers appeared to be appropriate for use in our laboratory, as demonstrated by the mean (SD) Z-scores for FEFV outcomes which approximated 0 (1) in our local healthy controls. 6,21 After switching to commercial equipment (Jaeger Masterscreen BabyBody; v4.67), we used similar data collection and analysis techniques and were initially reassured that FEFV results from healthy controls appeared to remain in agreement with published reference ranges. 5 However, direct comparison of a limited number of infants, using an identical jacket, suggested that flows were lower when using the Jaeger system, 25 and as further healthy controls were studied using this equipment we became increasingly aware of a potential bias. 17 During the validation study 25 (see online supplement (OLS) for details), we established that there were no within-subject differences in pressure transmission between the systems and that the bias could not be attributed to failure to attain flow limitation, which was assessed independently for both systems by experienced operators.

Despite rigorous and time-consuming attempts to identify the source, the underlying cause of the observed discrepancies in V' maxFRC remains unknown. All algorithms for deriving outcomes from the Jaeger system were based on our original RASP set-up and were manually checked for accuracy. In addition, when 'raw data' in ASCII format were exported from the Jaeger system and re-analysed with our original software, values displayed by Jaeger were, if anything, slightly higher (mean difference 5%; 95% CI: 3.4; 7.0%). This was attributed to minor differences in how endexpiratory level (i.e. FRC) was calculated by the two systems (see OLS for details).

The only major difference that we could identify between the two systems was with respect to BTPS (body temperature, pressure, saturated) corrections, 26 which were applied to the flow (and hence volume) signal during data collection in the Jaeger system, whereas in our original system (and most other 'in -house' systems at the time, including those from which reference data had been generated), data were saved in original ATPS format with BTPS corrections being applied at the analysis stage. The way in which such differences could potentially impact on results is discussed in the OLS.

Equipment-specific differences in lung function have been reported previously in older subjects, 27,28 and it has been suggested that such discrepancies may be due to device-dependent characteristics such as in the integration of flow to volume, which, together with BTPS corrections, may be inaccessible to the end-user. In contrast to adult spirometers, there are currently no accepted waveforms with which to compare outcome measures for infant FEFV equipment, and even if there were this would not tackle the more complex issues relating to BTPS corrections during in-vivo measurements. 29 We therefore cannot ascertain whether the previous 'in-house' systems or new commercially available devices best approximate the 'truth'. What is apparent is that published reference data are not appropriate when interpreting FEFV data from the infant Jaeger equipment.

All data for this study were collected using the same version of software and in accordance with ATS/ERS recommendations 11,12 by experienced investigators (AFH/SL) thereby minimizing the chance that the lower flows and volumes obtained with the new equipment were simply due to 10 failure to achieve flow-limitation or poor quality control. Previous data collected from ICH using the homemade RASP system were in close agreement with that from other centers and were included in the collated dataset for V' maxFRC prediction equations. 9 Given that the mean V' maxFRC Zscore for data collected in our laboratory using the RASP system (n=283) was -0.52, i.e. 0.88 Zscores higher than that from our recent Jaeger data, it is likely that the observed differences reflect differences in hardware and software rather than population differences or changes in practice.

This study was only possible because we retain full ethics approval to undertake lung function measurements in healthy infants and have always attempted to recruit a prospective control group for clinical research projects. In the past, many research groups prospectively recruited healthy controls, 1, 5-7, 30-32 but during recent years there has been ongoing debate as to whether it is ethical to undertake lung function tests under sedation in healthy infants. Given the results from this study, it could be argued that it is unethical to undertake lung function tests in infants with lung disease (who are far more at risk of any sedation related adverse events than healthy children) without appropriate reference equations with which to interpret results. Indeed, had we not continued to recruit healthy controls prospectively after switching to commercially available equipment, our clinical and research data from the past 5 years would be potentially invalid. It is accepted that recruiting healthy infants to lung function studies is far more demanding and time consuming than enrolling those with lung disease, but in over 30 years of practice we have never observed an adverse event related to chloral sedation in a healthy infant, this group representing those at least risk from such events. 33 The clinical implications of using inappropriate reference ranges can be seen from our results in early life. 34 In addition to the anxiety caused to parents, reports of apparently 'diminished' LF results in asymptomatic infants and young children could result in further potentially invasive investigations and more aggressive treatment than would be warranted if results have been underestimated, whereas errors in the reverse direction could lead to false reassurance and undertreatment.

