Mireille Desrochers-Couture

Sylvaine Cordier

Florence Rouget

Léah Michineau

Christine Monfort

Jean-Pierre Thomé

Philippe Kadhel

Luc Multigner

Gina Muckle
email: gina.muckle@psy.ulaval.ca

Visuospatial processing and fine motor function among 7-years old Guadeloupe children pre-and postnatally exposed to the organochlorine pesticide chlordecone

Keywords: chlordecone, organochlorine pesticide, motor function, tremor, visual processing, childhood Highlights

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Chlordecone is an organochlorine that was used as an insecticide since 1972 to control the banana weevil (Cosmopolites sordidus), a root borer, in the French West Indies, Guadeloupe and Martinique. After two decades of utilization, chlordecone was definitely banned in all French territories. As chlordecone molecules are very persistent in the environment, pollution in soils leading to contamination of water sources and foodstuff, is still present and will last for several decades [START_REF] Cabidoche | Long-term pollution by chlordecone of tropical volcanic soils in the French West Indies: A simple leaching model accounts for current residue[END_REF][START_REF] Dromard | Assessment of the contamination of marine fauna by chlordecone in Guadeloupe and Martinique (Lesser Antilles)[END_REF]. The first toxic and harmful effects of chlordecone were observed in 1975 following a poisoning of chlordecone plant workers in the industrial city of Hopewell, VA, USA [START_REF] Cannon | Epidemic Kepone poisoning in chemical workers[END_REF]. Symptoms observed among male workers were related to central nervous system, liver and fertility [START_REF] Cannon | Epidemic Kepone poisoning in chemical workers[END_REF][START_REF] Cohn | Treatment of chlordecone (Kepone) toxicity with cholestyramine[END_REF][START_REF] Taylor | Neurological manifestations in humans exposed to chlordecone and follow-up results[END_REF]. Major signs of neurological impairments included appendicular During the last decade, our group reported several health effects related to prenatal chlordecone exposure on child development from our prospective Guadeloupean mother-child cohort (TIMOUN study) that has been put in place in 2004. Hypotensive effects during pregnancy [START_REF] Saunders | Hypertensive disorders of pregnancy and gestational diabetes mellitus among French Caribbean women chronically exposed to chlordecone[END_REF], decreased length of gestation, increased risk of preterm birth [START_REF] Kadhel | Chlordecone Exposure, Length of Gestation, and Risk of Preterm Birth[END_REF], and decreased weight of newborns from Accepted manuscript / Final version mothers with excessive prenatal weight gain [START_REF] Hervé | Prenatal exposure to chlordecone, gestational weight gain, and birth weight in a Guadeloupean birth cohort[END_REF] were reported following prenatal chlordecone exposure. Among infants aged 3 months old, the impact of perinatal exposure to chlordecone on the thyroid hormone system was explored, and sex-specific associations were reported [START_REF] Cordier | Perinatal exposure to chlordecone, thyroid hormone status and neurodevelopment in infants: The Timoun cohort study in Guadeloupe (French West Indies)[END_REF]. Cord chlordecone was associated with an increase in thyroid stimulating hormone in boys, whereas postnatal exposure, through breastfeeding, was associated with a decrease in free thyroxine in girls and in free triiodothyronine overall. At 7-months old, prenatal chlordecone exposure was associated with poorer fine motor development [START_REF] Dallaire | Cognitive, visual, and motor development of 7-month-old Guadeloupean infants exposed to chlordecone[END_REF], which was again observed at 18-months of age but only among boys [START_REF] Boucher | Exposure to an organochlorine pesticide (chlordecone) and development of 18-month-old infants[END_REF]. This sex-specific effect might be related to chlordecone's estrogen-like activity, which is now well established [START_REF] Multigner | Chlordecone exposure and adverse effects in French West Indies populations[END_REF]. Recently, our group published the first results from the followup of the TIMOUN cohort at age 7 years. In utero and childhood chlordecone exposure have been associated with impairs visual contrast sensitivity in boys only [START_REF] Saint-Amour | Visual contrast sensitivity in school-age Guadeloupean children exposed to chlordecone[END_REF]. The objective of the present study is to document whether 1-effects of prenatal exposure to chlordecone previously reported on neuromotor function during infancy are lasting up to middle childhood, 2-deleterious effects are observed in domain of visual processing, 3-deleterious associations with postnatal exposure emerged, and 4there are sex-specific vulnerabilities.

Material and methods

Population and data collection

The TIMOUN study is an ongoing prospective epidemiological mother-child cohort in the Guadeloupe archipelago (French West Indies). Between November 2004 and December 2007, 1068 women planning to give birth at the public hospitals of Pointe-Accepted manuscript / Final version à-Pitre, Basse-Terre or at a local antenatal care dispensary were enrolled. At enrolment, a prenatal maternal interview was conducted by trained midwives to assess obstetrical, medical, personal, and sociodemographic characteristics. At birth, maternal diseases, adverse delivery incidents, and newborn anthropometric parameters and health information were collected from child and maternal medical records. At delivery, dietary habits, alcohol consumption and smoking status during pregnancy were collected, and a cord blood sample was obtained to document prenatal exposure to chlordecone and other environmental contaminants.

Follow-ups of a subsample of liveborn singletons in this cohort took place at 3, 7 and 18 months of age to document both potential confounders pertaining to sociodemographic and psychosocial domains, and the quality of stimulation provided by the family through maternal face-to-face interview. In this initial subsample, all children born preterm, or with intrauterine growth retardation, major birth defect or distress at birth, or born to mothers with severe disease during pregnancy were excluded [START_REF] Dallaire | Cognitive, visual, and motor development of 7-month-old Guadeloupean infants exposed to chlordecone[END_REF]. At 7 years-old, the whole cohort of liveborn singleton children (N = 1033) were invited to participate in one visit involving one maternal interview, direct child assessments of anthropometric and some health parameters, visual, motor and cognitive domains, as well as child's urine and blood sampling. The maternal interview included the administration of the non-verbal Raven Progressive Matrices (1996), which assesses nonverbal reasoning ability from principal caregiver. The test consists of 60 series of visual geometric design with a missing piece, in order of increasing difficulties, where the respondent is given six to eight choices to pick from and fill in the missing piece that fit the best to complement to problems to resolve. In total, 444 families could not be Accepted manuscript / Final version contacted or refused to participate, thus the remaining 589 children underwent the evaluation. The present analyses focused on visual processing and neuromotor function, and included 410 children with a cord blood sample and at least one score on any of these outcomes. The data collection took place in the Pointe-à-Pitre University hospital site between April 2011 and January 2015.

The study was approved by the relevant ethical committee for studies involving human subjects (Comité de Protection des Personnes Sud-Ouest et Outremer III; n° 2011-AOOSSI--40). Each participant provided written informed.

Child assessment

Visuospatial processing and neuromotor function were assessed in 7 years old children by trained examiners who followed verbatim of the standardized test administration instructions, with periodic quality control sessions performed by a child psychologist about every 6-months during the data collection period.

Visuospatial

Processing. The Stanford Binet copying (S-B copying) test was used to measure the non-verbal visuospatial processing [START_REF] Becker | History of the Stanford-Binet intelligence scales: Content and psychometrics[END_REF]. Each child was required to draw 16 two-dimensional geometric designs with pencil and paper. A composite score was derived from the test using the relaxed scoring system designed by Roberta F. White, neuropsychologist from Boston University School of Public health, to assess the overall gestalt (or configural awareness) of the children's drawing following mercury exposure [START_REF] Chevrier | Qualitative assessment of visuospatial errors in mercury-exposed Amazonian children[END_REF][START_REF] Cordier | Neurodevelopmental investigations among methylmercury-exposed children in French Guiana[END_REF]. This copying relaxed score ranging from 0 to 16 is described in details in [START_REF] Chevrier | Qualitative assessment of visuospatial errors in mercury-exposed Amazonian children[END_REF] and was proven to be sensitive to detect visuospatial mercury effects in 7-12 years old children from Brazil and Accepted manuscript / Final version French Guiana [START_REF] Chevrier | Qualitative assessment of visuospatial errors in mercury-exposed Amazonian children[END_REF][START_REF] Cordier | Neurodevelopmental investigations among methylmercury-exposed children in French Guiana[END_REF]. A larger value on the S-B copying score indicates a better performance.

