P. Imbert Z Caron

F Cavallier

Frédéric Lauwers

Boutault

Alice Prevost

Céline Dekeister

Philippe Caron

Philippe Imbert

Zoé Cavallier

Franck Boutault

Outcomes of orbital decompression using surgical navigation in thyroid-associated ophthalmopathy

Keywords: thyroid-associated ophthalmopathy, exophthalmos, proptosis, orbital decompression, computer-assisted surgery, neuronavigation

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

Introduction

The introduction of digital technologies in medicine, and digital imaging in particular, led to the progressive development of computer-assisted surgery (CAS) in the 1980s and 1990s. Craniomaxillofacial surgery, which involves surgery to bony structures with spatially complex geometries, was readily recognized as a particularly suitable indication for CAS [START_REF] Vannier | Three dimensional computer graphics for craniofacial surgical planning and evaluation[END_REF] . The surface images obtained with CAS can facilitate the diagnosis by providing a better understanding of the actual anatomy. They can also provide support for the initial planning and surgical simulations, and they can assist with evaluation of the postoperative results [START_REF] Vannier | Three-dimensional imaging, surgical planning, and image-guided therapy[END_REF][START_REF] Hassfeld | Computer assisted oral and maxillofacial surgery-a review and an assessment of technology[END_REF] . However, a navigation system, initially described in neurosurgery [START_REF] Watanabe | Threedimensional digitizer (neuronavigator): new equipment for computed tomographyguided stereotaxic surgery[END_REF] , is instrumental in guiding the surgical procedure by linking the anatomy of the patient with the preoperative digital data.

One of the many advantages of CAS is that it allows minimally invasive approaches to be performed without compromising the three-dimensional (3D) visualization of the surgical procedure. Therefore navigation appears to be particularly suitable for orbital surgery, and particularly in the management of thyroid-associated ophthalmopathy (TAO).

The incidence of TAO is estimated to be 16 cases per 100,000 individuals per year for females and 2.9 cases per 100,000 individuals per year for males [START_REF] Bartley | The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota[END_REF] .

Approximately 80% of TAO cases are associated with Graves' disease, and 5-10% of patients who develop TAO exhibit autoimmune hypothyroidism (Hashimoto's thyroiditis). For 5% of patients, thyroid function and autoimmunity screening are normal.

The aetiopathological basis of TAO is lymphocytic infiltration of the orbital muscles and of the periorbital fat [START_REF] Weetman | Thyroid-associated eye disease: pathophysiology[END_REF] . The progression of TAO is divided into two stages: an active inflammatory stage and a quiescent stage [Au ?1]. During the inflammatory stage, which lasts 12-18 months, flare-ups alternate with spontaneous remissions.

Ultimately, fibrosis sets in, leading to progressive regression within 12-18 months, without a return to the previous condition in most cases. In the inflammatory stage, sight-threatening orbitopathy can be due to compression of optical neuropathy associated with a certain degree of corneal involvement. Emergency decompression surgery is then sometimes indicated after the failure of medical treatment with intravenous steroids. Most of the time, however, the correction of proptosis is performed in the quiescent stage of the sequelae [Au ?1]. In this stage, proptosis is one of the three main signs of TAO, with the other two being retraction of the upper eyelid and oculomotor impairments [Au ?1].

The definition of proptosis can be radiological [START_REF] Gibson | Measurement of proptosis (exophthalmos) by computerised tomography[END_REF] or metric (using a Hertel exophthalmometer) [START_REF] Delmas | Comparative study of 3 exophthalmometers and computed tomographic biometry[END_REF] . The diagnosis of proptosis is made when protrusion measured with a Hertel exophthalmometer is ≥18 mm [START_REF] Frueh | Errors of single-mirror or prism Hertel exophthalmometers and recommendations for minimizing the errors[END_REF] .

The rehabilitative treatment of the orbitopathy sequelae should be considered only once euthyroidism has been established, and after having ensured that there is no residual intra-orbital inflammatory process by clinical (Clinical Activity Score) and magnetic resonance imaging (MRI) assessments. Treatment starts with the correction of the proptosis, if this is present. The correction of possible oculomotor impairments is then scheduled, and the eyelid surgery is performed last.

Since the first description of orbital decompression by Döllinger in 1911, various techniques for orbital decompression have been reported. There are therefore multiple options for the approach and the bone resection [START_REF] Finn | Au?5] A retrospective review of orbital decompression for thyroid orbitopathy with endoscopic preservation of the inferomedial orbital bone strut[END_REF] . The minimally invasive nature of these approaches, which do not allow the entire orbit to be exposed, and the anatomical complexity of the orbit reinforce the theoretical interest in navigation.

However, few studies to date have evaluated the use of navigation devices in orbital decompression for TAO. The objective of this retrospective study was to evaluate the benefits that may be derived by the use of navigation during decompression surgery for TAO.

Patients and methods

A retrospective comparative study was performed involving a cohort of patients treated over the past 20 years in the setting of multidisciplinary consultations for TAO at the Centre Hospitalier Universitaire (CHU) of Toulouse, who underwent an orbital decompression. Pre-, peri-, and postoperative data were collected systematically for each of the patients. Two groups were created based on whether the surgery had been performed with (group N+) or without (group N-) navigation.

Inclusion criteria

To be included, the patients had to have undergone a unilateral or bilateral orbital decompression by trepanation and resection of the orbital floor and the medial wall of the orbit, with a transconjunctival approach, between 1997 and March 2017.

The surgical indication was considered during the multidisciplinary consultation for TAO. This multidisciplinary consultation involved an endocrinologist, an ophthalmological surgeon, and a maxillofacial surgeon [START_REF] Leray | Diagnosis and treatment of dysthyroid orbitopathy: a multidisciplinary disease[END_REF] . Except in the emergency setting for patients with sight-threatening orbitopathy, the surgical treatment of proptosis was performed after considering the following criteria: (1) treatment of the endocrine disease (medical or surgical) in order to restore euthyroidism. (2) Adequate treatment of the inflammatory orbitopathy, if necessary, according to the EUGOGO (European Group on Graves' Orbitopathy) guidelines [START_REF] Bartalena | The 2016 European Thyroid Association/European Group on Graves' Orbitopathy guidelines for the management of Graves' orbitopathy[END_REF] .

(3) Endocrine and ophthalmological stability at two successive multidisciplinary consultations separated by 6 months, which allowed a stable euthyroid status and the sequelae stage of the orbitopathy (Clinical Activity Score < 3) to be confirmed. The Clinical Activity Score, based on the classical signs of acute inflammation (pain, redness, swelling, and impaired function), was proposed as a clinical classification to discriminate between the active and quiescent stages of the disease. (4) Aesthetic and/or functional indications of the sequelae stage; e.g., corneal irritation, lacrimation, or disfiguring proptosis (protrusion measured with a Hertel exophthalmometer of ≥18 mm).

Exclusion criteria

The criteria for exclusion were (1) emergency orbital decompression for sightthreatening ophthalmopathy; (2) an orbital decompression surgery technique other than trepanation and resection of the inferior and medial wall; and (3) insufficient postoperative follow-up (less than 2 months).

Criteria for assessment

The criteria reported below were compiled during the pre-and postoperative consultations. The patients were systematically reassessed at 2 months postoperative and then every 6 months in a multidisciplinary consultation. The pre-and postoperative protrusion of the eyeballs was measured with a Hertel exophthalmometer (by the same observer) to determine the following: (1) the postoperative proptosis reduction, which was the primary outcome measure (i.e., the preoperative measurement minus the postoperative measurement); (2) the symmetry of the protrusion of the eyeballs (i.e., the postoperative difference between the right and the left eye); (3) the duration of the surgical intervention; (4) the presence of debilitating postoperative diplopia. The diplopia was deemed to be debilitating if it involved the central vision, if oculomotor surgery or corrective lenses were needed, or if the patient exhibited neck pain secondary to a poor corrective neck posture.

Surgical technique

The surgical technique consisted of trepanation and resection of the orbital floor and the medial wall under general anaesthesia and orotracheal intubation. After local injection of xylocaine with adrenaline, the same transconjunctival approach was used in both groups. The approach was made in the inferior fornix that extended slightly transcaruncular. The dissection continued in the preseptal retromuscular plane up to the level of the inferior rim of the orbit, for which the periosteum was incised. The periorbita was then detached from the bone, allowing all of the floor and the lower two-thirds of the medial and lateral walls to be exposed. A strip of bone of 8-10 [Au?2] parallel to the inferior rim of the orbit had to be left so as to avoid postoperative vertical dystopia. The trepanation started behind this area, preferably using a Piezosurgery device, which is accurate and does not cause soft tissue trauma. This trepanation and resection was applied to the floor of the orbit, on either side of the infraorbital pedicle, making a connection between the orbital cavity and the maxillary sinus, as well as the medial wall of the orbit, while taking the ethmoidal foramina as the upper limit and the nasolacrimal canal as the anterior limit.