The fact that we needed to further adjust published equations for either length or age to obtain adequate fit in healthy infants emphasizes the importance of ensuring that future reference equations are based on a large number of healthy infants with a relatively even spread over the entire age range of interest, which has not always been the case previously. Derivation of equations from datasets which include just a few individuals at the extremes, or extrapolation of predictions beyond the age or length range studied in health is particularly likely to introduce errors when interpreting results from infants with lung disease. 35 Although the current study represents the largest collection of normative data using Jaeger infant equipment, given the rapid rate of growth and need for sex-specific equations, numbers are still insufficient to create reliable reference equations de novo. In addition, such equations would be based in data from a single centre which may not be applicable elsewhere. 35 Consequently, until further multi-centre data can be collated, we have chosen to express the results as Z-scores using available prediction equations to adjust for sex, age and body size, before deriving an equipmentspecific adjustment factor. We will continue to collect normative data and would welcome contributions from other centers that are using the same equipment to study healthy children during the first 2 years of life. In the meantime, those using the Jaeger infant equipment are urged to interpret their data cautiously and consider applying the enclosed corrections. It must be emphasized that the correction factors presented are specific to the Jaeger equipment in our and V' maxFRC , respectively, when using the unadjusted published references, of which 65% (13/20) and 80% (20/25) would have been mis-classified. collection and 'Squeeze' software for data analysis. V' maxFRC-J was obtained immediately afterwards within the same sleep epoch (delay < 10 min), using the same jacket. The mean of the 3 highest, technically acceptable manoeuvers from each system were compared. Data from 10 V' maxFRC-J trials, that had been simultaneously recorded as ASCII files, were imported into the `Squeeze´ software for re-analysis and results compared to those calculated by Jaeger.

F o r P e e r R e v i e w

Results:

1) Comparison of Algorithms:

As summarised in E-Table 1 and E-Figure 1, there were no differences in any of the measured parameters on reanalysis of Jaeger data, with the exception of V' maxFRC-J which was on average 5% higher (95% CI: 3.4; 7.0%) when calculated automatically. This was due to minor differences in method of calculating the end expiratory level. .

2) In vivo comparisons:

There were no significant differences in jacket pressure or breathing pattern between the 2 sets of measurements, although there was a tendency for V T to be slightly higher in Jaeger (p = 0.08; E-Table 2). However, mean V' maxFRC-J was on average 12.4% lower than V' maxFRC-RS (range: -37%, + 26%) (E-Figure 2). The mean (range) difference in z scores (J-RS) was -0. This study suggests that values of V' maxFRC are somewhat lower when measured using the Jaeger MasterScreen than our previously published data. Sex specific prediction equations for V' maxFRC have been published recently E-1 which should improve interpretation of results.

These discrepancies are NOT due to:

• differences in algorithms (Jaeger giving if anything slightly higher values)

• differences in jacket design or pressure transmission (identical for paired data collected using both systems)

• failure to reach flow limitation (this was assessed independently for both systems)

• differences in apparatus deadspace (14.1 vs 16.8 mL including 10 mL for mask deadspace for Jaeger and RASP

The observed discrepancies could, however, be due to the timing of assessments, since RASP was always assessed first as the "gold standard" for ongoing epidemiological studies, repeat measures with Jaeger only being performed in those who remained in quiet sleep. Repeated thoracoabdominal compression using pressures high enough to reach flow limitation may result in changes in lung and airway mechanics, including V' maxFRC .

Conclusion:

Validation of infant lung function equipment is notoriously difficult, not least because of limited duration of sleep and ethical restraints which generally preclude recruitment into a purely methodological study. Before Jaeger results can confidently be expressed in terms of published z-scores for V' maxFRC further work will be required to investigate the cause of observed discrepancies, including comparisons wherein measurements with the Jaeger system precede those with RASP.

BTPS correction

Failure to apply BTPS correction during data correction will lead to a downward drift of tidal volume against time (expired volume being greater than inspired volume) whereas overcorrection of inspiratory flow for BTPS conditions will lead to an upward drift of tidal volume.

While both scenarios can be adjusted by using a timed-based volume drift correction (as commonly employed in all lung function software, whether 'in house' or commercial), this is generally only applied to the volume signal and could thus alter the shape of the Flow-Volume curve and hence measured values of both forced expired flows and volumes.

