PharmD, MSc Lucile Dheyriat

MBBS Daniel Ward

MD, PhD Laurent Beaugerie

MD, DMSc Tine Jess

MD, PhD Julien Kirchgesner
email: julien.kirchgesner@gmx.com

Risk of recurrent acute arterial events associated with thiopurines and anti-TNF in inflammatory bowel diseases

Keywords: Disease, UC, Ulcerative Colitis, LTDs, Long-Term Diseases, anti-TNF, anti-Tumor Necrosis Factor agents, SNDS, Système ICD-10, International Classification of Diseases, 10th edition, CCAM, French Common Classification of Medical Procedures, PY, Person-Years Inflammatory bowel disease, cardiovascular risk, anti-TNF, thiopurines

teaching and research institutions in France or abroad, or from public or private research centers.

Risk of recurrent acute arterial events associated with thiopurines and anti-TNF in inflammatory bowel diseases

INTRODUCTION

Inflammatory bowel diseases (IBD) are chronic, systemic, relapsing and remitting inflammatory disorders which include Crohn's disease (CD) and ulcerative colitis (UC). 1 Several studies have highlighted an increased risk of acute arterial events (cerebrovascular disease, ischaemic heart disease, and peripheral artery disease) in patients with IBD compared to the general population. 2,3 This increased risk may be driven by the contribution of chronic systemic inflammation to atherosclerosis, 4 as well as disease activity which has been identified as an independent risk factor for acute arterial events. 3,5 Additionally, systemic inflammation is now considered to be a therapeutic target in cardiovascular diseases, 6 and use of IBD treatments may be associated with reduced acute arterial events in patients with IBD due to their anti-inflammatory properties. A nationwide French cohort study evaluating the impact of anti-TNF and thiopurines for primary prevention found exposure to anti-TNF to be associated with a decreased risk of acute arterial events, while the risk reduction associated with thiopurines exposure was at the limits of statistical significance. [START_REF] Kirchgesner | Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study[END_REF] However, that study excluded patients with a previous history of acute arterial events and other cardiovascular diseases, yet these patients may be at the highest cardiovascular risk and may particularly benefit from a potential protective effect. Notably, acute myocardial infarction recurrence after a first event affects approximately one in eight men and one in seven women within five years, [START_REF] Smolina | Long-term survival and recurrence after acute myocardial infarction in England, 2004 to 2010[END_REF] and stroke recurrence affects one in ten patients within five years. [START_REF] Lewsey | Temporal trends in hospitalisation for stroke recurrence following incident hospitalisation for stroke in Scotland[END_REF] To our knowledge, no study has specifically evaluated the impact of IBD treatments for the secondary prevention of acute arterial events in patients with IBD. The aim of this study was to assess the impact of anti-TNF and thiopurines exposures on the risk of recurrent acute arterial events in patients with IBD and a previous history of an acute arterial event.

METHODS

Data sources

We used the French administrative health databases 2006-2018 (Système national des données de santé [SNDS], which includes the French hospital discharge database (PMSI), to conduct a French nationwide cohort study. The SNDS includes details of clinical management such as prescriptions (indexed by Anatomical Therapeutic Chemical [ATC] codes), medical and surgical procedures, and diagnoses (indexed by International Classification of Diseases, 10th edition [ICD-10]). Three classifications of hospital discharge diagnoses are registered: the 'main' diagnosis is the reason for hospital admission, the 'related' diagnosis is a disease underlying the main diagnosis, and 'associated' diagnoses are other comorbidities. Chronic disease diagnoses that have been approved by a physician for complete reimbursement of related healthcare costs are designated 'long-term diseases' (LTDs).

Study population

The study population included all patients aged 18 years or older identified with IBD based on listed LTDs and/or main or related discharge diagnosis related to CD or UC, and with a previous history of an acute arterial event (ischaemic heart disease, cerebrovascular disease, or peripheral artery disease) based on listed LTDs and/or main, related, or associated discharge diagnosis, and/or medical procedures before January 1, 2018 from the SNDS). IBD diagnosis was adapted from a previously published definition applied in the SNDS, shown to produce treatment exposure, hospitalization, and surgery rates similar to current standard of care. [START_REF] Kirchgesner | Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014[END_REF] If a patient had multiple hospitalizations with ICD-10 codes related to both CD and UC, the most recent diagnosis at cohort entry was retained for IBD subtype classification. The date of IBD diagnosis was defined as the earliest of either the starting date of the LTD status or the first date of hospitalization discharge related to IBD. See Supplementary Table 1 for inclusion criteria, ICD-10 and procedure codes.