Further in, the surgical procedure needs to stay well away from the optical canal. At the end of the intervention, the periorbit was opened wide to allow fat to be removed by incision after light digital pressure on the eyeball. The transconjunctival approach did not require surgical closure. There was either no resection of fat [Au?3].

Postoperatively, moist, cold dressings were placed on the patient's eyelids for the first 24 hours, during which their visual acuity was checked regularly. They usually returned home on day 1 or day 2 postoperative. They were strictly forbidden from blowing their nose for a week.

The surgical navigation device

The optical surgical navigation involved several stages. The surgical navigation system allowed the tip of an instrument (probe) to be located at any time in the operating field and to show its corresponding position in the virtual model. Perioperative use of the navigation system allowed visualization of the entire orbit with a minimally invasive approach, and specification of the outline of the osteotomy while taking into account the surgical limits and the previously described anatomical structures.

The decision to use the navigation system depended mainly on the specific conditions of the patient and the surgeon's experience.

Statistical analysis

The statistical tests were performed using GraphPad Prism version 7.0 software (GraphPad Software, La Jolla, CA, USA) and Statis 8.5.1 (freeware). The analysis of quantitative data was based on the correlation coefficient test. Qualitative data were compared using the χ 2 test. Only the results with a P-value below 5% were considered to be statistically significant.

Results

Characteristics of the population

One hundred and ninety-one patients were included. One hundred and six interventions were undertaken with navigation (N+), including 99 bilateral orbital decompressions and seven unilateral orbital decompressions. Eighty-five interventions were undertaken without navigation (N-), including 60 bilateral orbital decompressions and 25 unilateral orbital decompressions (Table 1). There were no statistically significant differences between the two groups in terms of the characteristics studied. The two populations were therefore comparable.

[Table 1 here] Analysis of the preoperative protrusion of the right and left eyes did not indicate that there was a significant difference (Table 2). The results could therefore be merged, leading to a total number of 350 orbits, of which 205 were in the N+ group and 145 in the N-group.

[Table 2 here] The surgical navigation system has been used at CHU Toulouse since 1999 (Fig. 1). The majority of orbital decompressions performed before 2012 were done by a single surgeon. Only seven patients were operated on between 1997 and 1999. The resurgence of the use of navigation in 2013 was associated with the training of new surgeons in the surgical technique.

[Figure 1 here] Simultaneous analysis of the orbits (Fig. 2A), without distinction between the right/left eyes, showed that the use of the surgical navigation system resulted in a greater proptosis reduction of the eyeballs (mean 3.7 mm vs 3.3 mm); however, this was not statistically significant (P = 0.0501). The analysis of the right and left orbits separately (Fig. 2B) showed a mean postoperative proptosis reduction of 3.8 ± 0.2 mm for the right eye in the N+ group versus 3.2 ± 0.2 mm in the N-group; this difference was statistically significant (P = 0.03). There was, therefore, a more pronounced postoperative reduction for the right eye when the intervention was performed using navigation. A more pronounced postoperative proptosis reduction in the N+ group for the left eye was also found, although this difference was not statistically significant (3.6 ± 0.2 mm vs 3.4 ± 0.2 mm, P = 0.54).

[Figure 2 here] The symmetry of the ocular protrusion was analysed in 106 patients in the N+ group and 85 patients in the N-group. The difference in preoperative protrusion between the two eyes was a mean 1.1 mm in the N+ group and 1.9 mm in the Ngroup. The surgical procedure resulted in an improvement in the symmetry of the protrusion of the eyeballs: the postoperative asymmetry of the protrusion was determined to be 1.0 mm in the N+ group versus 1.3 mm in the N-group. This difference was only significant in the N-group (N-group, P = 0.0073 vs N+ group P = 0.38) (Fig. 3 [Au?4]).

[Figure 3 here]

Operating time

The average operating time for the unilateral orbital decompressions (Fig. 4) was 107 minutes in the N+ group (n = 7 patients) versus 60 minutes in the N-group (n = 25 patients); this difference was statistically significant (P = 0.0017). The average operating time for the bilateral orbital decompressions was 120 minutes in the N+ group (n = 99 patients) versus 87 minutes in the N-group (n = 60 patients); this difference was also statistically significant (P < 0.0001). On average, setting up the surgical navigation device increased the length of the intervention by 40 minutes.

[Figure 4 here] Fig. 5 shows the operative times for bilateral orbital decompression performed by one of the surgeons. The downward slant of the curve reflects the surgeon learning the surgical technique, as well as the set-up of the navigation system. Thus, once a substantial number of surgeries had been performed (n = 50), there was a significant reduction in the operating time by 37 minutes on average (P < 0.0001).

[Figure 5 here]

Navigation and postoperative diplopia

There did not appear to be an association between the postoperative and new onset of diplopia and use of surgical navigation (Table 3). Indeed, 50% of the 84 patients who exhibited a preoperative diplopia also exhibited a postoperative diplopia, without a significant difference between the N+ and N-groups (P = 0.5). Conversely, out of the 107 patients who did not present preoperative diplopia, 9.3% exhibited postoperative diplopia secondary to the intervention, without a difference between the N+ and Ngroups (P = 0.9).

[Table 3 here]

Discussion

This series is novel in evaluating the benefits of surgical navigation in a quantitative manner with a large number of patients. The results are comparable to those in the literature in terms of the postoperative proptosis reduction and diplopia.

It was found that the use of a surgical navigation system was associated with a more pronounced postoperative proptosis reduction of the right eyeball, by 0.6 mm.

We believe that this statistically significant difference may be of clinical relevance.

No statistically significant difference was seen for the left eye. This discordance can probably be explained by the insufficient statistical power of the study. Indeed, when all of the orbits were compared, without distinction right/left, use of the surgical navigation system resulted in a greater proptosis reduction of the eyeballs (mean 3.7 mm vs 3.3 mm), although this was not statistically significant (P = 0.0501). This discordance can also be explained by the fact that nearly all of the surgeons involved are right-handed and started from the right side. The size of the tripod for tracking placed on the left may get in the way of a right-handed individual when they are operating on the left orbit.

In terms of the symmetry of the protrusion of the eyeballs, it would appear that the preoperative difference between the two eyes was greater in the N-group than in the N+ group (1.9 mm vs 1.1 mm, respectively). Most of the unilateral exophthalmia patients underwent surgery without navigation, which may explain why the preoperative asymmetry was more important in the N-group and why the preoperative/postoperative difference was significant in the N-group.

The set-up of the system for navigation was responsible for an increase in the operating time of 40 minutes on average. The use of the surgical navigation system had no effect on the postoperative diplopia. This increase in the duration of the intervention linked to the set-up of the equipment became less as the surgeon became more proficient with use of the device. Indeed, the learning curve reflected a significant reduction (P < 0.0001) in the operative time of 37 minutes on average as more surgeries were performed. The 40 minutes linked with the set-up of the system was hence offset when the surgeon had become proficient with its use.

A number of methodological biases need to be considered. Although the Hertel exophthalmometer is used in daily clinical practice to define and measure proptosis, this method suffers from significant inter-observer variability [START_REF] Lam | Intra-observer and inter-observer variation of Hertel exophthalmometry[END_REF][START_REF] Afanasyeva | Computed exophthalmometry is an accurate and reproducible method for the measuring of eyeballs' protrusion[END_REF] .

Nevertheless, its use remains reliable and reproducible when used by a single operator (low intra-observer variability), as was the case in the present study. Radiological measurements of proptosis are generally considered to be less prone to bias compared with Hertel exophthalmometry, but they entail exposure to radiation and a higher cost [START_REF] Afanasyeva | Computed exophthalmometry is an accurate and reproducible method for the measuring of eyeballs' protrusion[END_REF] .

The decision of whether to use the navigation system depended mainly on the specific conditions of the patient and the surgeon's experience. Differences in the distribution of bilateral/unilateral decompression between the two groups can be explained by this lack of randomization. Indeed, navigation was mainly used for bilateral decompression and by young surgeons. The trained surgeons tended to use navigation less and less over time. This bias may explain the fact that the postoperative symmetry of the protrusion was better in the N-group. It should also be kept in mind that the decompressions were conducted by several surgeons, which may have affected the postoperative results.

The choice of surgical technique in the management of TAO is not consensusbased and acceptance of our management may, therefore, not be unanimous. A multicentre European study performed by EUGOGO studied the proptosis reduction, diplopia, and postoperative complications according to the surgical technique in 139 patients (248 orbits) [START_REF] Mourits | Au?5] Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures[END_REF] . Resection of three walls appeared to result in a reduction in the protrusion of between 5.6 mm and 6.5 mm, depending on whether or not the intraorbital fat was removed, versus a reduction of between 3.2 mm to 4.8 mm for resection of two walls. Resection of three walls was responsible for an increase in postoperative complications. Orbital decompressive surgery was responsible for 13% of the postoperative diplopia (9.3% in the present study). Mainville et al. [START_REF] Mainville | Effect of orbital decompression on diplopia in thyroid-related orbitopathy[END_REF] found a de novo onset of diplopia in 29.7% of patients secondary to the intervention. It would appear that perioperative opening of the periorbit was responsible for an increase in the postoperative diplopia (P < 0.01), although it allowed for a more pronounced proptosis reduction of the eyeballs (3.12 mm vs 2.9 mm).