While BTPS corrections have traditionally been applied in adult lung function systems to correct for the warming of inspired air and cooling of expired air during the breathing cycle, direct instantaneous measures of temperature change at the mouth during the breathing cycle in adults have indicated that some warming occurs through the equipment before the air passes through the pneumotach on inspiration, with some cooling on expiration. Consequently, Jaeger apply an 8% inspiratory and 3% expiratory correction to all flows in their 'adult and pediatric' systems, which generally results in a fairly stable tidal volume-time trace, Since such measurements have not been undertaken in infants due to their complexity, the Jaeger infant lung function system simply applies the theoretical 11% correction to inspired flows with no expiratory correction, E-4 which tends to result in some upward drift of tidal volume which is subsequently adjusted for during screen display using a volume-time drift correction. By contrast, in our original 'in-house' system we did not apply any BTPS correction during data collection, instead correcting the data to BTPS where appropriate at time of analysis, such that the tidal volume time-based tended to drift downwards, the drift correction being in the reverse direction. The 'truth' probably lies somewhere between these two approaches, the ideal situation being one in which accurate BTPS corrections are applied on a breath by breath basis; a Objectives: This study aimed to assess the validity of published reference equations for forced expiratory flow-volume (FEFV) data in infants when using current, commercially available equipment, and how this could impact on interpretation of results from infants with lung disease.

F

Methods:

The Jaeger Masterscreen BabyBody (v4.67) equipment was used to perform partial and raised volume FEFV maneuvers in healthy infants and those with cystic fibrosis (CF). Results were initially expressed as Z-scores using published reference equations. Multilevel modelling was used to calculate differences, if any, from predicted scores in healthy infants.

Results: Data were available from 66 healthy fullterm infants on 89 test occasions; [median (range) postnatal age 49.4(12-101) weeks. All FEFV outcomes were significantly lower than predicted, with mean (SD) Z-score differences of -0.4(1.1) for FVC; -0.6(1.0) for FEV 0.5 ; -1.0(1.0) for FEF 25-75 and -1.4(1.1) for V' maxFRC . After adjustments using multilevel modelling, mean Z-scores were within 0.1(SD~1.0) predicted for all outcomes in healthy infants. Among 50 infants with CF, studied on 85 test occasions, results were 'abnormal' (< -1.96 Z-scores) on 35 (41%) and 37 (45%) test occasions for FEV 0.5 and FEF 25-75 respectively when using published equations. This fell to 24(28%) and 20 (24%) respectively, after adjustment. growth and development of the airways during infancy [1][2][3] and, together with data derived from the raised volume RTC (RVRTC), have been found to discriminate clearly between health and disease within the research setting. [4][5][6][7][8] Nevertheless, if such tests are to be used in clinical management, reliable reference ranges are also required.

Conclusions

While prediction equations have been published for infant FEFV outcomes, 9, 10 these were derived from children studied using equipment developed 'in-house' and the extent to which they remain appropriate for current, commercially available equipment that was introduced following recommendations from the ATS-ERS task force on infant lung function [11][12][13] has yet to be determined. The need to assess whether selected prediction equations are appropriate for a given population or specific equipment is well-recognized, [14][15][16] but has rarely been done in infants due to the time-consuming nature of these tests and need for sedation. In addition, increasing difficulty in obtaining ethics committee approval for sedating healthy infants during the past decade has severely limited the extent to which normal growth and development of infant lung function can be assessed in several countries, including the USA.

The aims of this study were to: a) assess whether FEFV results obtained from healthy infants using the current Jaeger equipment differ from predicted values, b) investigate whether, in the event of any significant offset, it would be possible to adjust for any equipment-specific differences in order to facilitate interpretation in infants with lung disease and c) evaluate the impact of applying such a correction factor to a cohort of infants with cystic fibrosis (CF) studied using identical equipment and techniques. Some of the results included in this study have been reported previously.

MATERIALS AND METHODS

The study population was comprised of: a) healthy fullterm (>37 gestational weeks) white infants without congenital abnormalities or respiratory compromise (i.e. no current respiratory problems or history of respiratory illness requiring hospitalization) who had been recruited to epidemiological studies or as controls for clinical research 5,17,18 and b) Infants diagnosed with CF without severe congenital, cardiovascular or neuromuscular disorders that could impact on the respiratory system, who had been recruited to clinical research studies. 5 Children with a history of apneic episodes or upper airway pathology were excluded. Local

Research Ethics Committee approval was granted and written informed parental consent was obtained for all infants.

Equipment and study protocol: With the exception of two infants with CF who had had repeated respiratory exacerbations and were therefore tested as soon as asymptomatic for 14 days, lung function tests in all children were undertaken at least 3 weeks after any respiratory illness. Data were collected during quiet sleep, after oral sedation with chloral hydrate (50-100mg/kg depending on age). RTC and RVRTC data were collected using the Jaeger Masterscreen BabyBody System (CareFusion, San Diego). This equipment was designed in adherence with the ATS-ERS recommendations [11][12][13] and uses a low deadspace pneumotachometer with solid-state transducers.