Fine Motor Precision.

Fine motor function was assessed using the Bruininks Oseretsky Test of Motor Proficiency Second Edition (BOT-2; [START_REF] Bruininks | Bruininks-Oseretsky Test of Motor Proficiency -Second Edition[END_REF]. The BOT-2 is designed to evaluate gross and fine motor skills of individuals aged 4-21 years. In this study, we specifically selected the fine motor precision subtest which includes seven items representing five tasks which can be defined as (a) filling in shapes without protruding (2 items) (b) drawing lines through paths that are crooked and curved (2 items); (c) connecting dots; (d) folding paper; (e) cutting out a circle. In conformity with the test manual, item raw scores were converted into point scores with varying category width (i.e., 0-3 to 0-7). These seven items were then summed to obtain a total score of fine motor precision with a maximum of 41, indicating a better performance. Internal consistency in our sample was acceptable (αcronbach = 0.56).

Hand Tremor. The Computerized Adaptive Testing System (CATSYS)

was used to evaluated postural hand tremor (Danish Product Development Ltd, 2000).

Postural hand tremor was recorded bilaterally during 30 seconds by asking children to hold a light stylus in front of their abdomen, free of body contact or any obstacles. During the recording, the participants were asked to breathe normally and relax. The included measures were : 1) Tremor Intensitythe root mean square of accelerations, recorded in the 0.9-15.0 Hz band during the test period, where a larger values indicate larger tremor amplitude; and 2) Harmonic Indexcomparison of the tremor frequency pattern with a single harmonic oscillation, which decreases when they are many oscillations [START_REF] Després | Standardization of a neuromotor test battery : the CATSYS system[END_REF]. A more regular tremor, represented by higher values, is considered as Accepted manuscript / Final version detrimental to health. The calculation of the Harmonic Index developed by Edwards and Beuter 1999 was used. Technical problems involving the CATSYS equipment, principally caused by humidity in the data collection center, made it impossible to record the hand tremor for 44 children on either the dominant or the non-dominant hand. When more than one trial was needed either because of a technical problems or children not respecting the protocol, two scores were recorded, and the best performance score obtained between the two trials was kept for statistical analysis (n = 14).

Exposure assessment

Samples of cord blood and child blood at the 7-year visit were collected in EDTA tubes to document respectively prenatal and childhood exposure to chlordecone and to other environmental contaminants. Plasma samples were stored at -30°C in the Nunc® with a Ni36 electron capture detection. Preparation of samples and quantification method were previously described [START_REF] Debier | Quantitative dynamics of PCB transfer from mother to pup during lactation in UK grey seals Halichoerus grypus[END_REF][START_REF] Multigner | Chlordecone Exposure and Risk of Prostate Cancer[END_REF]. The limit of detection (LOD) was 0.06 µg/L for cord chlordecone and 0.05 µg/L for cord PCB-153 and cord p,p′-DDE. The LOD for chlordecone, PCB-153 and p,p′-DDE in child plasma sample was 0.02 µg/L. Total cholesterol and triglyceride concentrations in plasma were determined by standard enzymatic procedures (DiaSys Diagnostic Systems GmbH;

Accepted manuscript / Final version Holzheim, Germany), and total lipid concentrations were calculated as described by [START_REF] Bernert | Calculation of serum "total lipid" concentrations for the adjustment of persistent organohalogen toxicant measurements in human samples[END_REF]. Total mercury (Hg), lead (Pb), and selenium (Se) concentrations were quantified in whole blood sampled from the cord and child, and were measured by inductively coupled plasma mass spectrometry (ICP-MS) at the laboratory of the Centre de toxicologie du Québec. For Hg determination, blood samples were diluted 20-fold in a solution containing ammonium hydroxide before analysis. The LOD values for child Hg, Pb, and Se were 0.4 μg/L, 2 μg/L and 20 μg/L respectively. No values under LOD (Hg = 0.1 µg/L; Pb = 0.21 µg/L; Se = 7,87 µg/L) were observed in cord concentrations.

Confounding variables

The following variables were considered as potential confounders in the study of the association between prenatal and childhood chlordecone exposure and child outcomes documented at age 7 years: (1) maternal and family characteristics : birthplace of the mother, maternal age at 7-years old visit, parity before child birth, marital status at 7years old visit (% living with a partner), maternal education at recruitment (none or some elementary school; high school diploma; superior education), and monthly family income at 7-years old visit (≤ 1500 euros; 1501-3000 euros; ≥ 3001 euros); (2) child characteristics : birth weight (grams), breastfeeding duration (no breastfeeding; 0 < 7 months; 7 < 18 months; ≥ 18 months); (3) other prenatal and postnatal exposures : maternal smoking (no; yes) and alcohol consumption during pregnancy (no; yes), cord and child concentrations of PCB-153, p,p′-DDE, Hg, Pb, and Se. These components were selected based on their known influence on child neurodevelopment [START_REF] Budnik | Mercury pollution in modern times and its sociomedical consequences[END_REF][START_REF] Pessah | Neurotoxicity of polychlorinated biphenyls and related organohalogens[END_REF][START_REF] Maria | Lead (Pb) neurotoxicology and cognition[END_REF][START_REF] Skröder | Early-Life Selenium Status and Cognitive Function at 5 and 10 Years of Age in Bangladeshi Children[END_REF][START_REF] Vrijheid | Environmental pollutants and child health-A review of recent concerns[END_REF] and their presence in blood samples in this population.

Accepted manuscript / Final version

Statistical analyses

Normality of distribution was inspected visually for each variable and checked for skewness and kurtosis (normality range: -3.0 to 3.0). All exposure variables were log2transformed and variables with extreme values (> 3.0 standard deviations from the mean) were recoded to the highest observed non-outlying values [START_REF] Winter | Statistical principles in experimental desing[END_REF]. This was the case for tremor intensity scores on one hand (n = 3) and both hands (n =3) and S-B copying scores (n = 2). Because high percentage of chlordecone concentrations were below the LOD (21% and 29% for cord blood and child blood samples, respectively), both cord and child concentrations were categorized into three groups: ≤ LOD, low exposure, and high exposure, where low and high chlordecone exposure groups were determined by the median value of the blood chlordecone's distribution (Table 1). A log2transformed continuous variables was also computed with both, cord and child chlordecone. Missing value patterns were performed to assess potential bias. The proportion of missing data ranged from 0% to 29% (highest proportion on CATSYS hand tremor scores). Little's MCAR test indicated no systematic bias arising from missingness (χ 2 =434.65, df = 404, p = 0.14; Little 1988).

Sex, child age and maternal non-verbal IQ score obtained from the Raven' Progressive Matrices (Raven scores;[START_REF] Raven | Manual for Raven's Progressive Matrices and Vocabulary Scales: Standard Progressive Matrices[END_REF] were treated as obligatory covariates in all models. When some maternal Raven scores were missing at the 7-years follow-up (n = 24), we used the Raven score obtained at the 3-months postnatal visit. Linear regressions between potential confounding variables and child outcomes were performed to identify the final selection of confounding variables for each model. We first retained covariates associated (p < 0.20) with both the outcome and Accepted manuscript / Final version either cord or child chlordecone exposure. Associated variables were included together in multiple regression models to assess their confounding influence by removing them one by one and retained if their removal altered the association by ± 10% [START_REF] Rothman | Modern epidemiology[END_REF].