As shown by these studies, there is no consensus regarding the approach to the bone and/or fat resection. The benefit of fat resection, initially described by Olivari, is open to debate [START_REF] Olivari | Thyroid-associated orbitopathy: transpalpebral decompression by removal of intraorbital fat. Experience with 1362 orbits in 697 patients over 13 years[END_REF][START_REF] Cheng | Long-term outcomes of orbital fat decompression in Graves' orbitopathy[END_REF] . It may be a predictive factor of stability of the long-term postoperative outcomes, as suggested by Cheng et al. [START_REF] Cheng | Long-term outcomes of orbital fat decompression in Graves' orbitopathy[END_REF] . In their study involving 845 patients (1604 orbits), only a fat decompression was performed. The surgical procedure was preceded by oral corticosteroid therapy over 3-6 months. However, the study was a non-comparative study and thus it could not be concluded that surgical outcomes are more stable after lipectomy relative to a bone resection. It would seem logical that the postoperative reduction in protrusion would be more pronounced in accordance with the quantity of resected tissue (bone or fat), as has been shown in numerous studies [START_REF] Mourits | Au?5] Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures[END_REF][START_REF] Cansız | Three-wall orbital decompression superiority to 2-wall orbital decompression in thyroid-associated ophthalmopathy[END_REF] .

Therefore the surgical technique should be adjusted according to the preoperative clinical examination and the patient's wishes, as the degree of scarring is not insignificant with some of the approaches that are used.

Since this study was performed, changes have been made to our management of proptosis: we propose reserving resection of the lateral wall for proptosis of >25 mm. Valgus osteotomy of the zygomatic bone is only performed in the case of a protrusion of >30 mm.

Numerous studies have referred to the indications for surgical navigation in maxillofacial surgery, but without providing a quantitative analysis of the contribution of the device [START_REF] Hassfeld | Computer assisted oral and maxillofacial surgery-a review and an assessment of technology[END_REF][START_REF] Heiland | Indications and limitations of intraoperative navigation in maxillofacial surgery[END_REF][START_REF] Andrews | Au?5] A multicenter experience with image-guided surgical navigation[END_REF][START_REF] Steinbacher | Three-dimensional analysis and surgical planning in craniomaxillofacial surgery[END_REF][START_REF] Austin | Current applications of 3-d intraoperative navigation in craniomaxillofacial surgery: a retrospective clinical review[END_REF] . Navigation is used widely in primary and secondary reconstruction of the orbit [START_REF] Cai | Au?5] Computer-assisted navigational surgery improves outcomes in orbital reconstructive surgery[END_REF] . However, few publications regarding the benefits of surgical navigation in orbital decompressions could be found.

Mahoney et al. [START_REF] Mahoney | Computer-assisted threedimensional planning for orbital decompression[END_REF] reported two cases of orbital decompressions for dysthyroid diplopia by resection of three walls. Navigation was used as a straightforward tool for perioperative tracking, without quantitative or qualitative information regarding the outcome of the bone resection. Tavassol et al. [START_REF] Tavassol | A quantitative approach to orbital decompression in Graves' disease using computer-assisted surgery: a compilation of different techniques and introduction of the "temporal cage[END_REF] presented the results of a series of 12 patients treated by navigated bone resection of three walls with installation of a customized 'temporal cage' to improve the proptosis reduction of the eyeballs (4.3 mm on average) by preventing the temporal muscle from filling the bone cavity. Wu and Kahana 27 offer a navigation system with a 'facemask'. This is a self-adhesive mask containing numerous LEDs that allows the placement of a tracking device at the level of the scalp of the patient to be avoided. This technique is also associated with a substantial increase in the operative time and in the cost of the intervention (US$ 500 per patient), without providing a real benefit for the patient. Luboz et al. [START_REF] Luboz | Computer assisted planning and orbital surgery: patient-related prediction of osteotomy size in proptosis reduction[END_REF][START_REF] Luboz | Intra-operative quantification of the surgical gesture in orbital surgery: application to the proptosis reduction[END_REF] have devised a biomechanical formula associated with an intraorbital pressure sensor in an attempt to determine the reduction in protrusion perioperatively.

The use of navigation allows 3D visualization of the surgical procedure and also allows a minimally invasive approach to be used, such as a transconjunctival approach. It also allows the identification of the anatomical structures to be taken into account and therefore has clear relevance in regard to educational purposes and teaching. The educational interest of navigation has been studied by some authors, in particular in orthopaedic surgery, for example by Seyler et al. [START_REF] Seyler | Does computerassisted surgery improve accuracy and decrease the learning curve in hip resurfacing? A radiographic analysis[END_REF] . In their study, CAS resulted in improved accuracy and precision in positioning the femoral component (for hip resurfacing). In addition, CAS led to a reduction in the length of the learning curve for beginners in hip resurfacing and improved the surgeon's ability to perform this procedure safely.

In conclusion, the use of a surgical navigation system in the treatment of thyroid-associated ophthalmopathy resulted in a slightly more pronounced proptosis reduction of the eyeballs and it may be of use for training junior surgeons.

Figure captions

  A preoperative computed tomography (CT) scan of the facial bones, without contrast agent, was performed in millimetre-sized slices. The DICOM data (Digital Imaging and Communications in Medicine) were then transferred into iPlan Net CMF Brainlab Image Guidance System virtual planning software (iPlan Net; Brainlab AG, Munich, Germany). Use of the software allowed 3D preoperative visualization of the surgical procedure, localization of the anatomical structures to be considered, and planning of the potential outlines of the osteotomy. During the intervention, and prior to the orbital procedure, the tripod for tracking was temporarily set percutaneously to the cranial vault, at the frontotemporal junction. Registration of the radiological imaging data with the patient was then conducted [Au?1]. From 1999 to 2000, this was done by surface matching using an active light reflecting diode [Au?1]. Since 2010, the registration method has been based on laser surface scanning [Au?1]. The consistency of the calibration was then verified by the identification of several specific anatomical positions.

Fig. 1 .Fig. 2 .Fig. 3 .Fig. 4 .Fig. 5 .

 12345 Fig. 1. Number of surgical navigation procedures in patients operated on for thyroidassociated ophthalmopathy between 1999 [Au?6] and 2017. (N+, with surgical navigation; N-, without surgical navigation.)

Figure 1 Figure 2

 12 Figure 1

Figure

  Figure 5

5 Table 1 .

 51 Characteristics of the population.

		Surgical		P-value
		N+ (n = 106)	N-(n = 85)
	Male/female (number)	19/87	19/66
	Sex ratio	0.22	0.29	0.5
	Age (years), mean ± SD	46.3 ± 12.1	47.7 ± 13.6	0.48
	Proptosis (mm), mean ±	23.1 ± 2.7	± 2.9	0.06
	Follow-up (months), mean ± SD	16.9 ± 25.4	15 ± 20 [Au?7]	0.58

SD, standard deviation; N+, with navigation; N-, without navigation.

Table 2 .

 2 Preoperative protrusion of the right/left eye.

		eye (mm)	Left eye (mm)	P-value
		Mean ± SD	Mean ± SD
	N+ group (n = 205)	23.3 ± 2.7	23.1 ± 2.6	0.15
	N-group (n = 145)	± 3.0	22.7 ± 2.8	0.34
	SD, standard deviation; N+, with navigation; N-, without navigation.

Table 3 .

 3 Impact of navigation on postoperative diplopia. [Au?8]

		Postoperative diplopia	Postoperative diplopia
			absent
	With preoperative
	diplopia (n = 84)
	N-	18 (45%)	22 (55%)	40
	N+	24 (55%)	20 (45%)	44
	Total	42	42	84
		χ 2 = 0.763, P = 0.5
	Without preoperative
	diplopia (n = 107)
	N-	4 (9%)	41 (91%)	45
	N+	6 (10%)	56 (90%)	62
	Total	10	97	107
		χ 2 = 0.039, P = 0.9
	N+, with navigation; N-, without navigation.

Funding

Nothing to declare.

Competing interests

Nothing to declare.

Ethical approval

This study met all necessary French ethical and regulatory requirements [Au?1].

Patient consent

Patient consent was not required.