Follow-up

All the patients had both an IBD diagnosis and a first acute arterial event at cohort entry. They were followed from the date of latest of the two diagnoses, or from January 1, 2009 if both occurred before this date. If the first acute arterial event occurred after January 1, 2009 and after IBD diagnosis, a 3-month gap between first acute arterial event diagnosis and cohort entry was introduced to reduce misclassification between a first event-related intervention and a real recurrent event. The date of cohort entry was limited to January 1, 2018, so each patient was followed for at least one year. Patients were followed until recurrence of an acute arterial event (either identical or different from the previous history), loss to follow-up, death, or the end of the study (December 31, 2018), whichever occurred first. In case of loss to follow-up, the end of follow-up was the last known contact date, defined as the last claim in the database. Graphical visualization of the cohort study design is available in Supplementary Figure 1.

Drug exposure

Exposure to anti-TNF (including infliximab, adalimumab, and golimumab) or thiopurine (azathioprine and mercaptopurine) was assessed at cohort entry and during follow-up.

Patients who received adalimumab, golimumab, or thiopurines were considered exposed for one month following delivery, those who received infliximab were considered exposed for two months following the infusion. Treatment withdrawal was defined by a period of at least three months, after the last day of exposure, without any new treatment delivery. See Supplementary Table 2 for IBD treatments related ATC codes.

Outcomes

The primary outcome was the recurrence of any acute arterial event subtype leading to hospitalization, including ischaemic heart disease, cerebrovascular disease, or peripheral artery disease. These diagnoses were identified as the main discharge diagnosis and/or medical procedures. We did not use LTDs since these codes could be related to the patient's first acute arterial event. We did not include acute mesenteric ischaemia, since local intestinal inflammation rather than systemic inflammation may be associated with acute mesenteric ischaemia in patients with IBD. [START_REF] Hatoum | The vasculature and inflammatory bowel disease: contribution to pathogenesis and clinical pathology[END_REF] The secondary outcomes were each individual subtype separately assessed. See Supplementary Table 3 for outcomes related ICD-10 and procedure codes.

Covariates

Time-fixed covariates presented in Table 1 were assessed at cohort entry and included: sex; age; socio-economic status (coverage of universal complementary healthcare insurance available for people with low annual income); IBD subtype (CD or UC); IBD disease duration; exposure to methotrexate, oral aminosalicylates, thiopurines, and anti-TNF within the previous six months; exposure to oral corticosteroids within the previous three months; IBD-related endoscopy (lower or upper), gastrointestinal imaging, hospitalization ≥ 24h, and surgery related to IBD within the last year; exposure to anticoagulants or antiplatelets within the previous six and three months, respectively. We also assessed various comorbidities with potential cardiovascular impact (chronic pulmonary, kidney, and liver diseases; rheumatic diseases: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis; cancer; venous thromboembolism; serious infection; heart failure; atrial fibrillation; cardiomyopathy; cardiac or vascular prosthesis, implant or graft; and atherosclerosis), traditional cardiovascular risk factors (arterial hypertension, dyslipidemia, diabetes, obesity, smoking behavior, and chronic alcohol abuse), and history of acute arterial events. Of note, patients with a previous history of acute arterial events before January 1, 2009 could have been diagnosed with more than one subtype of acute arterial events. Duration since the first acute arterial event was also evaluated at cohort entry. Time-varying covariates were assessed at 3-month intervals throughout follow-up.

These included: surrogate markers of severe IBD activity (including exposure to corticosteroids and occurrence of IBD-related hospitalization or surgery) and exposure to antiplatelet drugs. Covariates were identified using all available listed LTDs, main, related, or associated discharge diagnosis, medical procedures, and drug reimbursements. Only the main discharge diagnoses were used to identify a hospitalization related to IBD activity or serious infection. See Supplementary Table 1 for covariates related ICD-10, procedure, and ATC codes and Supplementary Table 2 for IBD treatments related ATC codes.