We tested linear regressions with a Full information maximum likelihood (FIML) estimator to minimise the exclusion of participants because of missing values [START_REF] Enders | The Relative Performance of Full Information Maximum Likelihood Estimation for Missing Data in Structural Equation Models[END_REF]. Our data were considered missing completely at random based on Little's MCAR test [START_REF] Asparouhov | Weighted least squares estimation with missing data[END_REF]. The bias-corrected and accelerated 95% confidence intervals (95% CI) were estimated by bootstrap (5000 resamples; Hayes and Scharkow 2013). We explored associations with cord and child exposure separately and with mutual adjustment. An interaction term (child sex × chlordecone concentrations) was also added to the corresponding model while controlling for the same covariates with continuous chlordecone concentrations.

Descriptive statistics and correlations were performed using IBM SPSS 26 for Windows. Missing data pattern analysis and the missing completely at random (MCAR) assumption were performed with the BaylorEdPsych package using R 4.0.1 software [START_REF] Beaujean | BaylorEdPsych: R Package for Baylor University Educational Psychology Quantitative Courses[END_REF]R Core Team, 2018). Regression models and sex interactions were tested with Mplus 8.1 [START_REF] Muthén | Mplus User's Guide, Eighth Edi[END_REF].

Results

Descriptive statistics

Descriptive data for the study participants, children's scores from the visual, motor and cognitive tests, and concentrations of contaminants are presented in Table 1.

Accepted manuscript / Final version

Most of the mothers were born in the French West Indies and more than a half achieved superior education. The child mean age at testing was 7.7 years, half were female and 42% were still breast fed at 7 months. While the vast majority of children had a score on the S-B copying (n =405) and BOT-2 fine motor precision (n =407), CATSYS hand tremor scores were obtained only for 71% children (n =292). Smoking and alcohol consumption during pregnancy was relatively uncommon (less than 4%). Chlordecone was detected in 79% and 71% of cord and child blood samples, respectively. The median chlordecone concentration in cord blood (0.21 µg/L) was four times higher than the one observed in child blood samples (0.05 µg/L). The percentage of detected values for prenatal and postnatal exposure to other chemicals were all greater than 80% except for cord PCB-153 where 54% of the values were detected. Cord and child chlordecone blood concentrations were poorly associated (rsp = 0.09, p = 0.14) and were only slightly correlated with other chemicals: the highest correlation with cord chlordecone was with cord p,p′-DDE (rsp = 0.16, p < 0.01; data not shown), while the contaminants most highly related to child chlordecone was child Pb (rsp = -0.22, p < 0.01; data not shown). Spearman correlation coefficients among child assessment scores are presented in supplemental materials. The correlation between scores of S-B copying and BOT-2 fine motor precision is moderate (rsp = 0.39, p < 0.01). No significant correlation was observed between S-B copying score and hand tremor scores (Table S1). A significant association was observed between BOT-2 fine motor precision score and Harmonic Index scores with dominant hand (rsp = 0.16 p < 0.01). Harmonic index (non-dominant hand) was negatively correlated with tremor intensity (both hands; rsp = -0.16 to -0.17, p < 0.01) and positively with dominant hand harmonic index (rsp =0.22, p < 0.01). Tremor intensity

Accepted manuscript / Final version

Multiple linear relationships between chlordecone concentrations and child outcomes

Results from confounder-adjusted multiple regression models presented in Table 2 showed that S-B copying score was not significantly related to cord chlordecone concentrations, nor with child chlordecone concentrations on a continuous scale. However, analysis conducted according to 3 categorical child chlordecone levels indicated that this association with the S-B copying score reached the significance in the low exposed group, and was marginally significant (p = 0.06) in the high exposed group. Stronger negative association was found after accounting for other environmental exposures in Model 3.

With regard to the associations with BOT-2 fine motor precision score, no significant association with prenatal or child chlordecone exposure was observed (Table 2). -0.10 (-0.21, 0.01) -0.10 (-0.21, 0.01) -0.09 (-0.19, 0.02) Sex interaction a -0.09 (-0.30, 0.12) -0.09 (-0.30, 0.12) -0.06 (-0.26, 0.14) Abbreviations: CI, Confidence interval; LOD, limit of detection; BOT-2, Bruininks Oseretsky Test of Motor Proficiency Second Edition.

Accepted manuscript / Final version

a Sex variable where 1 = boy and 0 = girl.

Stanford-Binet: Model 1: both prenatal and child chlordecone exposure models adjusted for child sex and age and maternal Raven score. Child chlordecone exposure models were also adjusted for breastfeeding duration. Model 2: additional adjustments for complementary chlordecone exposure (i.e., child levels when Accepted manuscript / Final version cord levels was the variable of interest and vice versa). Model 3: additional adjustments for prenatal and child contaminants exposure. Cord models included child PCB-153 and child selenium. Child models included cord mercury exposure and child selenium exposure.

BOT-2: Model 1: both prenatal and child chlordecone exposure models are adjusted for child sex and age and maternal Raven score. Model 2: additional adjustments for complementary chlordecone exposure (i.e., child levels when cord levels was the variable of interest and vice versa). Model 3: additional adjustments for prenatal and postnatal environmental exposure: cord and child models included child PCB-153 and child selenium.

Accepted manuscript / Final version

Results with scores from the computerized CATSYS system are presented in Table 3. Cord and child chlordecone concentrations were not associated with Tremor Intensity scores. Significant associations were found between prenatal exposure and Harmonic Index scores with both dominant [Model 3: 0.02 (0.002, 0.03)] and nondominant hands [Model 3: 0.02 (0.01, 0.04)], while child exposure was not. That meant that higher cord chlordecone concentrations were associated with a pattern of regular subtle tremor in both hands (as indicated by the Harmonic Index), which may suggest a detrimental-type of tremor (Table 3).

Finally, we did not find significant moderation by sex between continuous cord or child chlordecone exposure and any outcome scores (Tables 2 and3), nor between categorical cord or child chlordecone exposure and any child outcomes (results not shown). Model 2: additional adjustments for complementary chlordecone exposure (i.e., child levels when cord levels was the variable of interest and vice versa).

Accepted manuscript / Final version

Model 3: additional adjustments for prenatal and postnatal environmental exposure: cord models included child PCB-153 and child models included cord mercury Accepted manuscript / Final version

Discussion

The main objective of this study was to document whether associations between prenatal exposure to chlordecone and neuromotor functions reported at two points in time during infancy in the TIMOUN cohort are still observed at school age, and whether exposure occurring during childhood is associated with negative outcomes. We are reporting that cord chlordecone concentrations are associated with a regular frequency pattern of subtle hand tremors in both hands, and not related to visual processing and fine motor precision. Additionally, chlordecone concentrations in child blood sample collected at testing time are associated with poorer visual processing when copying geometric figures (S-B copying test). No sex-specific vulnerability was reported in any of the outcomes.