Tidal and raised volume maneuvers were performed in accordance with international recommendations 11,12 as previously described, 19,20 with the tidal RTC being performed prior to raised volume maneuvers. 21 The RVRTC was performed from an inflation pressure of 30 cmH 2 O, the maneuver being repeated until a minimum of three acceptable and reproducible FEFV curves was obtained. Forced expiratory volume in 0.5 second (FEV 0.5 ), forced vital capacity (FVC), forced expiratory flow when 75% FVC had been expired (FEF 75 ) and FEF between 25-75% FVC (FEF 25- 75 ) were reported from the "best" raised volume curve. The latter was defined as the technically 11 For RTC, the mean V' maxFRC from at least two (usually three) reproducible FEFV curves was reported. 12

Statistical Analysis

Power calculations demonstrated that FEFV measurements from 65 healthy children would enable differences equivalent to 0.4 SD (or Z-scores) to be detected between the controls and the published reference population with 90% power at the 0.05 significance level. Standard software packages were used for data inspection, distribution and descriptive statistics (SPSS for Windows, v15.0, SPSS Inc.). Results from healthy controls were expressed as Z-scores using published prediction equations. 9,10 To ensure that we would still be able to detect differences between those exposed to maternal smoking during pregnancy compared to those who were not, the calculation of Z-scores for RVRTC data was made with smoking status during pregnancy being set to 0 (zero) . The extent to which these Z-scores differed from zero according to sex, age and body size was inspected and univariable regression analysis was used to establish the association between each FEFV outcome and likely explanatory variables. Where potentially significant associations existed, these were further explored using multivariable, multilevel regression modeling (MLwiN, version 2.12;

Institute of Education, UK). These highly flexible models adjust for the correlated nature of repeated measurements in individuals and allow inclusion of variable numbers of measurements per child to provide the most precise characterization of changes over time. [22][23][24] To quantify the extent to which age or length was independently associated, after adjusting for factors accounted for by the Jones and Hoo equations 9, 10 , a stepwise approach was used in developing the multivariable models: each dependent (FVC, FEV 0.5 etc) was adjusted for potential determinants such as length, age, sex etc. The derived regression equations for the LF variables were then applied to results from children with CF to evaluate the potential impact of applying such an adjustment factor on clinical management. Data management was undertaken using Re-Base software (J7IS Ltd). published reference data, all FEFV outcomes derived from healthy infants tested with the current Jaeger equipment were significantly lower than predicted (Table 1).

On multilevel, univariable analysis, FVC, FEV 0.5 , FEV 75 , FEF 25-75 and V' maxFRC were all significantly and negatively associated with length (Table 2a) and age (Table 2b) at test. However after adjusting for length or age, addition of the other variable did not add significantly to the model, and length was chosen in preference to age to prevent any bias due to restricted growth when applying such equations to children with lung disease. Sex had already been taken into account in the original prediction equations, and was not further associated with any of the adjusted FEFV Z-scores.

After adjustment, the mean (SD) Z-scores for all FEFV outcomes in healthy controls approximated 0 (1.0), suggesting that the correction factors derived from these equations were appropriate (Table 1 and Figure 1).

Infants with CF

Data collected using the Jaeger equipment were available from 54 infants and young children with CF on 96 test occasions (mean (SD) age: 53.5 (26.7) w; length 73.9 (8.5) cm; weight 8.8 (2.2) kg).

When results were expressed in relation to published reference equations, an abnormal FEV 0.5 (< -1.96 Z-scores) was detected on 35/85 (41%) test occasions, whereas after applying the adjustment factor, this fell to 24 (28%). Similar results were observed for FEF 25-75 and V' maxFRC (Table 1 and

DISCUSSION

We have shown that, when using the Jaeger Masterscreen, FEFV data from healthy infants are significantly lower than published reference data, which could lead to over-diagnosis of lung disease in children with CF or other respiratory diseases. While published reference data for infant FEFV maneuvers 9,10 are clearly inappropriate for data collected using the Jaeger Masterscreen, application of an appropriate adjustment factor may minimize such errors until sufficient multicentre data are available to construct reliable equipment-specific reference ranges in this age group.