Statistical analysis

Descriptive analysis

Descriptive analysis of patients' characteristics at cohort entry were performed according to subsequent treatment exposure (unexposed to anti-TNF and thiopurines, or exposed to anti-TNF and/or thiopurines at least once), and according to subsequent occurrence of recurrent acute arterial event during follow-up. Incidence rates of recurrent acute arterial events according to treatment exposure were estimated during follow-up. As patients could have been exposed successively to different treatment sequences, they could have therefore contributed follow-up time to more than one exposure classification.

Cumulative incidences of recurrent acute arterial events were estimated for the whole cohort and also separately for patients entering the cohort three months after the first acute arterial event.

Outcome model

Marginal structural Cox proportional hazard models adjusted for all the time-fixed and time-dependent covariates were used to estimate the risk of acute arterial event recurrence associated with exposures to anti-TNF and thiopurines, both compared to the absence of exposure to either medication. [START_REF] Robins | Marginal structural models and causal inference in epidemiology[END_REF] The use of marginal structural models is appropriate in the presence of time-varying cofounders that are associated with both subsequent exposure and outcomes, and that are also affected by past exposure, such as disease activity in our study. Time-varying inverse probability treatment weighting and time-varying inverse probability censoring weighting were used. [START_REF] Cole | Constructing inverse probability weights for marginal structural models[END_REF] Since anti-TNF and thiopurines may be used as combination therapy in clinical practice, an interaction term was introduced in the outcome model between anti-TNF and thiopurines exposures to provide unbiased estimates for each drug class. [START_REF] Lusivika-Nzinga | Performance of the marginal structural cox model for estimating individual and joined effects of treatments given in combination[END_REF] The impact of combination therapy, defined as concomitant exposure to anti-TNF and thiopurines, on the risk of acute arterial event recurrence was additionally assessed.

More details of the applied statistical method are provided in the Supplemental methods.

Subgroup and sensitivity analyses

In subgroups analyses, the cohort was stratified by IBD subtype, sex, and age at cohort entry (< 55 or ≥ 55 years of age), as cardiovascular risk may differ with these key characteristics.

Several sensitivity analyses were performed to test the robustness of the results, including restricting to patients with incident IBD diagnosis, to new users only, to patients included three months after the first acute arterial event, excluding patients with heart failure, and censoring at initiation of other biologics or small molecules. We performed analyses evaluating the risk of acute arterial events either different from or identical to the subtype of the previous event. See Supplementary Methods for details of these and further sensitivity analyses.

The study was approved by the French Data Protection Agency. All data were obtained from anonymized patient records. The statistical analyses were performed with SAS (V.9.4) statistical software (SAS Institute, Cary, NC, USA).

RESULTS

Characteristics of the cohort

Our nationwide cohort of patients with IBD comprised 305 911 individuals, 27 185 (8.9%) of whom had a previous history of an acute arterial event.

During follow-up, 22 496 (82.8%) patients were unexposed to anti-TNF and thiopurines, while 2 578 (9.5%) and 3 157 (11.6%) were exposed to anti-TNF and thiopurines at least once, accounting for 7 435 person-years (PY), and 8 763 PY of follow-up, respectively (Table 1 and2). The median duration of follow-up was 4.0 years (IQR 2.0-6.8). Combination therapy was prescribed to 147 (0.5%) patients during follow-up, accounting for 1 108 PY.

Overall, the mean age of patients was 66.2 years (SD 14.2), 61.7% were men, and 63.4% were diagnosed with ulcerative colitis. Mean duration of IBD at cohort entry was 5.8 years (SD 7.2). Unexposed patients were older compared to patients exposed to anti-TNF or thiopurines, with a mean age of 67.8 years (SD 13.7), 56.6 years (SD 14.1), and 58.9 years (SD 14.1), respectively. The majority of unexposed patients were diagnosed with UC (67.3%), while CD was predominant in patients exposed to anti-TNF (59.0%) or exposed to thiopurines (51.4%). The most common previous acute arterial event was ischaemic heart disease (66.2%), followed by cerebrovascular disease (26.9%), and peripheral artery disease (14.7%). Mean duration since first acute arterial event at cohort entry was 3.1 years (SD 4.9).