Rahim Kallal

Abir Haddaji

Zied Ftiti
email: zied.ftiti@edcparis.edu

ICT diffusion and economic growth: Evidence from the sectorial analysis of a periphery country

Keywords: ICT, economic growth, sectorial, panel autoregressive distributed lag (ARDL), Tunisia. JEL Classification: C23, O33, P18, Q55, Q57, Saudi Arabia, Somalia, Sudan

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

1 much higher than the average of the Arab countries 1 except for the indicator "Active mobilebroadband subscriptions." Moreover, ICT is a priority sector in the case of Tunisia for two reasons. First, ICT is considered as a development vector for other economic sectors. Indeed, the ICT sector is a dynamic sector of innovation directed toward export, foreign investment, partnership, and subcontracting, especially African countries. According to a report related to Tunisia by the Trade Commissioner Service of Canada, 2 the sector contributed 7.5% of GDP and employed around 86,000 people in 2018. It is made up of 2,120 private companies, 219 shared service centers, and 8 development centers serving multinationals. Therefore, it is promising to investigate the case of Tunisian ICT diffusion, which provides implications for Tunisian policymakers as well as those of neighboring countries. Regarding the developing countries, previous studies [START_REF] Dewan | Information technology and productivity: evidence from countrylevel data[END_REF][START_REF] Papaioannou | Information technology as a factor of economic development: evidence from developed and developing countries[END_REF][START_REF] Stanley | Does ICT generate economic growth? A metaregression analysis[END_REF][START_REF] Niebel | The contribution of intangible assets to sectoral productivity growth in the EU[END_REF][START_REF] Niebel | ICT and economic growth-comparing developing, emerging and developed countries[END_REF][START_REF] Cheng | ICT diffusion, financial development, and economic growth: an international cross-country analysis[END_REF] are rather mixed about ICT effects on economic growth. Moreover, studies focusing on developing countries are still scarce. This lack of consistency in findings may be explained by two factors. First, the relationship between ICT and economic growth is based on aggregated data. However, for developing economies, disaggregated data are unable to represent either realistic ICT integration in the economy or the heterogeneity of ICT development across different economic sectors. Second, most developing economies suffer from poor ICT infrastructure, which leads to substantial investment in ICT projects, which might affect profitability, at least in the short run. Therefore, we suggest distinguishing short-term from long-term effects. Finally, the relationship between ICT and economic growth depends on the capacity of countries to absorb technology through their potential to develop a highly skilled workforce. As a result, it is of interest to fill this literature gap by investigating the case of a developing country based on sectorial analysis.

This study extends previous studies on developing countries with the potential to develop a highly skilled workforce. Contrary to previous studies, our study assesses the impact of ICT diffusion on economic growth from a sectorial perspective and distinguishes between short-and long-term impacts. We propose an ICT diffusion index that measures the share of ICT in the input of economic sectors by using the Input-Output Table (IOT) of the Tunisian economy. The development of an ICT index aims to overcome the inability of the disaggregated data to reproduce realistic ICT integration in the economy. Such data is also particularly unable to reproduce the heterogeneity of ICT development across different economic sectors. The choice of Tunisia is not arbitrary but is based on several reasons. First, Tunisia has recently experienced important economic, social, and political transformations.

Second, it has significant potential to develop a highly skilled workforce in the Middle East and North Africa (MENA) region, as highlighted above in Table 1. 3Based on data collected from the National Institute of Statistics of Tunisia over the period from 1997 to 2015, our study has two main findings. First, we show that ICT has a positive long-term effect on Tunisian economic growth and contributes to sustainable development. Second, this effect is negative in the short run due to substantial ICT investment, as Tunisian ICT infrastructure is not well developed. These findings have important policy implications for both investors and policymakers. Indeed, our sectorial index helps investors identify the sectors with the highest potential growth after ICT improvement.

More importantly, our analysis can serve as a framework for policymakers to boost ICT across different sectors.

Our study contributes to the literature as follows. We propose a novel sectorial approach. Specifically, our sectorial ICT diffusion index reflects the factual ICT level in the economy. Furthermore, it provides information segregated by sector, product, activity, and year. Hence, it is possible to compare the various sectors of the economy. Moreover, this technique helps follow ICT evolution over time, creating a dashboard for policymakers. Then we control for the substantial investment bias by analyzing the relationship between ICT diffusion and economic growth by distinguishing between short-and long-term effects.

The remainder of the paper is organized as follows. Section 2 reviews the literature on the effect of ICT diffusion on economic growth. Section 3 presents the methodology used to construct the ICT diffusion index, and Section 4 details the econometric modeling. Section 5 discusses the results and Section 6 gives our conclusions and recommendations for further research.

Literature review

The relationship between ICT and economic growth has been widely discussed since the 1980s, based on the theories that consider technological progress as fundamentally stimulating economic growth [START_REF] Romer | Increasing returns and long-run growth[END_REF][START_REF] Romer | Endogenous technological change[END_REF][START_REF] Lucas | On the mechanics of economic development[END_REF][START_REF] Grossman | Innovation and growth in the global economy[END_REF][START_REF] Aghion | A model of growth through creative destruction[END_REF]. The first stream of empirical studies focused on ICT's impact on economic growth, especially for developed economies. This strand of literature expanded in the 1990s as researchers sought to understand the productivity boom observed in 1990 by determining whether ICT might be the driver of the boom in the United States. For instance, [START_REF] Oliner | The resurgence of growth in the late 1990s: is information technology the story?[END_REF] focus on the US economy between 1995 and 1999,

showing that ICT represented 1.5 percentage points of the 2.6% annual growth rate in the labor productivity of the US business sector between 1996 and 1999. [START_REF] Röller | Telecommunications infrastructure and economic development: a simultaneous approach[END_REF] investigated how telecommunications infrastructure affects economic growth. Based on a sample of 21 OECD countries during the 1971-1990 period, they estimate a microeconomic model for telecommunication investment with a macroeconomic production function. They conclude that around one-third of total output could be attributed to ICT, and the authors particularly highlighted that the extent of telecommunications infrastructure is associated with economic growth. Further, [START_REF] Oulton | ICT and productivity growth in the United Kingdom[END_REF] developed new estimates of investment in and output of ICT based on a growth-accounting approach, aiming to measure the contribution of ICT to the growth of both aggregate output and aggregate input. The author showed that ICT's contribution to GDP growth in the United Kingdom increased from 13.5% in 1979-1989to 20.7% in 1989[START_REF] Pesaran | An autoregressive distributed lag modelling approach to cointegration analysis[END_REF]. ICT contributed 55% of capital deepening during 1989[START_REF] Pesaran | An autoregressive distributed lag modelling approach to cointegration analysis[END_REF]and 90% from 1994[START_REF] Pesaran | An autoregressive distributed lag modelling approach to cointegration analysis[END_REF]. Stiroh (2002a) examined the link between information technology (IT) and the US productivity revival in the late 1990s. Industry-level data showed a broad productivity resurgence that reflects both the production and the use of IT. We suggest a strong correlation between IT capital accumulation and labor productivity, and calculate the acceleration for IT-intensive industries is approximately 2% more than other industries. [START_REF] Stiroh | Information technology and the US productivity revival: what do the industry data say?[END_REF] shows that diffused ICT has intensively enhanced productivity growth during [START_REF] Basu | Are apparent productive spillovers a figment of specification error?[END_REF]-2000compared to 1987[START_REF] Basu | Are apparent productive spillovers a figment of specification error?[END_REF]for US industries. Stiroh (2002b) R&D has a stronger effect on economic growth than public R&D.

The second stream of literature has investigated ICT diffusion and its impact on economic growth based on international comparisons, mainly between developing and developed economies. [START_REF] Dewan | Information technology and productivity: evidence from countrylevel data[END_REF] estimated an intercountry production function relating IT and non-IT inputs to GDP output. They based their function on panel data from 36 countries (22 developed countries and 14 developing countries) over the 1985-1993 period. They found significant differences between developed and developing countries concerning their structure of returns from capital investment. They stipulated that ICT has an insignificant effect on developing countries and a significant one in developed countries. This finding can be explained by the presence of human capital and technological infrastructure, allowing the former countries to benefit from ICT opportunities. Similarly, [START_REF] Papaioannou | Information technology as a factor of economic development: evidence from developed and developing countries[END_REF] used [START_REF] Arellano | Some tests of specification for panel data: Monte Carlo evidence and an application to employment equations[END_REF] Although studies dealing with developed economies generally agree on the positive effect of ICT diffusion, the second literature stream that provides comparisons between developed and developing economies does not exhibit general agreement. We suggest that a panel approach between different countries might be a source of bias resulting from a high level of heterogeneity, particularly for structural reasons. Hence, a third stream of literature has investigated the issue of ICT diffusion only in developing economies. [START_REF] Sassi | Financial development, ICT diffusion, and economic growth: lessons from MENA region[END_REF] distributed lag (ARDL) approach, an insignificant impact of ICT on CO2 emissions as a measure of pollution, and no impact of ICT on sustainable development. [START_REF] Asongu | Inequality, information technology and inclusive education in sub-Saharan Africa[END_REF] examined linkages between inequality, ICT, and inclusive education for 42 sub-Saharan Africa countries during the period ranged between 2004-2014. The authors affirmed that ICT promotes inclusive education, but only after reaching a certain threshold.