When using our original 'in-house' equipment and software (RASP), published reference data for both partial 9 and full 10 FEFV maneuvers appeared to be appropriate for use in our laboratory, as demonstrated by the mean (SD) Z-scores for FEFV outcomes which approximated 0 (1) in our local healthy controls. 6,21 After switching to commercial equipment (Jaeger Masterscreen BabyBody; v4.67), we used similar data collection and analysis techniques and were initially reassured that FEFV results from healthy controls appeared to remain in agreement with published reference ranges. 5 However, direct comparison of a limited number of infants, using an identical jacket, suggested that flows were lower when using the Jaeger system, 25 and as further healthy controls were studied using this equipment we became increasingly aware of a potential bias. 17 During the validation study 25 (see online supplement (OLS) for details), we established that there were no within-subject differences in pressure transmission between the systems and that the bias could not be attributed to failure to attain flow limitation, which was assessed independently for both systems by experienced operators.

Despite rigorous and time-consuming attempts to identify the source, the underlying cause of the observed discrepancies in V' maxFRC remains unknown. All algorithms for deriving outcomes from the Jaeger system were based on our original RASP set-up and were manually checked for accuracy. In addition, when 'raw data' in ASCII format were exported from the Jaeger system and re-analysed with our original software, values displayed by Jaeger were, if anything, slightly higher (mean difference 5%; 95% CI: 3.4; 7.0%). This was attributed to minor differences in how endexpiratory level (i.e. FRC) was calculated by the two systems (see OLS for details).

The only major difference that we could identify between the two systems was with respect to BTPS (body temperature, pressure, saturated) corrections, 26 which were applied to the flow (and hence volume) signal during data collection in the Jaeger system, whereas in our original system (and most other 'in -house' systems at the time, including those from which reference data had been generated), data were saved in original ATPS format with BTPS corrections being applied at the analysis stage. The way in which such differences could potentially impact on results is discussed in the OLS.

Equipment-specific differences in lung function have been reported previously in older subjects, 27,28 and it has been suggested that such discrepancies may be due to device-dependent characteristics such as in the integration of flow to volume, which, together with BTPS corrections, may be inaccessible to the end-user. In contrast to adult spirometers, there are currently no accepted waveforms with which to compare outcome measures for infant FEFV equipment, and even if there were this would not tackle the more complex issues relating to BTPS corrections during in-vivo measurements. 29 We therefore cannot ascertain whether the previous 'in-house' systems or new commercially available devices best approximate the 'truth'. What is apparent is that published reference data are not appropriate when interpreting FEFV data from the infant Jaeger equipment.

All data for this study were collected using the same version of software and in accordance with ATS/ERS recommendations 11,12 by experienced investigators (AFH/SL) thereby minimizing the chance that the lower flows and volumes obtained with the new equipment were simply due to Previous data collected from ICH using the homemade RASP system were in close agreement with that from other centers and were included in the collated dataset for V' maxFRC prediction equations. 9 Given that the mean V' maxFRC Zscore for data collected in our laboratory using the RASP system (n=283) was -0.52, i.e. 0.88 Zscores higher than that from our recent Jaeger data, it is likely that the observed differences reflect differences in hardware and software rather than population differences or changes in practice.

This study was only possible because we retain full ethics approval to undertake lung function measurements in healthy infants and have always attempted to recruit a prospective control group for clinical research projects. In the past, many research groups prospectively recruited healthy controls, 1, 5-7, 30-32 but during recent years there has been ongoing debate as to whether it is ethical to undertake lung function tests under sedation in healthy infants. Given the results from this study, it could be argued that it is unethical to undertake lung function tests in infants with lung disease (who are far more at risk of any sedation related adverse events than healthy children) without appropriate reference equations with which to interpret results. Indeed, had we not continued to recruit healthy controls prospectively after switching to commercially available equipment, our clinical and research data from the past 5 years would be potentially invalid. It is accepted that recruiting healthy infants to lung function studies is far more demanding and time consuming than enrolling those with lung disease, but in over 30 years of practice we have never observed an adverse event related to chloral sedation in a healthy infant, this group representing those at least risk from such events. 33 The clinical implications of using inappropriate reference ranges can be seen from our results in early life. 34 In addition to the anxiety caused to parents, reports of apparently 'diminished' LF results in asymptomatic infants and young children could result in further potentially invasive investigations and more aggressive treatment than would be warranted if results have been underestimated, whereas errors in the reverse direction could lead to false reassurance and undertreatment.