Among patients with a recurrent acute arterial event, a higher proportion were male (69.1%) compared to patients without recurrent event (59.2%). As expected, prevalence of traditional cardiovascular risk factors was higher in patients with recurrent event, especially for arterial hypertension, dyslipidemia, and diabetes (Supplementary Table 4).

Incidence rates of recurrent acute arterial events

Overall, 6 865 new acute arterial events occurred during follow-up representing a crude incidence rate of 56.4 (95% CI 55.0-57.7) events per 1000 PY (Table 2). Most of these events were ischaemic heart disease (56.7%), followed by peripheral artery disease (22.7%) and cerebrovascular disease (20.6%). Among the overall cohort, the cumulative incidence of recurrent acute arterial events after five years of follow-up was 24.8% (95% CI 24.2-25.4).

The cumulative incidence rates after five years of follow-up for ischaemic heart disease, cerebrovascular disease, and peripheral artery disease, were 15.0% (95% CI 14.5-15.5), 5.6% (95% CI 5.2-5.9), and 6.3% (95% CI 6.0-6.7), respectively (Supplementary Figure 2).

Risk of recurrent acute arterial events associated with IBD treatments

Both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events (HR 0.75; 95% CI 0.63-0.90 and HR 0.76; 95% CI 0.66-0.88, respectively) (Figure 1). Anti-TNF and thiopurines tended also to be associated with a decreased risk of ischaemic heart disease, cerebrovascular disease, and peripheral artery disease separately (Figure 1). Exposure to combination therapy tended to be associated with a decreased risk of recurrent acute arterial events although it did not reach statistical significance (HR, 0.77; 95% CI 0.55-1.09).

In subgroup analyses, the magnitude of risk reduction was similar for men and women for both exposure to anti-TNF and thiopurines (Figure 2). The magnitude of risk reduction was more pronounced for patients aged 18-54 years compared to patients aged ≥ 55 years under anti-TNF exposure, while it was similar between the two age categories under thiopurines exposure. Regarding IBD subtype, the trend for risk reduction was more pronounced for patients with CD under anti-TNF exposure, while it was more pronounced for patients with UC under thiopurines exposure (Figure 2).

The results remained similar in sensitivity analyses (Supplementary Table 5). Analysis restricted to patients starting follow-up three months after the first acute arterial event were consistent with the main analysis (Supplementary Figure 3). Differences in risk reduction associated with anti-TNF or thiopurines according to the subtype of first or recurrent acute arterial events were minimal (Supplementary Figure 4).

DISCUSSION

Based on a nationwide population-based cohort of patients with IBD and a previous history of acute arterial event, our findings suggest a reduced risk for all recurrent acute arterial events associated with both exposure to anti-TNF (HR 0.75), and thiopurines (HR 0.76). Results were not substantially altered in sensitivity analyses. Our study also highlighted the high risk of recurrent acute arterial events in this population, with 24.8% of patients experiencing a recurrent acute arterial event within 5 years.

To our knowledge, no study had previously assessed the risk of subsequent acute arterial events according to treatment exposures in patients with IBD, while few studies assessed the risk of primary acute arterial event according to IBD treatments. A cohort study based on US claims data including patients with CD reported a decreased risk of major adverse cardiovascular events and a reduced risk of death associated with anti-TNF exposure compared to prolonged corticosteroids exposure. [START_REF] Lewis | Increased Mortality Rates With Prolonged Corticosteroid Therapy When Compared With Antitumor Necrosis Factor-α-Directed Therapy for Inflammatory Bowel Disease[END_REF] A previous nationwide French cohort study reported a decreased risk of a first acute arterial event in patients with IBD and exposed to anti-TNF, however, exposure to thiopurines was not associated with a significantly decreased risk. [START_REF] Kirchgesner | Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study[END_REF] Our finding of a protective effect of anti-TNF exposure on acute arterial risk is consistent with the previous French study, whereas the beneficial effect of thiopurines exposure suggested in the present study may be related to the higher baseline cardiovascular risk in the population included.