The impact of ICT on economic growth is still ambiguous for developing countries

(Table A in appendix).
Our study is related to this third strand of literature, and we contribute to it through performing a new sectorial analysis for a selected MENA country. The sectorial analysis will be useful for policymakers to overcome the gaps in ICT diffusion across all economic sectors. Our proposed sectorial analysis aims to overcome the limits of disaggregated data in the case of developing economies. Disaggregated data is unable to depict realistic ICT integration and to reproduce the heterogeneity of ICT development across different economic sectors. Second, as highlighted in the introduction we will deal with the promising case study of Tunisia in terms of ICT diffusion. Indeed, we suggest that studies dealing with both developed and developing economies (Table A in the Appendix) might be a source of bias resulting from a high level of heterogeneity, particularly structural ones. Hence, dealing with a case study of a developing economy investigated across sectors will contribute substantially to the literature. Our sectorial analysis will be useful for policymakers, as it might serve as a dashboard to implement appropriate policies that improve ICT diffusion across different sectors, and thus impact economic growth.

Methodology and data

Methodology

We develop a sectorial ICT diffusion index to measure the percentage of ICT diffusion in each sector, which will then be used to assess the ICT contribution to added value across Tunisian economic sectors.

Sectorial ICT diffusion index construction

The construction of the ICT diffusion index is developed based on the following steps.

We first segregated Tunisian economic output into 18 sectors. We have used the Tunisian IOT (see Table 2) for the contribution of each sector to the input for other sectors. This describes a complete picture of the flows of goods and services in an economy for a given year (Leontief, 1986). This approach allows for detailing the relationship between producers and consumers as well as the interdependencies between sectors. For the Tunisian economy, the construction of the ICT diffusion index is motivated by several reasons. It provides the country's economic decision-makers a relevant indicator to adapt their policies and strategies to promote ICT and, consequently, boost economic growth. Moreover, it will be useful for ICT investors to learn more about a sector that might be a source of interesting growth. In other words, this index might be a driver for economic growth in the case of Tunisia. Data are from the Tunisian IOT, it is the share of ICT in the total input, expressed as a percentage. 4 We made some adjustments to get a table consistent with OECD nomenclature, which allows us to make a proper estimate during analysis. 5 The ICT sector has been defined as the following group of ISIC Rev. 3 industries: Manufacturing: 3000 -Office, accounting and computing machinery; 3130 -Insulated wire and cable; 3210 -Electronic valves and tubes and other electronic components; 3220 -Television and radio transmitters and apparatus for line telephony and line telegraphy; 3230 -Television and radio receivers, sound or video recording or reproducing apparatus and associated goods; 3312 -Instruments and appliances for measuring, checking, testing, navigating and other purposes, except industrial process equipment; 3313 -Industrial process equipment.

Services: 5150 -Wholesaling of machinery, equipment and supplies (if possible, only the wholesaling of ICT goods should be included); 7123 -Renting of office machinery and equipment (including computers); 6420 -Telecommunications; 72 -Computer and related activities.

Does ICT contribute to economic growth?

After determining ICT diffusion, we investigate whether ICT capital contributes to added value across other Tunisian economic sectors. The method used to measure the direct effects of ICT diffusion is based on the neoclassical production function model [START_REF] Griliches | Issues in assessing the contribution of research and development to productivity growth[END_REF], Stiroh, 2002a). The production function framework relates output to labor, capital, ICT diffusion, and TFP. In this study, the added value is considered as an output of the production function where these factors are independent variables. There are both advantages and disadvantages in using added value instead of gross output [START_REF] Jorgenson | Productivity-information technology and the American growth resurgence[END_REF]. One advantage is the use of the added value as a nominal added value sum rather than the GDP.

The disadvantage is related to the fact that added value requires stricter assumptions of perfect competition [START_REF] Basu | Are apparent productive spillovers a figment of specification error?[END_REF].

The production function framework involves total factor productivity TFP , output to labor L , ICT diffusion (ICTD), and stocks of capital (K). Assuming an augmented Cobb-Douglas production function, we express the following equation:

VA = TFP ICTD K L ,
where VA is the real value-added at time t for sector i, TFP is the Hicks natural total factor productivity, ICTD is an ICT diffusion index, K is stocks of capital, L is labor input, and ε is the disturbance term for the sector at time .

Growth accounting assesses the contribution of GDP inputs, assuming constant returns to scale and that each factor receives compensation equal to its marginal product [START_REF] Jorgenson | A retrospective look at the U.S. productivity growth resurgence[END_REF][START_REF] Inklaar | ICT and Europe's productivity performance: industrylevel growth account comparisons with the United States[END_REF]. We log-linearize the model presented in (Eq. 1):

! = " # + " % &'( ! + " ) *+&, ! + " -. ! + " / 0 ! + 1 ! ,
where the logarithmic functions of the studied variables are considered.

Eq. 2 models the relationship between economic growth, proxied through the added value for all economic sectors, and ICT diffusion.

Method of estimation

As ICT implementation required an important investment, which impacted the profitability of all projects in the short term, it is useful to investigate the relationship between ICT diffusion and added value by distinguishing between the short and long terms. This allows us to control for investment bias. To do so, we employ the pooled mean group (PMG)

form of the ARDL proposed by [START_REF] Pesaran | An autoregressive distributed lag modelling approach to cointegration analysis[END_REF] and [START_REF] Pesaran | Bounds testing approaches to the analysis of level relationships[END_REF] to estimate Eq. 2.

This PMG framework of the panel ARDL model helps to resolve some of the inappropriateness of statistical features in the traditional panel model, such as a small sample.

As a result, it is more appropriate to use a panel PMG estimation, since data availability is limited. A panel PMG estimation uses both time and cross-sectional dimensions, thus increasing the total number of observations and their variation. Additionally, it decreases the noise from individual time-series estimations.

According to [START_REF] Pesaran | Dynamic linear models for heterogeneous panels[END_REF][START_REF] Pesaran | Bounds testing approaches to the analysis of level relationships[END_REF], the symmetric version of the panel ARDL is expressed as follows: + ε ?@ , 3

ΔVA ! = 3 + " % !4% + " )
where the level terms reflect long-run dynamics, while the first-difference terms reflect shortrun effects. The error term is signified by εit and Δ signifies the first-difference operator. For each cross-section, the long-run slope (elasticity) coefficients on TFP, ICTD, K, and L are respectively computed as

4B CD B ED
for l=2, 3, 4, 5. The choice of the lagged variable F, G is determined according to the Akaike information criterion or Schwarz-Bayesian information criterion. Using the Wald test, the presence of cointegration relationship is tested by the following hypothesis:6

H # : " % = " ) = " -= " / = " 5 = 0 absence of a long -run relationship , H % : " % ≠ " ) ≠ " -≠ " / ≠ " 5 ≠ 0 presence of a long -run relationship .

Furthermore, Eq. 3 can be specified as an error correction model, yielding the following: where ^b 9 are the short-run coefficients for l=1, 2, 3, 5. The value of _ is supposed to be negative, significant, and between 0 and 1 in absolute value, and is the error-correcting speed of the adjustment term of the model in equilibrium.

ΔVA ! = ^ +

Data and preliminary analysis

All the data presented above, except for the ICT diffusion index, are collected from the Tunisian National Institute of Statistics for the period 1997-2015. For the ICT diffusion index, we have developed a sectorial measure based on the methodology presented below.

Table 2 presents the diffusion of ICT in Tunisian economic sectors over the period 1997-2015. We argue that the share of ICT in total input is relatively different across sectors, depending on its use. We note that the integration of ICT was steady during 1997-2015 for most sectors, whereas it increased progressively for public administration. This finding confirms the tendency for electronic government in Tunisia. The ICT level is very low in Tunisia (below 2% for most sectors), but it is relatively high in the sectors Post and telecommunication and Financial services (above 30%). Therefore, we conclude that despite awareness of the importance of ICT diffusion, ICT in Tunisia is insignificant due to the lack of financial, technical, and human resources. that not all variables are normally distributed, which is confirmed by the Jarque-Bera statistic.

When we examine the relationships between all variables based on the correlation matrix, the results show no excessive correlation between variables, thus excluding multicollinearity.

Particularly, the results show a potential connection between VA and ICTD.

Results and discussion

The macro and micro-level empirical studies on the relationship between ICT and economic growth have generated recommendations on how the development of ICT might affect economic growth. In this section, we empirically examine to what extent the development of telecommunications has contributed to the growth of sectors of the Tunisian economy in the short and long run.

Table 5 reports the results for the long-term elasticity of ICT diffusion in terms of economic growth, total factor productivity (TFP), labor (L), and stocks of capital (K). The coefficient on the error correction term is significant and negative (-0.5228). This implies that the model converges to equilibrium over the long term.