The fact that we needed to further adjust published equations for either length or age to obtain adequate fit in healthy infants emphasizes the importance of ensuring that future reference equations are based on a large number of healthy infants with a relatively even spread over the entire age range of interest, which has not always been the case previously. Derivation of equations from datasets which include just a few individuals at the extremes, or extrapolation of predictions beyond the age or length range studied in health is particularly likely to introduce errors when interpreting results from infants with lung disease. 35 Although the current study represents the largest collection of normative data using Jaeger infant equipment, given the rapid rate of growth and need for sex-specific equations, numbers are still insufficient to create reliable reference equations de novo. In addition, such equations would be based in data from a single centre which may not be applicable elsewhere. 35 Consequently, until further multi-centre data can be collated, we have chosen to express the results as Z-scores using available prediction equations to adjust for sex, age and body size, before deriving an equipmentspecific adjustment factor. We will continue to collect normative data and would welcome contributions from other centers that are using the same equipment to study healthy children during the first 2 years of life. In the meantime, those using the Jaeger infant equipment are urged to interpret their data cautiously and consider applying the enclosed corrections. It must be emphasized that the correction factors presented are specific to the Jaeger equipment in our Adjusted V' maxFRC = zV' maxFRC (Hoo) + (0.074 x length, cm) -4.17

  FEFV curve with the highest sum of FVC and FEV 0.5.

  infants with CF. The use of published reference equations would have resulted in significant overdiagnosis of abnormal lung function, and over-estimation of the rate of change in lung function during the first two years of life. Such findings are particularly pertinent at a time when there is increased emphasis on early intervention studies and the need for objective outcome measures in

  that there is an urgent need for users of other commercially available systems to undertake a similar exercise.CONCLUSIONS AND FUTUREDIRECTIONS: The marked differences observed between FEFV data from healthy infants when collected with modern commercially available infant lung function equipment and published reference data emphasize the need for prospective recruitment of healthy controls during clinical research studies and for the development of device-specific normative data with which to interpret results from infants with lung disease. If infant lung function tests are to have any significant future role, a concerted effort from members of the ATS/ERS working group on infant and lung function tests to present the rationale and safety data to support recruitment of healthy infants for lung function tests, and discourage usage of such tests in the absence of adequate controls, is urgently needed in order to address the recent barriers introduced by the FDA and certain ethics committees.

Figure 1 :

 1 Figure1: FEFV data from healthy infants expressed as Z-scores plotted against length at test, A) according to published reference equations (FEV 0.5, FEF 25-75 using Jones et al,10 and V' maxFRC according to Hoo et al9 and B) after adjusting for the Jaeger equipment used. Open circles

Figure 2 :

 2 Figure 2: Comparison of FEFV data from healthy infants (HC) and those with CF; A) before and

Figure 1 :Figure 2 :Lung function in healthy infants_OLS 1 POTENTIAL 4 and

 1214 Figure 1: FEFV data from healthy infants expressed as Z-scores plotted against length at test, A) according to published reference equations (FEV0.5, FEF25-75 using Jones et al, 10 and V'maxFRC according to Hoo et al 9 and B) after adjusting for the Jaeger equipment used. Open circles represent girls and closed circles are boys. The Upper and Lower Limit of the Normal range (ULN and LLN, as defined by ± 1.96 Z-scores) are shown. Data from only one test occasion per child are shown on these graphs. 254x190mm (96 x 96 DPI)

:INTRODUCTION

  Dependence on published equations for interpreting FEFV data in infants may lead to misinterpretation of lung function status, which could impact adversely both in the research setting and on clinical management. Use of a contemporary control group or establishment of equipmentspecific reference data is essential for meaningful interpretation of infant lung function data. Keywords: Infant; forced expiratory maneuvers; pulmonary function test; Reference values; Assessments of forced expiration have been used extensively in older children and adults to assess the nature and severity of airway disease, response to therapeutic intervention and to monitor disease progression or resolution in both the clinical and research environments. While infants cannot be instructed to perform such maneuvers, forced expiratory flow-volume (FEFV) loops can be obtained by substituting voluntary effort with externally applied pressure to the chest and abdomen to force expiration. Measurements of maximal flow at functional residual capacity (V' maxFRC ) from the tidal rapid thoraco-compression technique (RTC) have been used to characterize

  FEFV curve with the highest sum of FVC and FEV 0.5.