In this same cohort, parental reports of deficits on fine motor skills assessed at 7months [START_REF] Dallaire | Cognitive, visual, and motor development of 7-month-old Guadeloupean infants exposed to chlordecone[END_REF] and at 18-months old [START_REF] Boucher | Exposure to an organochlorine pesticide (chlordecone) and development of 18-month-old infants[END_REF] were associated with higher cord blood chlordecone concentrations. We found no such association at 7 years old when using the fine motor precision subtest from the BOT-2, which includes seven tasks involving paper, pencil and scissors. While this subtest was selected to document fine motor skills independent from parental assessment, as we previously reported deleterious effects of prenatal chlordecone exposure on this developmental domain, its internal consistency was only acceptable in our population. This suggests we may have faced a lack of sensitivity using this measure, which could have resulted in this negative result. We used the CATSYS to evaluate postural hand tremor, which is a test proven to be sensitive in evaluating neurologic and neurodegenerative disorders, showing its ability to discriminate pathologic from Accepted manuscript / Final version physiologic (normal) tremor in Parkinson's disease [START_REF] Papapetropoulos | Objective quantification of neuromotor symptoms in parkinson's disease: Implementation of a portable, computerized measurement tool[END_REF] and also in the assessment of subtle neurological impact of exposure to toxic agents such as in manganese exposed population, but also within populations exposed to methylmercury, and tobacco [START_REF] Beuter | Quantifying postural tremor in workers exposed to low levels of manganese[END_REF][START_REF] Bowler | Environmental exposure to manganese in air: Associations with tremor and motor function[END_REF][START_REF] Chiu | Manganese Exposure on Neuromotor Function in Adolescents[END_REF][START_REF] Ellingsen | Hand tremor related to smoking habits and the consumption of caffeine in male industrial workers[END_REF][START_REF] Ellingsen | A follow-up study of neurobehavioral functions in welders exposed to manganese[END_REF][START_REF] Kim | Motor function in adults of an Ohio community with environmental manganese exposure[END_REF][START_REF] Kornblith | Environmental exposure to manganease in air: Tremor, motor and cognitive symptom profiles[END_REF][START_REF] Netterstrøm | Acute mercury intoxication examined with coordination ability and tremor[END_REF]. In our study population exposed to chlordecone, we are reporting associations of cord chlordecone concentrations with a regular frequency pattern of subtle tremors in both hands, considered as detrimental to health [START_REF] Després | Standardization of a neuromotor test battery : the CATSYS system[END_REF]. This specific sign is in accordance with the severe and consistent tremors observed among Hopewell employees accidently intoxicated during chlordecone production [START_REF] Cannon | Epidemic Kepone poisoning in chemical workers[END_REF], and with the results of experimental animal's studies exposed either during neonatal period [START_REF] Mactutus | Evaluation of neonatal chlordecone neurotoxicity during early development: initial characterization[END_REF] or in adulthood [START_REF] Dietz | Comparative effects of Mirex and Kepone on schedule-controlled behavior in the rat. I. Multiple fixed-ratio 12 fixed-interval 2min schedule[END_REF]. In animal studies, tremors were apparent at earlier times when higher doses were used compared to lower doses (Agency for Toxic Substances and Disease Registry, 2019).

The S-B copying test measures both visuospatial processing and fine motor skills, as the child is required to do a visual integration of two-dimensional geometric figures and to transpose them using pencil and paper. This task elicits two distinctive neuromotor functions at the same time. Thus, in our study, although no association was observed with prenatal exposure, the negative associations we observed of child chlordecone concentrations with the visual processing score from the S-B copying test can emerge partly from poorer manual dexterity and coordination required to copy geometric figures in addition to alterations in visuospatial processing per se. In parallel to the present study, we previously reported that higher child chlordecone concentrations were related to Accepted manuscript / Final version chlordecone, products that were not included in the market control system (IREPS Guadeloupe and ARS Guadeloupe -Saint-Martin, 2014;[START_REF] Nedellec | Public health and chronic low chlordecone exposures in Guadeloupe; Part 2: Health impacts, and benefits of prevention[END_REF]. Finally, the fourth action plan proposed by the French Government was put in place in February 2021, aiming to strengthen the measures already undertaken to reduce the exposure of populations to chlordecone in Guadeloupe and Martinique, as well as to deploy appropriate support measures to meet the population needs (Ministère des solidarités et de la santé, 2021).This study has several strengths and limits. The main strengths are its prospective design with assessment of both prenatal and childhood exposure using sensitive biomarkers, repeated neurodevelopmental assessments during infancy and at school-aged, and collection of extensive data on potential confounders and co-exposures from the prenatal to the school-aged period. A large number of socioeconomic and medical covariates, and other recognized neurotoxicants (Hg,Pb,p, were examined in the analyses. Nevertheless, we cannot completely exclude residual confounding. We considered potential bias from socioeconomic status by running sensitivity analyses since children from higher-income families might have better access to pencils and materials for creative work. In the same way, additional adjustment for family income did not modify the strength of any association between chlordecone exposure and any outcome measured at school age. Finally, as children vulnerability to neurotoxicants continue to be high during the first years of life when systems are immature, it is crucial to keep documenting hand tremors and other possible impact on neuromotor functions using comprehensive screening tools.

Accepted manuscript / Final version

Conclusions

These results we are reporting here at school aged expand those previously reported in the same cohort during infancy at age 7-and 18 months, and corroborate the long lasting negative effects of prenatal chlordecone exposure on fine motor function in absence of intoxication. Negative associations of child chlordecone exposure with the visual processing score from the S-B copying test can be related to alterations in visuospatial processing per se in coherence with deficits in contrast sensitivity at low spatial frequencies in boys reported in a parallel evaluation. The investigation of these neuromotor functions needs to be further explored since abilities like fine motor writing and object manipulation are significant predictors of later academic achievement [START_REF] Dinehart | Associations Between Low-Income Children's Fine Motor Skills in Preschool and Academic Performance in Second Grade[END_REF].

  intentional tremors, ataxia, oculomotors dysfunctions and slurred speech. Years later, chlordecone was included on the list of priority pollutants by the Stockholm Convention (Secreteriat of the Stockholm Convention and United Nations Environment Programme, 2010) and since 2003, actions have been taken by the French Government to reduce chlordecone exposure in Guadeloupe and Martinique (Direction générale de la santé, 2015, 2013, 2008; Ministère des solidarités et de la santé, 2021).

  polypropylene tubes following centrifugation. Chlordecone, p,p′-dichlorodiphenyl dichloroethylene (DDE), PCB congener 153 (PCB-153), and lipids were measured in plasma. Determination of chlordecone, p,p′-DDE, and PCB-153 concentrations were done by the Center for Analytical and Research Technology at Liege University (Belgium). Contaminant concentrations were analyzed by high-resolution gas chromatography (Thermo Quest Trace 2000 gas chromatograph, Milan, Italy) quipped

a

  Maternal Raven score at the 7-years old visit (n = 382) but when missing (n = 24), the RAVEN score obtained the 3-month postnatal visit was used. b Blood concentrations, geometric mean ± geometric standard deviation calculated on all values.

a

  Sex variable where 1 = boy and 0 = girl. b Based on the calculation developed by Edwards and Beuter 1999. Model 1: both prenatal and child chlordecone exposure models are adjusted for child sex and age, and maternal Raven score.