The impact of ICT diffusion on economic growth is significantly positive (2.93%) in the long term (Table 5, Panel A), whereas it is significantly negative (-2.37%) in the short term (Table 5, Panel B). This trend is explained by the significant fixed cost of the initial ICT investment and the large-scale economic growth in the long term. In other words, the more important ICT capital investment is, the lower its cost is. Therefore, the contribution of ICT diffusion to economic growth is not instant. One reason could be that the effects from investing in ICT diffusion materialize with a lag. This phenomenon is called the time lag effect. The negative short-run impact of ICT on economic growth is explained by the fact that, in Tunisia, the infrastructure is not developed enough to quickly benefit from ICT opportunities. Further, the positive long-run effect is explained by the fact that ICT enhances the activity of the various economic sectors through various channels. A high level of ICT diffusion allows for the integration of ICT capital stock in the economy through the use of computer hardware, software, and communication equipment. Therefore, sectors will use various types of ICT, such as computer technology, Internet access, mobile Internet, landlines, cell phones, processing power, artificial intelligence, 3D printing, big data, the Internet of Things, or cloud technologies. For example, in the financial sector, ICT integration will lead to technologies with better telecommunications infrastructure. Consequently, ICT diffusion leads to transforming the structure of sectors, which are subsequently characterized by economic performance, productivity improvement, cost reduction, and labor efficiency.

However, economic growth due to ICT is based on knowledge. Specifically, human capital is a necessary factor for effective ICT diffusion. For this reason, the government should allocate more resources to improve human capital, especially through the school completion rate. Moreover, a favorable environment and incentives for the diffusion of ICT should be created by changing regulations and the economic sectorial composition, reinforcing sectorial know-how, and improving the telecommunication infrastructure.

Similarly, this trend also holds for stocks of capital, with a rate of return of 8.29% in the long term. This validates the role of capital stock as a pillar for economic growth in the long term.

However, the negative and significant coefficient of the stocks of capital in the short run (-6.98%) possibly indicates that the benefit of this variable to improve economic growth is not instantaneous; rather, it takes time before stocks of capital can contribute positively to the economic growth of the Tunisian economy.

These findings are in line with previous empirical studies, such as [START_REF] Erumban | Information and communication technology and economic growth in India[END_REF], [START_REF] Ishida | The effect of ICT development on economic growth and energy consumption in Japan[END_REF], [START_REF] Pradhan | Economic growth and the development of telecommunications infrastructure in the G-20 countries: a panel-VAR approach[END_REF] [START_REF] Shahiduzzaman | The long-run impact of information and communication technology on economic output: the case of Australia[END_REF], [START_REF] Vu | ICT as a source of economic growth in the information age: empirical evidence from the 1996-2005 period[END_REF], [START_REF] Latif | The dynamics of ICT, foreign direct investment, globalization, and economic growth: panel estimation robust to heterogeneity and cross-sectional dependence[END_REF][START_REF] Cheng | ICT diffusion, financial development, and economic growth: an international cross-country analysis[END_REF]. Furthermore, the effect of stocks of capital on economic growth is more important than ICT's effect. This is explained by the fact that the non-ICT capital share (traditional capital) remains the most important, with an average share above 90%. To benefit from economies of scale, Tunisia should invest in ICT capital and integrate it into the various sectors to ensure its contribution to economic growth.

Another result confirmed by this study is that labor contributes positively and significantly to economic growth. This positive effect is observed in short and long terms, as in the long term the sensitivity of economic growth to labor is around 29% and for the short run is around 27%. The finding supports the notion that labor productivity is promoted by ICT diffusion in the short and long runs.

This can be explained by ICT's positive effects on labor quality and learning by doing.

Therefore, according to the empirical results, ICT capital has a positive impact on labor, which is explained by the fact that it updates the skills of personnel and develops human capital. Moreover, as labor productivity is enhanced by knowledge growth, workers can learn and update their skills through the use of ICT.

However, the positive interaction between ICT and labor depends on several conditions, such as the level of computerization of society and the general level of ICT knowledge. This relationship depends on training efforts and changes in work tasks, as well as on teaching and learning techniques. Hence, we consider the presence of the knockoff labor factor on productivity. In addition, the adoption of ICT makes businesses more competitive and adaptable in the context of the digital economy.

However, the positive interaction between ICT and labor depends on several conditions, such as the level of informatization of society and that of ICT knowledge. This relationship depends on the training efforts and the changes in work tasks, as well as education, training, skill acquisition, among others. Therefore, a labor spillover generates productivity improvements due to training. Moreover, ICT adoption makes enterprises more competitive and adaptable in the context of the digital economy.

We observe that TFP contributes positively and significantly to economic growth in both the short and long term, at 6.10 % and 8.6%, respectively (Table 5). This result is confirmed by previous theoretical and empirical literature, which considered that TFP is key to economic growth, such as [START_REF] Cronin | Telecommunications infrastructure and economic growth: an analysis of causality[END_REF], [START_REF] Dutta | Telecommunications and economic activity: an analysis of Granger causality[END_REF], [START_REF] Beil | On the relationship between telecommunications investment and economic growth in the United States[END_REF], Mehmood and Siddiqui (2013), [START_REF] Kumar | The effects of ICT on output per worker: a study of the Chinese economy[END_REF][START_REF] Pradhan | Economic growth, development of telecommunications infrastructure, and financial development in Asia, 1991-2012[END_REF]. Moreover, TFP's contribution is higher in the long term than in the short term. This progress can be explained by the positive contribution of ICT diffusion, the consolidation of existing technologies, innovation, and learning by doing. This result confirms Van Ark et al.'s (2003) findings.

Conclusions and policy implications

This study evaluates the relationship between ICT diffusion and economic growth in the Tunisian economy. The study was motivated by the view that empirical research on the relationship between ICT diffusion and economic growth has mostly focused on developed economies with few studies focused on developing countries. This paper contributes to the empirical analysis of the impact of ICT diffusion on economic growth. We have proposed a new approach to evaluating the impact of ICT diffusion across different sectors of the Tunisian economy. Our contribution consists of the construction of an index using the IOT.

Then we posed the question of whether Tunisia gains better access to ICT. In comparison to existing empirical studies, to estimate this effect, we have used the panel ARDL PMG technique to analyze the period from 1997 to 2015. We found that ICT has a positive effect on long-term economic growth and contributes to the sustainability of the country's development, but these conclusions are not valid in the short term.

Despite the Tunisian government's effort to promote the usage and diffusion of ICT, it is still in its infancy. The low usage is explained by limited knowledge and skills, high cost of ICT acquisition, lack of financial resources, and poor infrastructure. However, the lower level of ICT diffusion in developing countries has a negative impact on economic development.

This impact is mainly explained by low productivity, low investment, insufficient trade of ICT goods and services, and a marginal contribution to job creation. Developing countries are still lagging behind developed ones in terms of ICT usage and diffusion. Therefore, the results regarding a country's level of economic development follow those already described in the literature.

As such, to boost economic growth, ICT investments must be increased and consolidated, since ICT can generate positive externalities in other sectors of the economy.

Capital remains an important factor, contributing significantly to economic growth. Therefore, the Tunisian government should first stabilize the economic and social environment to facilitate strong economic growth. Then it should incentivize the industry toward the adoption and diffusion of ICT and the digitalization of all the economic sectors. Additionally, the government should give priority to the allocation of ICT-related resources and ensure the adoption of these technologies and provision of the necessary labor. This will lead to an improvement in human capital that will benefit economic growth.

In future research, it will be useful to investigate foreign direct investment across sectors in terms of ICT and to investigate the determinants of investment from a regional perspective. This future avenue might complete our study from a macroeconomic perspective, allowing a country to realize a comparative advantage regarding its competitors in the ICT field.

Appendix: Summary of literature review -1971-1990 Micromodel for telecommunication investment with a macro production function -Around one-third of output could be attributed to ICT -The extent of telecommunications infrastructure is associated with economic growth. -1984-1999 ICT capital including the total value of hardware, software, and telecommunications equipment.

-The industries with the highest investments in ICT registered the highest increases in labor productivity Finds some positive effects of ICT on average labor productivity but not TFP.

-ICT capital has a negative association with productivity.

-No strong evidence of spillover-type effects of ICT on productivity.

  Source: International Telecommunication, World Telecommunications Indicators Database, July 2020.

  investigated the effects of financial development and ICT diffusion on economic growth for 17 MENA countries from 1960 to 2009. Based on a dynamic panel model with system GMM estimators, the authors showed that ICT (with different proxies) affected economic growth positively. Interestingly, the authors showed that the impact of financial development on growth is strengthened by a better-developed ICT infrastructure, such countries benefiting from financial development only once an ICT development threshold is reached. Asongu et al. (2017) analyzed whether ICT might lessen the potentially negative effect of environmental pollution on human development for 49 countries in sub-Saharan Africa during the period 2000-2012. Based on instrumental variable Tobit regressions, they concluded the ICT boosts inclusive human development. Tchamyou et al. (2019) investigated the role of ICT on income inequality through financial development from banking and financial system perspectives in 48 African countries during the period 1996-2014. Based on the GMM, they verify a strong correlation between the level of penetration of mobile telephony and financial inclusion in these countries. Amri et al. (2019) examined the linkage between carbon dioxide (CO2) emissions, total factor productivity (TFP) as a measure of income, and ICT in Tunisia from 1975 to 2014. They show, based on an autoregressive

  published by the Tunisian National Institute ofStatistics over 1997-2015. 4 Then, based on the OECD definition, 5 we determined that the Post and telecommunication sector is the main ICT sector in Tunisia. The sector includes IT equipment, communications equipment, and software. These components are integrated into economic sectors as input (or intermediate consumption). In other words, economic sectors use the components of Post and telecommunication to obtain their final outputs. Therefore, our methodology for constructing a Tunisian ICT Diffusion Index aims to determine the share of the ICT sector in the added value of other sectors based on the IOT. This share is defined as the contribution of ICT to the added value of the sector, representing the diffusion of ICT. From an analytical point of view,

Table 1 :

 1 ICT diffusion indicators, per 100 inhabitants, 2005ICT diffusion indicators, per 100 inhabitants, -2019

	Arab	Tunisia
	countries

  TFP !4% + " -*+&, !4% + " / . !4% + " 5 0 !4%

	+ 6 δ %8 ΔVA !49 : ;4% 9<% >4% + 6 δ 58 Δ0 !49 8<#	6 δ )8 ΔTFP !49 =4% 9<#	+ 6 δ -8 Δ*+&, !49 >4% 8<#	>4% + 6 δ /8 Δ. !49 8<#

Table 2 .