7 RESULTS

 7 Healthy Infants: Data were available from 66 healthy infants (40% boys) on 89 test occasions, [mean (SD) age: 51.2 (25.0) w; length 75.4 (7.5) cm; weight 9.3 (2.0) kg]. When compared with

Figure 2

 2 Figure2).

  flow-limitation or poor quality control.

  infants with CF. The use of published reference equations would have resulted in significant overdiagnosis of abnormal lung function, and over-estimation of the rate of change in lung function during the first two years of life. Such findings are particularly pertinent at a time when there is increased emphasis on early intervention studies and the need for objective outcome measures in

  that there is an urgent need for users of other commercially available systems to undertake a similar exercise.CONCLUSIONS AND FUTUREDIRECTIONS: The marked differences observed between FEFV data from healthy infants when collected with modern commercially available infant lung function equipment and published reference data emphasize the need for prospective recruitment of healthy controls during clinical research studies and for the development of device-specific normative data with which to interpret results from infants with lung disease. If infant lung function tests are to have any significant future role, a concerted effort from members of the ATS/ERS working group on infant and lung function tests to present the rationale and safety data to support recruitment of healthy infants for lung function tests, and discourage usage of such tests in the absence of adequate controls, is urgently needed in order to address the recent barriers introduced by the FDA and certain ethics committees.

Figure 1 :

 1 Figure1: FEFV data from healthy infants expressed as Z-scores plotted against length at test, A) according to published reference equations (FEV 0.5, FEF 25-75 using Jones et al,10 and V' maxFRC according to Hoo et al9 and B) after adjusting for the Jaeger equipment used. Open circles

Figure 2 :

 2 Figure 2: Comparison of FEFV data from healthy infants (HC) and those with CF; A) before and

FEF 10 b

 10 38 (-0.68; -0.07) * Data expressed as Mean (SD) Z-scores; *: p < 0.05; ***: p < 0.001 a Jones 2000 AJRCCM, with smoking during pregnancy status set to 0. Hoo 2002 AJRCCM. 9 c n = 85; d significance of difference based on comparison of Z-score results from healthy controls and that predicted from published reference equations (i.e mean (SD) of 0 (1).

  Adjusted prediction equations taking length into account (Jaeger Z-scores) Adjusted zFVC = zFVC (Jones) + (0.057 x length, cm) -3.90 Adjusted zFEV 0.5 = zFEV 0.5(Jones) + (0.058 x length, cm) -3.83 Adjusted zFEF 75 = zFEF 75 (Jones) + (0.037 x length, cm) -1.94 Adjusted zFEF 25-75 = zFEF 25-75 (Jones) + (0.040 x length, cm) -1.94

Table 1 :

 1 Comparison of FEFV data between healthy infants and those with CF, before and after adjusting the prediction equations.

	Published reference

* Data expressed as Mean (SD) Z-scores; *: p < 0.05; ***: p < 0.001 a Jones 2000 AJRCCM, with smoking during pregnancy status set to 0. 10 b Hoo 2002 AJRCCM. 9 c n = 85; d significance of difference based on comparison of Z-score results from healthy controls and that predicted from published reference equations (i.e

Table 2a :

 2a Adjusted prediction equations taking length into account (Jaeger Z-scores)

	Adjusted zFVC	= zFVC (Jones) + (0.057 x length, cm) -3.90
	Adjusted zFEV 0.5	= zFEV 0.5(Jones) + (0.058 x length, cm) -3.83
	Adjusted zFEF 75	= zFEF 75 (Jones) + (0.037 x length, cm) -1.94
	Adjusted zFEF 25-75	= zFEF 25-75 (Jones) + (0.040 x length, cm) -1.94
	Adjusted V' maxFRC	= zV' maxFRC (Hoo) + (0.074 x length, cm) -4.17

Table 2b :

 2b Adjusted prediction equations taking age into account

	Adjusted zFVC	= zFVC (Jones) + (0.018 * age, weeks) -0.538
	Adjusted zFEV 0.5	= zFEV 0.5(Jones) + (0.018 * age, weeks) -0.341
	Adjusted zFEF 75

= zFEF 75 (Jones) + (0.010 * age, weeks) -0.347 Adjusted zFEF 25-75 = zFEF 25-75 (Jones) +(0.011 * age, weeks) -0.491 Adjusted V' maxFRC = zV' maxFRC (Hoo) + (0.020 * age, weeks) -0.355

Age and length contributed equally and significantly to these models. After adjusting for length or age, addition of the other variable did not add significantly to the model, and length was chosen in preference to age to prevent any bias due to restricted growth when applying such equations to children with lung disease.