Table 1 -

 1 Descriptive characteristics of the study sample

	304
	Variables	N	Mean ± SD or n	Median	Range
			(%)
	Maternal and family characteristics
	Birthplace of mother	410
	Guadeloupe or Martinique		321 (78.3)
	Others Caribbean		40 (9.8)
	French Mainland or others		49 (12.0)
	Maternal age at 7-years old visit	410	38.99 ± 6.79	40.00	22.00 -52.00
	Parity before child birth	410	1.19 ± 1.32	1.00	0.00 -8.00
	Marital status at 7-years old visit (%	410	262 (63.9)
	living with a partner)
	Education at recruitment (achieved level) 410
	Primary or none		18 (4.4)
	High school		185 (45.1)
	Superior education		207 (50.5)
	Family income at 7-years old visit (per	402
	month)
	≤ 1500 euros		163 (40.5)
	1501-3000 euros		138 (34.3)
	≥ 3001 euros		101 (25.1)
	Maternal RAVEN score a	406	35.69 ± 12.38	38.00	9.00 -59.00
	Child characteristics
	Age at visit (years)	410	7.67 ± 0.21	7.7	7.00 -8.00
	Sex (% female)	410	217 (52.9)
	Birth weight (g)	410	3136.44 ± 517.72	3160.00	1315.00 -4585.00
	Gestational age (weeks)	410	38.72 ± 1.68	39.00	32.30 -41.30
	Breastfeeding duration (months)	408
	No breastfeeding		65 (15.9)
	0 ≤ 6		173 (42.4)
	7 < 18		91 (22.3)
	≥ 18		79 (19.4)
	Child outcomes
	Stanford-Binet copying score	405	13.25 ± 1.70	14.00	7.00 -16.00
	BOT-2 fine motor precision score	407	34.64 ± 4.20	36.00	12.00 -41.00
	CATSYS hand tremor scores
	Tremor Intensity, dom.	292	0.27 ± 0.13	0.23	0.02 -0.72
	Harmonic Index, dom.	292	0.85 ± 0.05	0.85	0.69 -0.99
	Tremor Intensity, non-dom.	287	0.31 ± 0.18	0.26	0.06 -1.00
	Harmonic Index, non-dom.	287	0.86 ± 0.05	0.86	0.74 -0.98
	Prenatal exposures
	Cord chlordecone (µg/L) b	380	0.12 ± 8.20	0.21	< LOD -29.78
	≤ LOD (0.06)		81 (21.3)
	Low exposure (0.061-0.29)		149 (39.2)
	High exposure (> 0.29)		150 (39.5)
	Tobacco during pregnancy (% yes)	410	13 (3.2)
	Alcohol during pregnancy (% yes)	398	10 (2.4)
	Cord PCB-153 (µg/L) b	379	0.02 ± 13.50	0.06	< LOD -1.75
	Cord p,p′-DDE (µg/L) b	379	0.20 ± 7.41	0.28	< LOD -12.50
	Cord Hg (µg/L) b	401	6.18 ± 1.82	6.60	0.69 -46.12
	Cord Pb (µg/L) b	401	13.85 ± 1.59	13.3	3.52 -99.46
	Cord Se (µg/L) b	401	116.49 ± 1.22	118.44	64.00 -221.09

Table 2 -

 2 Regression coefficients examining the relation between prenatal and postnatal chlordecone exposure, Stanford-Binet copying relaxed scores and BOT-

	2 fine motor precision scores (n = 410)
		Model 1	Model 2	Model 3
	Exposures	β (95% CI)	β (95% CI)	β (95% CI)
	Stanford-Binet copying scores
	Cord levels (µg/L)
	≤ LOD	Reference	Reference	Reference
	Low chlordecone (≤ 0.29)	0.22 (-0.27, 0.72)	0.19 (-0.31, 0.70)	0.23 (-0.27, 0.76)
	High chlordecone (> 0.29)	-0.08 (-0.58, 0.45)	-0.06 (-0.56, 0.47)	0.03 (-0.47, 0.58)
	Continuous (log2)	-0.02 (-0.07, 0.04)	-0.02 (-0.07, 0.05)	-0.01 (-0.06, 0.06)
	Sex interaction a 0.02 (-0.10, 0.15)	0.03 (-0.09, 0.15)	0.02 (-0.11, 0.14)
	Child levels (µg/L)
	≤ LOD	Reference	Reference	Reference
	Low chlordecone (≤ 0.07)	-0.44 (-0.88, 0.02)	-0.46 (-0.90, -0.01)	-0.47 (-0.89, -0.03)
	High chlordecone (> 0.07)	-0.44 (-0.90, 0.02)	-0.46 (-0.91, 0.01)	-0.45 (-0.90, 0.01)
	Continuous (log2)	-0.04 (-0.09, 0.01)	-0.04 (-0.09, 0.01)	-0.05 (-0.09, 0.01)
	Sex interaction a 0.04 (-0.05, 0.14)	0.05 (-0.05, 0.15)	0.06 (-0.03, 0.16)
	BOT-2 fine motor precision scores
	Cord levels (µg/L)
	≤ LOD	Reference	Reference	Reference
	Low chlordecone (≤ 0.29)	-0.05 (-1.12, 1.21)	-0.12 (-1.20, 1.11)	0.04 (-1.03, 1.24)
	High chlordecone (> 0.29)	-0.45 (-1.62, 0.83)	-0.41 (-1.60, 0.86)	-0.14 (-1.28, 1.10)
	Continuous (log2)	-0.04 (-0.17, 0.10)	-0.04 (-0.16, 0.11)	-0.01 (-0.13, 0.13)
	Sex interaction a 0.21 (-0.05, 0.48)	0.22 (-0.03, 0.50)	0.18 (-0.07, 0.46)
	Child levels (µg/L)
	≤ LOD	Reference	Reference	Reference
	Low chlordecone (≤ 0.07)	-0.41 (-1.43, 0.67)	-0.44 (-1.44, 0.64)	-0.36 (-1.38, 0.70)
	High chlordecone (> 0.07)	-0.86 (-1.95, 0.18)	-0.86 (-1.95, 0.19)	-0.58 (-1.65, 0.43)
	Continuous (log2)

Table 3 -

 3 Regression coefficients examining the relation between prenatal and postnatal chlordecone exposure and CATSYS tremor scores with dominant and non-

	349
	350	dominant hand (n = 410)
		Tremor Intensity

(non-dominant hand) was positively correlated with dominant hand tremor intensity (rsp =0.68, p < 0.01) and negatively with harmonic index (rsp = -0.12, p = 0.04).Accepted manuscript / Final version

Acknowledgements

We would like to thank Emmanuel Ouellet for his participation in the training of child testers and quality control of the child data, and Yohann Courtemanche for his help with the preparation of the manuscript. We are grateful to all the families of the TIMOUN cohort, to the staff of the follow-up at 7 years (Marie-Fred Noyon, Nathalie Surville Barland, Annie-Claude Coriolan, Chantale Emeville, Colette Danquin, Sabrina Mimifir, Tania Plumain, Indira Oujagir, Agnès Desiré, Katia Galbas, Stéphanie Reine), and to Catherine Adam, laboratory technician at the LEAE-CART, for her valuable help in organochlorine analysis

Accepted manuscript / Final version

Funding This work was supported by grants from the General Health Directorate (DGS RMC11129NNA & R17142NN), and the Fondation de France (N° 69263) Accepted manuscript / Final version

deficits in contrast sensitivity at low spatial frequencies in boys using the Freiburg Visual Acuity and Contrast Test (FrAcT;[START_REF] Saint-Amour | Visual contrast sensitivity in school-age Guadeloupean children exposed to chlordecone[END_REF]. The vast majority of children (91%) had visual acuity within the normal range, and chlordecone was unrelated to visual acuity. In concordance with what was already proposed by [START_REF] Waksman | Contrast Sensitivity in Occupational and Environmental Neurotoxicology: What Does it Really Mean?[END_REF], Saint-Amour and his colleagues concluded that the "deficits in contrast sensitivity observed at low spatial frequencies reflect predominantly defects in post-retinal neural processing" [START_REF] Saint-Amour | Visual contrast sensitivity in school-age Guadeloupean children exposed to chlordecone[END_REF][START_REF] Waksman | Contrast Sensitivity in Occupational and Environmental Neurotoxicology: What Does it Really Mean?[END_REF].