 2 ICT diffusion to different economic sectors

		1997-2000	2001-2005	2006-2010	2011-2015	1997-2015
	Agriculture and fishing	0.42%	0.51%	0.35%	0.25%	0.38%
	Mining	1.01%	1.15%	1.39%	1.18%	1.18%
	Agrifoods industries	1.16%	1.89%	2.00%	2.09%	1.79%
	Textile, clothing, and leather	1.81%	2.77%	3.39%	3.70%	2.92%
	Oil	5.38%	6.98%	7.76%	5.07%	6.30%
	Chemical industries	0.54%	0.58%	0.46%	0.33%	0.48%
	Building materials, ceramic, and glass	1.61%	6.01%	1.64%	1.62%	2.72%
	Mechanical and electrical industries	6.60%	4.64%	1.89%	3.45%	4.15%

Table 3

 3

presents the descriptive statics and correlation matrix for the variables. The average ICT diffusion is around 4.8%, which indicates a poor level of ICT across the different sectors. Interestingly, the ICT's standard deviation is relatively high, confirming the heterogeneity of the ICT distribution across economic sectors. Kurtosis and skewness show

Table 3 .

 3 Descriptive statistics and correlation matrix

		cd	efgh	gij	k	l
			Descriptive statistics
	Mean	0.0367	4.8004	0.0168	0.0555	0.0278
	Median	0.0360	5.2473	0.0178	0.0260	0.0233
	Max	0.2925	11.1476	0.2414	0.2195	0.5521
	Min	-0.5290	-0.2652	-0.4791	0.0057	-0.2415
	STD	0.0769	2.1301	0.0817	0.0592	0.0775
	Skew	-1.4871	-0.1174	-1.1507	1.3917	1.3492
	Kurt	14.7611	2.0319	8.8784	3.6237	10.9172
	JB test	2,097.183	14.1393	567.900	115.95	997.009
	Prob	0.0000	0.0008	0.0000	0.0000	0.0000
			Correlation matrix
	VA	1.0000
	ICTD	0.2080	1.0000	1.0000	1.0000	1.0000

Table 4 .

 4 Table4presents results of the unit tests. We used a variety of panel unit root tests, such as the[START_REF] Levin | Unit root test in panel data: asymptotic and finite sample properties[END_REF], hereafter LLC;[START_REF] Im | Testing for unit roots in heterogeneous panels[END_REF], hereafter IPS; augmented[START_REF] Dickey | Likelihood ratio statistics for autoregressive time series with a unit root[END_REF], hereafter ADF; and[START_REF] Phillips | Testing for a unit root in time series regression[END_REF], hereafter PP. The assumption is of a homogeneous self-regressive unit root under the alternative hypothesis. The LLC hypothesis is rectified by the IPS, specifically the homogeneous nature of the unit root under the alternative hypothesis. The ADF test suggested by[START_REF] Levin | Unit root test in panel data: asymptotic and finite sample properties[END_REF], assumes the homogeneity of autoregressive coefficient dynamics for all panel units. The PP test is a nonparametric adaptation of the Dickey-Fuller test. For all tests, the null hypothesis is the presence of a unit root. Panel unit roots test results

	Unit root test			VA	ICTD	L	TFP	K
	LLC	Level First	Intercept Trend Intercept	-1.269 (0.09) -0.072 (0.473) -7.076 (0.0000)	-11.1059 (0.9931) -8.322 (0.3512) -13.1134 (0.0000)	-8.208 (0.0000) -7.11 (0.0000) -14.171 (0.0000)	-7.177 (0.0000) -5.468 (0.0000) -11.073 (0.0000)	1.09358 (0.8629) 5.7473 (0.9878) -17.0793 (0.0000)
		difference	Trend	-5.73 (0.0000)	-9.157 (0.0000)	-10.572 (0.0000)	-7.875 (0.0000)	-10.346 (0.0000)
	IPS	Level First	Intercept Trend Intercept	0.603 (0.723) 0.981 (0.837) -7.419 (0.0000)	-11.0748 (0.4587) -7.782 (0.6843) -14.665 (0.0000)	-7.815 (0.0000) -6.021 (0.0000) -16.355 (0.0000)	-7.717 (0.0000) -5.598 (0.0000) -14.05 (0.0000)	-4.86051 (0.3658) -0.666 (0.2526) -9866 (0.0000)
		difference	Trend	-5.183 (0.0000)	-11.1705 (0.0000)	-13.278 (0.0000)	-10.855 (0.0000)	-7.937 (0.0000)
	ADF	Level	Intercept Trend	31.517 (0.6817) 32.447 (0.638)	180.596 (0.8762) 124.313 (0.2346)	128.589 (0.0000) 97.984 (0.0000)	126.614 (0.0000) 94.367 (0.0000)	96.056 (0.3581) 61.467 (0.4368)
		First difference	Intercept	121.431 (0.0000)	235.702 (0.0000)	262.565 (0.0000)	226.314 (0.0000)	167.187 (0.0000)

As we have examined the stationarity of the variable through several panel unit roots tests, we can conclude that VA, ICTD, and K are integrated into the first order. However, TFP and L are level stationary. These findings justify the adoption of the ARDL model.

Table 5 :

 5 Results of estimation for the impact of ICT on added value

	Coefficient	t-Statistic	Prob

Note: ECT(-1) denotes the coefficient of the error correction term. ∆ is the first-difference operator. ***, **, and * indicate significance at the 1%, 5%, & 10% levels, respectively.

Comparison between developing and developed economies

  The European ICT sector played an important role in the flow of information across the economic network, which positively impacted economic growth.-ICT helps technologies spread and businesses innovate because it facilitates business transactions and does not depend on other sectors to be successful.-ICT can improve the economy in Korea and regulations regarding ICT investment are needed to continue sustainable growth. Significant differences between developed and developing countries for their structure of returns from capital investment.-ICT has an insignificant effect on developing countries and a significant one in developed countries. ICT diffusion can improve economic growth in high-income countries, but the effect is ambiguous for middle-and low-income countries.-In middle & low-income countries, only the growth of the mobile sector can positively impact economic growth, whereas increasing the Internet or secure Internet servers cannot. ICT development contributes positively to economic growth.-Financial sector development hurts growth and that ICT development reinforces the role of financial sector development on economic growth in these countries. ICT boosts inclusive human development.-The effect varies across the fundamentals of human development and ICT specificities -Evidence of synergy from mobile phones is driven by non-oil exporting countries. The established inequality thresholds should not be exceeded for ICT to promote inclusive education in sampled countries.

	Gruber and Koutroumpis (2011) García-Muñiz and Vicente (2014) Dewan and Kraemer (2000) -Papaioannou and -192 countries -1990-2007 Panel regressions -The contribution of mobile telecommunication is significantly smaller for low penetration countries than for high penetration countries. -This suggests that nonconstant returns to scale exist, at least for ICT. -European ICT sectors (59 products) -2000, 2005, and 2007. Input-output tables -36 countries (22 developed countries and 14 developing countries) -1985-1993 Panel regressions Dimelis (2007) -22 developed and 20 developing countries -1993-2001 Panel regressions -ICT capital stock affects labor productivity growth more strongly in developed countries than in developing ones. Asongu et al. (2017) -49 countries in sub-Saharan Africa. -2000-2012. Tobit model regression -Amri. F et al. (2019) -Tunisia Economy -1975 to 2014 ARDL approach -Insignificant impact of ICT on CO2 emissions as a measure of pollution. -There is no impact of ICT on sustainable development. -Hwang and Shin (2017) -2000-2012 past and 2013-2030 future -ICT's contribution to future economic growth is examined via policy simulations (2013-2030) Hong J.P (2017) -Korean economy -1988-2013 Granger Causality -Private R&D has a stronger effect on economic growth in comparison with public R&D. Cheng et al. (2020) -72 countries -2000-2015 Dynamic panel model with system GMM estimators -Developing economies (2000-2012) -Korean economy -measured the contribution of ICT to past economic growth is revealed by growth accounting methodology Niebel (2018) -59 countries -1995-2010 Panel regressions -Developing countries do not benefit more from ICT investments -2004 to 2014 compared to developed countries. Asongu (2019) -42 countries in sub-Saharan Africa Panel GMM -
	Sassi and Goaied	-17 MENA countries	Dynamic panel model with system GMM
	(2013)	-1960-2009	estimators.
	Lee et al. (2016) Tchamyou et al. (2019),	-40 countries -1999-2013 -48 African countries -1996-2014	Panel regressions Panel GMM	-That the development of network infrastructures, education, interaction with international trade, and socioeconomic factors affect ICT development. -A strong correlation between the level of penetration of mobile telephony and financial inclusion in these countries.
				-Technology Upgrading of middle-income (MI) economies is
	Radosevic. S & Yoruk. E (2018)	-42 countries -2012	OLS regression	different from that of high-income economies. -That MI countries' activities are not reflected in income levels
				implying a middle-income trap.