Table 2 :

 2 In vivo comparison: Jaeger vs RASP

	35 (-0.98 to

POTENTIAL MISINTERPRETATION OF INFANT LUNG FUNCTION UNLESS PROSPECTIVE HEALTHY CONTROLS ARE STUDIED Sooky Lum, PhD 1 ; Ah-Fong Hoo, PhD 1,2 ; Georg Hulskamp, MD 3 ; Angie Wade, PhD 4 and Janet Stocks, PhD 1

	SUMMARY
	scenario yet to be realized in any adult lung function software for adults, let alone the more
	Rationale: Reliable interpretation of pulmonary function tests relies on appropriate reference data
	complex situation faced when testing infants.
	which remain very limited for infants.
	1 Portex Unit: Respiratory Physiology and Medicine, UCL, Institute of Child Health, London,
	2 Great Ormond Street Hospital for Children NHS Trust, London, 3 Department of Paediatrics,
	o r F o r Universitätsklinikum and Clemenshospital, Münster, Germany and 4 Centre for Paediatric Epidemiology and Biostatistics Unit, London, UK. F o r
		P P P
		e e e
		e r e r e r
	Corresponding author: Sooky Lum	R R R
	Portex Respiratory Unit		e e e
	UCL, Institute of Child Health 30 Guilford Street		v i e v i e v i e
	London WC1N 1EH		w w w
	Email: s.lum@ich.ucl.ac.uk
	Tel: +44 (0)20 7905 2382	Fax: +44 (0)20 7829 8634
	Reprints are not available from the authors.
	Abbreviated title: Lung function in healthy infants
	This article has an online data supplement.
			2

Funding source: Medical Research Council, UK; Cystic Fibrosis Trust; British Lung Foundation. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive.

Table 1 :

 1 Comparison of FEFV data between healthy infants and those with CF, before and after adjusting the prediction equations.

	Published reference

Table 2b :

 2b Adjusted prediction equations taking age into account Adjusted zFVC = zFVC (Jones) + (0.018 * age, weeks) -0.538 Adjusted zFEV 0.5 = zFEV 0.5(Jones) + (0.018 * age, weeks) -0.341 Adjusted zFEF 75 = zFEF 75 (Jones) + (0.010 * age, weeks) -0.347 Adjusted zFEF 25-75 = zFEF 25-75 (Jones) +(0.011 * age, weeks) -0.491 Adjusted V' maxFRC = zV' maxFRC (Hoo) + (0.020 * age, weeks) -0.355 Age and length contributed equally and significantly to these models. After adjusting for length or age, addition of the other variable did not add significantly to the model, and length was chosen in preference to age to prevent any bias due to restricted growth when applying such equations to children with lung disease.

John Wiley & Sons, Inc.Pediatric Pulmonology

John Wiley & Sons, Inc.

ACKNOWLEDGEMENTS

The authors thank the infants and their parents who participated in this study. We also thank Dr Padmaja Subbarao, Dr Amit Gupta, Ms Joanne Chittenden and Ms Alicia Bolton who provided valuable assistance in subject recruitment and performing the measurements.

ACKNOWLEDGEMENTS

The authors thank the infants and their parents who participated in this study. We also thank Dr Padmaja Subbarao, Dr Amit Gupta, Ms Joanne Chittenden and Ms Alicia Bolton who provided valuable assistance in subject recruitment and performing the measurements.

Medical Research Council, UK; Cystic Fibrosis Trust; British Lung Foundation. Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive.

ADDITIONAL DATA

The following details described a small validation study presented at the European Respiratory Society conference, 2002. E-1 Abstract title: V' maxFRC -Validation of a new commercially available equipment Background:

Measurements of maximal flow at functional residual capacity (V' maxFRC ) using the tidal rapid thoraco-abdominal compression technique (RTC) are the most popular method for assessing small airway function in infants and young children.

Sex specific prediction equations for V' maxFRC have been published recently E-2 which should improve interpretation of results. However, it is not yet known whether these equations will be appropriate for use with data collected using new commercially available equipment such as the Jaeger MasterScreen infant lung function system (Lab4 software version 4.53, Jaeger Toennies, Viasys Healthcare) Aim:

To investigate whether published z scores for V' maxFRC during infancy are appropriate for data collected with the Jaeger system by • validating algorithms used by the Jaeger system against the established `Squeeze´ software [Version 2.04, Imperial College, London, 1999].

• comparing paired measurements of V' maxFRC using the Jaeger (J) and the previously validated RASP-Squeeze (RS) system on the same occasion.

Subjects and methods:

V' maxFRC was measured using ERS/ATS recommendations E-3 on 17 occasions in 12 healthy babies recruited to ongoing epidemiological studies (range for weight: 3.6 -11.1 kg; length: 53 -81 cm; age: 7.6 -62.3 weeks). V' maxFRC-RS was measured initially using RASP for data