In this same cohort, sex-specific effects from cord chlordecone exposure were observed in boys at 18-months on fine motor functions [START_REF] Boucher | Exposure to an organochlorine pesticide (chlordecone) and development of 18-month-old infants[END_REF] and at 7 years from current chlordecone exposure on visual contrast sensitivity [START_REF] Saint-Amour | Visual contrast sensitivity in school-age Guadeloupean children exposed to chlordecone[END_REF]. In the present study, no sex-specific effect was found on fine motor functions evaluated at 7-years. Still, chlordecone hormone-like properties have been clearly established both in vivo and in vitro [START_REF] Eroschenko | Estrogenic activity of the insecticide chlordecone in the reproductive tract of birds and mammals[END_REF][START_REF] Hammond | Estrogenic activity of the insecticide chlordecone (Kepone) and interaction with uterine estrogen receptors[END_REF]. The integration of sex-specific analyses while investigating exposure to chlordecone, as well as other endocrine disruptor chemicals, in relation with children neurodevelopment needs to be pursued. Furthermore, the reduced chlordecone concentration overtime observed in our study sample might be explained by some actions taken by the French Government since 2003 (Direction générale de la santé, 2015, 2013, 2008). The main activities were to withdraw food from the market and water from the distribution system when chlordecone was above the limit values (Agence Française de Sécurité Sanitaire des Aliments, 2007).

In 2009, the "Family Gardens" program was put in place in Guadeloupe to inform and support families who cultivate a vegetable garden potentially contaminated by

Accepted manuscript / Final version

Supplemental Material


Ali Koudri
email: ali.koudri@fr.thalesgroup.com

Denis Aulagnier
email: denis.aulagnier@fr.thalesgroup.com

Didier Vojtisek
email: didier.vojtisek@irisa.fr

Philippe Soulard

Christophe Moy
email: christophe.moy@supelec.fr

Joël Champeau
email: ensietajoel.champeau@ensieta.fr

Jorgiano Vidal
email: lab-sticcjorgiano.vidal@univ-ubs.fr

Jean-Christophe Le Lann
email: thomsonjean-christophe.le-lann@thomson.net

Using MARTE in a Co-Design Methodology

The Model Driven Architecture is a promising approach aiming to fill the productivity gap due to the increasing technology and time to market pressure. In the field of real time embedded systems, this approach requires the use of well-adapted formalisms in a reliable process that guarantees the quality of the products. MARTE, the new standardized UML profile, provides those formalisms that are applied in the process defined in the MoPCoM SoC/SoPC research program, aiming to develop SoC and SoPC applications. In this paper, we discuss the main phases of this process and their use of MARTE.

I. INTRODUCTION

Nowadays, embedded equipments rely more and more on components such as System on Chip(SoC) or System on Programmable Components (SoPC) based on Field Programmable Gate Array(FPGA) for low volume of production.

Embedded applications require more and more computing resources. These needs can be fulfilled by SoC / SoPC integrating on the same component analog circuits, hardwired ASIC Gates, programmable logical cells, memory blocks, high speed links, DSP and processor cores. Nevertheless, the SoC/SoPC development requires challenging productivity improvement to be able to address the component design complexity [START_REF] Itrs | The international technology roadmap for semiconductors : Design[END_REF].

Moreover, some embedded applications are constrained by certification norms like ARP-4754 (system), DO-178B (software) and DO-254 (hardware). In such case, SoC/SoPC developments have to be handled by rigorous methodologies based on well-adapted formalisms [START_REF] Koudri | Fpga rf transceiver development based on uml mda approach[END_REF].

In this paper, we discuss a new methodology to develop SoC/SoPC applications. This methodology is based on UML and MDA (Model Driven Architecture), and takes into account the achievements of codesign community. MDA [START_REF] Omg | Mda guide version 1.0.1[END_REF], promoted by the OMG (Object Management Group) replaces classical waterfall process (specification, design, coding), by a succession of models transformations, among these models:

• CIM (Computation Independent Model) models the requirements for the system and how the the system will be used, • PIM (Platform Independent Model) is the view of the application independent from the target platform and can be considered as a functional description, • PM (Platform Model) represents the target architecture used to implement the application,

• PSM (Platform Specific Model) results from the mapping of the PIM on the PM.

Actually, several PM of the SoC/SoPC Platform with different levels of abstraction are required to achieve the final implementation. For each PM, the process of allocation results in new PSM and analysis models. This approach enables to increase flexibility, reuse and separation of concerns.

The MDA approach was initially proposed in the context of software development and can be applied in the codesign domain. Indeed, "MDA notions" have been introduced long time ago in this field. For example, the Y-Chart methodology proposed by Gajski and Kuhn identifies behavioural, structural and geometric viewpoints [START_REF] Gajski | Guest editor introduction : New vlsi tools[END_REF].

Compared to conventional codesign methodologies, the use of UML/MDA for SoC/SoPC development enables to take advantage of the standards and the tooling developed by the UML/MDA community, such as the new UML profile for Modeling and Analysis of Real Time Embedded Systems (MARTE) [START_REF] Omg | Uml profile for marte, beta 1[END_REF]. This profile enriches UML adding new notions for real time systems such as Non-Functional Properties or Time Access. Those features are seen in the section III.

In this paper, we present a new Co-Design methodology defined in the MOPCOM research project, aiming to provide a full MDA compliant tool to design SoC/SoPC applications. In this methodology, system analysis follows the Telelogic Harmony TM System Engineering process, based on the use of SysML [START_REF] Omg | Sysml profile[END_REF], improved with the use of MARTE. It is then refined to address platform and allocation modeling. Three levels of abstraction have been defined to describe the platform on which the application is mapped (see fig. 1):

• APA (Abstract Platform Architecture) considering the platform as a set of basic services without notion of time, • EPA (Execution Platform Architecture) refining the APA model taking into account software and hardware nature of APA components and timing constraints, • DPA (Detailed Platform Architecture) detailing the EPA model, taking into account other constraints (power consumption, surface, etc).

In order to favor analysis, reuse or separation of concerns (computation / communication), the description of the com- At each level, several analysis models (performance, power consumption, etc.) can be generated from each allocation in order to validate design choices. This approach allows early errors detection and design space exploration, fastering simulation speed. Moreover, in order to add meaningful properties to our methodology (predictability, maintainability, improvability, etc.) and automate it, we have used the SPEM profile [START_REF][END_REF] to formalize it.

In this paper, we present our use of the UML MARTE profile through each phase of our methodology and we discuss the encountered problems from implementation or conceptual point of view.

II. RELATED WORKS

The relevance of model based approaches in Co-Design have been widely discussed by the litterature. In [START_REF] Boulet | Model driven engineering for system-on-chip design[END_REF], authors enumerate the main advantages of such approaches: cost decrease, silicon complexity handling, productivity increase, etc. Athough several methodologies based on the use of UML/MDA have been applied, UML were not tailored to design SoC/SoPC applications. Then, it was extended and tooled by each of those methodologies, thanks to the profiling mechanism provided since UML 1.3. For example, in [START_REF] Boulet | Uml 2.0 structure diagram for intensive signal processing application specification[END_REF], authors propose extensions to describe Intensive Signal Processing Applications in a profile called ISP UML Profile. In [START_REF] Riccobene | A soc design methodology involving a uml 2.0 profile for systemc[END_REF], authors apply a SoC Design Methodology based on the use of a UML profile called UML for SystemC Profile. This profile allows direct mapping between the models and the concepts of the SystemC language. The same kind of approach is presented in [WZZ + 06]. A SystemC UML profile is used to generate a TLM/PV SystemC code skeleton. In [CSL + ], a design environment called Metropolis and aiming to design embedded systems is proposed. It tailors UML in order to describe execution platforms and their refinments. They provide set of stereotypes representing structural parts of the platform and corresponding model of computation.

In [START_REF] Riccobene | Designing a Unified Process for Embedded Systems[END_REF] a development process for embedded systems called UPES 1 , based on the use of SystemC profile, is presented.