-

The labor code paradoxically contributes to the exploitation of workers and job insecurity (p. 173): "The levels of secondary education of the Tunisian workforce are among the highest in the region and

percent of the workforce surveyed has a minimum of 10 years education." http://pubdocs.worldbank.org/en/878411500382424335/the-unfinished-revolution-eng-chap5.pdf

[START_REF] Pesaran | Bounds testing approaches to the analysis of level relationships[END_REF] developed two critical values. The first is defined under the assumption that all variables are assumed to be I(0), while the second is computed under the assumption that they are I(1). H0 is rejected when the value of the Fisher statistic exceeds the two critical values. Otherwise, the hypothesis is supported. When the Fisher statistic is between the two limits, no conclusions can be drawn.

://www.tradecommissioner.gc.ca/tunisia-tunisie/market-reports


Cyrille Haddar

Paul O Verhoeven

Thomas Bourlet

Bruno Pozzetto

Sylvie Pillet
email: sylvie.pillet@chu-st-etienne.fr

Brief comparative evaluation of six open one-step RT-qPCR mastermixes for the detection of SARS-CoV-2 RNA using a Taqman probe

Keywords: Coronavirus, SARS-CoV-2, RNA virus, emerging virus, laboratory-developed assay, RT-qPCR

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

Background

The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Europe lead the clinical laboratories to urgently assess a home-brew molecular assay [START_REF] Reusken | On Behalf Of Evd-LabNet And Erli-Net, Laboratory readiness and response for novel coronavirus (2019-nCoV) in expert laboratories in 30[END_REF]. Between mid-February and mid-March, a period when no commercial kits were available to cope with the huge amount of molecular tests to be carried out, all the laboratories equipped for molecular biology testing referred both to the already published techniques [START_REF] Corman | Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR[END_REF] and the National Reference Centres [START_REF] Lescure | Clinical and virological data of the first cases of COVID-19 in Europe: a case series[END_REF][START_REF] Etievant | Sensitivity assessment of SARS-CoV-2 PCR assays developed by WHO referral laboratories[END_REF]. However, they were confronted with a shortage of consumables and reagents, linked to the use of the same protocol by many laboratories. Mögling et al. recently reported the delayed response to the pandemic in relation to primers and probe contamination [START_REF] Mögling | Delayed Laboratory Response to COVID-19 Caused by Molecular Diagnostic Contamination[END_REF]. Another pitfall was the huge delivery delays of enzymes, especially the SuperScript™ III Platinum™ One-Step qRT-PCR kit (abbreviated as SIII in this study, Invitrogen, Cergy-Pontoise). Our aim was to compare five open one step RT-qPCR reagents available on the French market to urgently find an alternative solution for SARS-CoV-2 RNA detection.

Study design

A total of 51 respiratory specimens (45 nasopharyngeal e-swabs, 3 tracheal aspirations and 3 sputum specimens) sampled from patients suspect of SARS-CoV-2 infection and sent at the Laboratory of infectious agents and hygiene of the University Hospital of Saint-Etienne were processed as described [START_REF] Lescure | Clinical and virological data of the first cases of COVID-19 in Europe: a case series[END_REF][START_REF] Etievant | Sensitivity assessment of SARS-CoV-2 PCR assays developed by WHO referral laboratories[END_REF][START_REF] Danis | Investigation Team, Cluster of coronavirus disease 2019 (Covid-19) in the French Alps[END_REF] and using a ABI7500 thermocycler (Thermofisher) after extraction on eMAG (bioMérieux). The assay targeted the viral RNA dependant RNA polymerase (RdRp) gene. A multiplex assay was set up in our laboratory by adding to the mastermix the primers (0.2µM) and a Taqman probe (0.1µM) targeting the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA [START_REF] Ishida | Novel approach to quantitative reverse transcription PCR assay of mRNA component in autopsy material using the TaqMan fluorogenic detection system: dynamics of pulmonary surfactant apoprotein A[END_REF] to manage the whole analytical process together with the sample cellularity. After testing with this reference assay, the extract (conserved at 4°C; 5µL for each assay) was tested on the same day using the same concentrations of primers and probes as those used in the reference assay and one of the five other mastermixes depicted in the Table . The cycle threshold (CT) values were recorded for each assay and compared to the reference assay by estimating their agreement with the concordance percentage and the Cohen kappa coefficient. The positive specimens were drawn on Linear regression and Bland Altman plot.

Results

The analysis focused for the CT values of the IP4 region of the viral RdR) and those of the GAPDH mRNA. All the specimens were positive for the GAPDH region, with CT values comprised between 20.1 and 28.7 using the reference assay; the GAPDH mRNAs were also detected in all tested clinical specimens with all the tested reagents (data not shown). The analysis of CT values for the IP4 region showed a global good agreement between the mixes in comparison to the reference assay (Table ). Only 3 samples were not detected by at least one of five reagents, but all exhibited extremely low viral loads with the reference assay (CT values between 38.9 and 40.7). After excluding these discordant samples, the correlation of the CT values was analysed on the remaining 48 specimens (Figure). All CT values were <35 using the reference assay. The mean difference of CT values was higher (> 0.5) for PrimeScript and GoTaq and lower (<-0.5) for LC MM than SIII. Fast Virus and Luna exhibited similar CT values than that of SIII (mean difference of CT value comprised between -0.5 and 0.5). The dispersion of CT values was higher with PrimeScript.

Discussion

The SuperScript™ III Platinum™ One-Step qRT-PCR kit, both exhibiting high analytical performances and being easy to use, is often recommended for the development of techniques for emerging viruses detection such as influenza viruses or MERS-CoV; it was also proposed for SARS-CoV-2 RNA detection in the early reports [START_REF] Corman | Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR[END_REF][START_REF] Lescure | Clinical and virological data of the first cases of COVID-19 in Europe: a case series[END_REF][START_REF] Etievant | Sensitivity assessment of SARS-CoV-2 PCR assays developed by WHO referral laboratories[END_REF].

However, due to its own success, its widespread use resulted in disruption of deliveries for high throughput testing. This study showed that several other reagents could successfully be used as an alternative. Although our study included a limited number of samples, no replicates were analysed, and only one thermocycler was used, it provides an overview of the results that can be obtained with these alternative solutions. Discrepancies were mainly observed for high CT values that corresponds to extremely low viral loads in respiratory samples. CT values are not necessarily comparable between techniques and the observed differences do not predict the sensitivity of the assay. The limit of detection should therefore be determined by each laboratory under its own conditions and the primers and probe sets chosen [START_REF] Etievant | Sensitivity assessment of SARS-CoV-2 PCR assays developed by WHO referral laboratories[END_REF]. The sensitivity of the molecular assay for SARS-CoV-2 RNA detection by using laboratory-developed assay is currently not the goal to achieve for respiratory specimens testing as CT values > 35 are observed at late stage of the COVID 19 and even correspond to non-infectious viral genomes [START_REF] Scola | Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards[END_REF][START_REF] Wölfel | Virological assessment of hospitalized patients with COVID-2019[END_REF][START_REF] Bullard | Predicting infectious SARS-CoV-2 from diagnostic samples[END_REF]; consequently, sensitivity of the assays was not the aim of this comparison. Several commercial solutions are now available for SARS-CoV-2 RNA detection [START_REF] Van Kasteren | Comparison of seven commercial RT-PCR diagnostic kits for COVID-19[END_REF][START_REF] Iglói | Comparison of commercial realtime reverse transcription PCR assays for the detection of SARS-CoV-2[END_REF]; manufacturers and clinical laboratories are now prepared to meet strong demands of SARS-CoV-2 detection by using RT-qPCR assay. However, we consider that our study may be useful in the event of a future RNA virus emergence.

Declaration of Competing Interest:

None. Despite the affiliation of CH to the BioSpeedia company (a spin-off of the Pasteur Institute, Paris), BioSpeedia did not interfere to the design of the study, the production of the results, nor to the redaction of the manuscript.

Table: Overall