It is interesting to notice how, through all those approaches, common needs like platform and allocation description at several levels of abstraction are filfulled by different approaches. Some of them propose a direct mapping of the platform concepts to the target languages while others use target languages as concrete syntax in purpose of generation or execution. The problem with those approaches are the dependency to the tools implementing very specific profiles or DSL (Domain Specific Languages). With the standardization of the MARTE profile, we think this drawback will be handled by the use of common formalisms to describe real time and embedded systems.

III. USE OF MARTE IN THE MOPCOM SOC/SOPC RESEARCH PROJECT

The MoPCoM process is a Co-Design Process based on the use of models and transformations. Since one of the main features of the MDA is the separation of concerns, there is a need to dispose of well-adapted formalisms to describe each part of the MDA model. For several reasons, such as communication improvements or tooling, we have made the choice to use standardized metamodels and profiles. The new standardized UML MARTE Profile add semantics to UML for Real time Embedded System Modeling. This profile is organized around several packages capturing different concerns :

• The Non Functional Properties (NFP) package enables to describe features that are not directly related to the business model (performance, memory usage, power consumption, etc.) and mechanisms to attach them to model elements, • The Time package enables modeling of time structure and access (continuous time, clock, etc.),

• The Generic Resource Modeling (GRM) package enables modeling platform resources from high level perspective and mechanisms to manage access to those resources,

A. System Analysis

The system analysis goes from the requirements analysis to the system design and is covered by the SysML profile [START_REF] Omg | Sysml profile[END_REF]. Since this part is not really in the scope of this paper, we will just give a quick overview in the following points:

• requirements elicitation,

• static validation of the requirements,

• manual transformation of the requirements into use cases and interactions, • use cases validation through simulation,

• identification of the subsystems, • operational contracts allocation, • interaction refinements, • system design validation. During this stage, we use some concepts of the NFP packages in order to describe the required quality of services in term of real-time features of behaviors and interactions. At the end of this stage, an annotated functional architecture is provided for following steps, including allocations and refinements.

B. Abstract Platform Architecture

The platform is defined as a set of resources like processing resources, communication media or storage resources. The purpose of this level is to describe applied mechanisms in order to realize high level functions. Communications between APA blocks are point-to-point and realized through abstract channels providing set of basic services allowing data transport. Actually, what we aim to describe at this level is the underlying model of computation supporting the execution of the application and since we just want to demonstrate the functional correction of this model, it is thus untimed. Synchronization mechanisms ensure the characterization of the causal relations between processing elements and then ensure the predictability of the system behavior. The fact that the model is untimed doesn't mean that timing constraints inherited from the application model are not taken into account. Functional delays can be then inserted into the APA model, regarding the functional constraints.

Once the platform has been defined by the software or hardware engineering teams, allocation can be modelled using well-adapted formalisms provided by the allocation package of MARTE. The allocation can be of spatial, temporal or hybrid nature. Since many allocations with different characteristics (performance or schedulability) are possible, models of allocation are concerned with the functional correctness issue. The figure 2 summarizes issues related to the allocation at the APA level. The application is modelled through business components communicating through (a)synchronous operation calls or events send/reception while the platform is modelled through APA blocks communicating through channels implementing data transport services. The execution semantic described in the business model must be verified through the allocation. Since the APA platform is untimed, there is no notion of protocol at this level. In order to describe the APA platform, one need to describe resources from a high level perspective, without prejudging of their hardware or software nature, and take into account their quality of service. The GRM package of MARTE provides all needed stereotypes and tagged values to represent resources (computing resources, storage resource, communication media, etc.) and their use. This package is used in conjunction with the NFP package for the quality of services and Time Modeling package for timing constraints. The GRM package provides also mechanisms of synchronization and resource management that fulfills the needs for APA modeling. The package Allocation Modeling provides all needed stereotypes to allocate business model to APA plaform. Since an allocation comprises at least one application end and one execution platform end, we need to constraint the set of possible mappings for this level refining the allocation definition.

C. Execution Platform Architecture

The MOPCOM EPA platform level aims at providing a more precise platform than the APA level : while APA focused on point-to-point communication, EPA provides more details with respect to the expected final topology on the system. The right methodological tools at this level are clearly MARTE sub-profile HRM -Hardware Resource Modeling on which MOPCOM relies. Concerning the usage of MARTE, the stereotypes used here are hwComputingResource (processor,...), hwCommunication( bus,...).

EPA is geared towards architects willing to depict global scenario of data movement over the chip and computing resources, comitting to IP choice. EPA is thus fundamental to preserve the representativity of application with respect to the platform, while enabling fast design space exploration and high-speed simulation, based on generic highlevel components.

In this sense, many hardware resources must be adequately identified at this level, without over-specifying them, which is often the case when architects are not provided with apropriate tools to help their specification. A natural companion modeling concept of EPA is transaction-level modeling, as promoted by Gajski and SystemC community in general.

Among those resources, communication media like busses, NoCs and buffering medium need to appear in EPA (the right stereotypes here are HWI/O and HWStorage). Beyond the communication aspects, computing resources are also included in this model, possibly still in an abstract (behavioral) version. For instance, instead of describing a real RISC processor or accelerator, EPA proposes to aleviate the need for deep hardware description and invites to keep the functions executed by these processing elements as the representative of the blocks themselves.

Thus a wrapper needs to ensure that the function can indeed have access to the communication media : here we prone a simplified version of generic DMA at the I/O of the functionnal data-intensive blocks, possibly assisted with control/status registers that ensure the high-level control of the application in a processor-like manner. Using this approach, it is possible to set up dummy experiments to test these notions and their adequacy to a broader set of other experiments. In the following drawing, we depict typical experiment within reach of an EPA model : the goal is to move data from DDR zones to other DDR zones, after some modifications executed on the set of data. A global controler, mimicking a microcontroler/processor, observes the completion of the various data transfers in order to enable the next transfers. Entire data structures can be moved from one location to another without any serialization mecanism to low level data representation. As a consequence of this separation of concerns, early application porting debug activity can start, while studying the underlying lower level mecanisms constraints that need to be fullfilled to respect the expected final behavior. Clearly here, the EPA level envisions the mapping process as a simple binding of application functions to processing elements and point-to-point communication links to concrete communication elements, with no further notion of compilation to dedicated binary format, nor the resort to ISS/interpreters : functions can still be seen as abstract tasks, just as in the APA level. Note that some such blocks or units may be in charge of executing several functions : in this case, this coarse grain resource sharing then assumes the presence of a basic abstract arbitration mecanism.

The performances of the final hardware cannot be measured at the EPA level. However, the unambiguous identification of computing resources types allows for analysis and parameterized estimations : we keep as much room as possible for architectural exploration, by tuning these parameters adequately. The metrics on which it is possible to focus on are the channels required bandwidth and relative computation power of the processing units. MARTE SAM package (schedulability analysis model) are clearly in line with the requirements at the EPA level. For instance we reinforce the EPA structural model with behavioral scenarios with the help of Message Sequence Charts : synchronization aspects of locking/unlocking busses can be handled through (Metaclass) BasicInteractions::Message, even if it has been promoted with OS in mind. In the same manner, many elements of PAM package seem adequate to analyze non-functional properties especially concerning communication side. Their exact concrete usage is still under study.

As emphasized here, EPA prones to resort to behavioral descriptions instead of deeply detailed descriptions. For instance, concerning the processors, the further refinement to real binary code (on the embedded SW side) and cycle & pin accurate hardware will be treated in the 'next' level, i.e DPA level, where measures becomes meaningfull. The same applied for communications, where the complete protocols will need to be fully modeled.

One interesting question is about the minimum set of hardware features to embed in this EPA level so that the model of computation can be implemented either manually or handled by the MDA toolflow : register control, DMA control etc.

D. Detailed Platform Architecture

The DPA is the last level before generate the RTL code. At this level, all information about the RTL system is specified, so it can be generated. The platform is defined as a set of IPs that communicate among them through busses, as in EPA level. The purpose is to have a cycle accurate platform model, where all transaction is done by a refined and precise protocol, defined here at a cycle level. The internal state of the IP blocks can be observed at each clock cycle. There are three main improvements from the EPA level:

• Existence of hardware clock -All synchronous elements must be connected to a clock. • Definitinion of a RTL communication protocol -All communications must be well defined in terms of signals and clock cycle. • Physical hardware details -card layout and power consumption. To fulfill these improvements, MARTE elements are used. The hwClock MARTE stereotype is used to model clocks. The clock values are then defined with NFP package (frequency, counter, . . . ). MARTE does not provide an explicity way to precise a protocol, it just have the elements to define a protocol, that means: bus (with their signals) and the behavior is modeled with a UML state machine. The protocol constrains is done by NFP and RTMoCC MARTE elements (RtAction,. . . ). One possibility is to use a protocol library/stereotype to speed up the design process, such solution is under study.

The figure 4 shows the main issues related to the allocation at the DPA level. The application is refined to allow cycle precising and the platform contains all hardware details to support these definitions. The stereotypes used at EPA level are now refined to be detailed at implementation level, i.e. a processor type, ISS and registers will precise elements to have a cycle accuracy. This is achieved with the tags in HRM MARTE sub-profile.

The platform is modelled through DPA blocks communicating through buses with a detailed cycle-accurate protocol. The protocol must be able to implement at a RTL level the Model of Computation defined at higher levels. Here, the exploration is done at protocol level, with a clock, bus/protocol to achieve the desired performance. Now, the meaning of a communication implementation is important, where complex The real performance of the system can be measured at DPA level, possibiliting the last refinements to achieve an optimal configuration of the PEs (physical characteristics and logical refinements) and how they communicate. All protocol details allows the observation of the system at the precision of the physical clock cycle tick. All the real-time constrains specified at application level must be verified here.

The MARTE sub-profile HRM -Hardware Resource Modeling -is used to specify the DPA elements, but, refined from the EPA model, it must be detailed. Thus this profile we can specify all the hardware elements and, for that, the final physical hardware characteristics is done by the HWPhysical (HRM sub-profile) and is composed by:

• HwLayout: Component (card, channel, chip, port) • HwPower: power supply, cooling supply An element, already stereotyped with its logical characteristic (processor, bus, IO, . . . ) and detailed in DPA level is now stereotyped also with the physical characteristics. Such definition allows the final allocation to be made. For instance, with the HwPort stereotype it is possible to define its pin number, area, weight, etc (from HwComponent), which allows the application port to be allocated into hardware ports. Such allocation allows a really refined unbiguous hardware platform definition, where each application element is allocated into a final hardware element, RTL-detailed.

We precise the time with the Timing sub profile. The stereotypes are "tagged" with NFP elements to define the details of the platform. The allocation is done by the Alloc sub-profile. Also, the use MARTE PAM -Performance Analysis Modeling -and SAM -Schedulability Analysis Modeling -sub profiles allows the specification of the system performance.

Modeling constraints must be defined to allow an automatic code generation, for now, the constraints are:

• Must use of HRM stereotypes to all hardware elements. Need to define which tags are or not optional for each stereotype.

• Protocol specification. For now, the only way is to use a UML state machine to handle communication. The use of a library and/or new stereotypes is in progress. • Every synchronous element MUST be connected to a clock. With a refine cycle accurate specification, it is possible to measure the final system performances. As the final hardware is detailed at DPA level all the communication details can be verified. The RTL model of the system can be automaticaly generated. This model can be used to measure and generate the final system in the target desired languages (for Hardware and Software).

IV. DISCUSSIONS

The development methodology we have presented above is being experimented on a video application for SoC and a RF digital receiver application for SoPC. Despite we think that MARTE can fulfil most of the requirements of a modelling languague for SoC/SoPC design and analysis, we faced some limitations applying MARTE. Those limitations are either related to the implementation of the profile or missing concepts in the profile.

Allocation: MARTE proposes to specify the "allocate" relationship between business components and resource components with notation based on a dashed line with an open arrow head. This graphical approach can be very cumbersome and messy for large models. Some tooling, using widgets for example, could be developed to facilitate the allocation activity.

Model of Computation and Communication: MARTE foundation enables to define alternative MoCC. Modelling or implementation of embedded applications generaly rely on heterogenous MoCCs such as Synchronous Data Flow (SDF), Communication sequential process (CSP), Petri Net (PN), Kahn Process Network (KPN). These specific MoCCs should be introduced in MARTE.

Action Semantics: In the purpose of executing and testing models, UML has introduced the Action Semantics to provide software independent language specification for actions in their models. Nevertheless, those action semantics have been defined in the context of software development, and then do not integrate concerns from other domains like system or real time domain. Typically, actions defined by the UML specification are related to other UML concepts and since new concepts have been introduced in MARTE, we think it would have been interesting to add meaningful actions related to them and also provide associated concrete textual syntax.

V. CONCLUSION AND FUTURE WORKS

In this paper, we have discussed a co-design process called MoPCoM based on the use of the MARTE profile. For each phase of this process, we have presented the selected stereotypes of the profile and constraints related to their use. We have outlined the main encountered problems from conceptual and implementation perspective. Future works are related to VHDL et SystemC code generation after the allocation of the application on the Detailed Platform Architecture. This development is done using MDWorkbench transformation tooling from Sodius2 . Further works will be carried out on modelling and implementing dynamically reconfigurable applications.

Fig. 1 .

 1 Fig. 1. MoPCoM overview

Fig

  Fig. 2. APA allocation

Fig. 3 .

 3 Fig. 3. EPA typical experiment : data are moved from one location to another, through well identified communication links, possibly simulated at a behavioral level, abstracting away details about finer details.

Fig. 4 .

 4 Fig. 4. DPA allocation

  • The Allocation package enables modeling of spatial and temporal allocations, • The Detailed Resource Modeling (DRM) package allows modeling of hardware and software resources at several levels of granularity; it contains two sub-packages enabling the modeling of Software Resource (SRM) and Hardware Resource (HRM), • The Generic Quantitative Analysis Modeling (GQAM) package allows several types; It contains two subpackages for modeling Performance Analysis (PAM) and Schedulability Analysis (SAM). The array in Table I sum up the requirements of the process and formalisms that satisfy those requirements. The system properties, mesurable or not, like power consumption or latency, can be expressed using the Value Specification Language (VSL) provided by MARTE at each stage of the process.

	MoPCoM Process Requirements	Solutions
	Model Computational Independent	SysML + MARTE NFP and RTE-
	Model				MoCC
	Model	Platform	Independent	SysML + MARTE NFP and RTE-
	Model				MoCC
	Model Abstract Platform Architec-	MARTE GRM and NFP
	ture
	Model Execution Platform Archi-	MARTE DRM + NFP + Time
	tecture
	Model Detailed Platform Architec-	MARTE DRM + NFP + Time
	ture
	Model	Allocation	(PIM	to	MARTE Allocation + NFP
	APA/EPA/DPA)
	Model Analysis Models		MARTE PAM and SAM

TABLE I MOPCOM

 I PROCESS REQUIREMENTS

http://www.sodius.com

http://www.mopcom.fr

ACKNOWLEDGMENTS

The research program MOPCOM 3 SoC/SoPC is supported by the French National Research Agency (ANR), the "cluster of clusters" and "Media and Networks" from Brittany and Pays de la Loire regions. The program partners are the end-user companies Thales, Thomson, Sodius as an UML tool provider and the academic research institutions ENSIETA, LESTER, Supelec and INRIA.