Subgroup analyses revealed that the trend for risk reduction under anti-TNF exposure was similar for both men and women. However, the previous French study evaluating impact of IBD treatments for primary prevention showed a beneficial effect of anti-TNF exposure predominantly in men compared with women, explained by the hypothesis of a more severe IBD prognosis in male patients resulting in a higher acute arterial risk. [START_REF] Kirchgesner | Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study[END_REF][START_REF] Severs | Sex-Related Differences in Patients With Inflammatory Bowel Disease: Results of 2 Prospective Cohort Studies[END_REF][START_REF] Auzolle | Male gender, active smoking and previous intestinal resection are risk factors for post-operative endoscopic recurrence in Crohn's disease: results from a prospective cohort study[END_REF] Our latest results suggest that previous history of acute arterial events may have a more pronounced impact on global cardiovascular risk than patient's sex. Considering IBD subtype and age, we found a more pronounced risk reduction in patients with CD compared with patients with UC, and in patients aged 18-54 years compared with those aged ≥ 55 years, under anti-TNF exposure.

This was similar to previous findings, [START_REF] Kirchgesner | Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study[END_REF] and may be related to higher systemic inflammation in CD, [START_REF] Henriksen | C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study[END_REF][START_REF] Gross | Evidence for continuous stimulation of interleukin-6 production in Crohn's disease[END_REF] and more traditional risk factors in older patients that outweigh the role of IBD in acute arterial events occurrence.

This study has several strengths. First, our study was based on a nationwide cohort of French patients with IBD. From this cohort, we included 27 185 patients with IBD and a previous history of acute arterial events, which provided adequate statistical for power subgroup and sensitivity analyses. Second, the SNDS provided a rich source of medical information which enabled us to adjust for many baseline covariates, either related to IBD or with potential cardiovascular impact. As corticosteroids and disease activity are associated with an increased risk of acute arterial events, 3,[START_REF] Lewis | Increased Mortality Rates With Prolonged Corticosteroid Therapy When Compared With Antitumor Necrosis Factor-α-Directed Therapy for Inflammatory Bowel Disease[END_REF][START_REF] Ng | Glucocorticoid treatment and cardiovascular disease[END_REF] and both may be associated with past and future IBD treatments, we adjusted on these parameters as time-varying covariates in marginal structural Cox proportional hazard models to assess the unbiased effect of treatments. [START_REF] Robins | Marginal structural models and causal inference in epidemiology[END_REF] Third, the median follow-up of patients was four years, which allowed medium term assessment of recurrent acute arterial events.

Relevant limitations to this study include the use of disease definitions that were not previously validated, hence interpretation of the results should be tentative. Nevertheless, the definition of IBD diagnosis was similar to a definition applied in other studies using the SNDS. [START_REF] Kirchgesner | Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study[END_REF][START_REF] Kirchgesner | Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014[END_REF][START_REF] Kirchgesner | Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases[END_REF][START_REF] Kirchgesner | Risk of Serious Infections With Vedolizumab Versus Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease[END_REF] Moreover, the method to identify acute arterial events produced crude incidence rates of recurrent events consistent with other studies: in a trial including patients with previous myocardial infarction, incidence rates for new nonfatal myocardial infarction and for nonfatal stroke in the placebo group were 24.3 per 1000 PY and 7.4 per 1000 PY, respectively ), 6 and in a Scottish population-based cohort study of patients with rheumatoid arthritis and a previous history of cardiovascular diseases the incident rate of new nonfatal myocardial infarction was 14.1 per 1000 PY in patients exposed to statins and 38.5 per 1000 PY in unexposed patients. [START_REF] Sheng | Effectiveness of statins on total cholesterol and cardiovascular disease and all-cause mortality in osteoarthritis and rheumatoid arthritis[END_REF] Further limitations include incomplete data in the SNDS on factors such as tobacco smoking, obesity, and chronic alcohol abuse, and their prevalence may have been underestimated. Some behavioral factors with cardiovascular impact such as sedentary lifestyle, physical inactivity, or medication adherence to secondary prevention treatments were also not available. It has been identified that smoking reduces the risk of UC occurrence while increasing the risk of CD occurrence, and disease activity in patients with CD. 1 Additionally, patients with CD treated with thiopurines or anti-TNF are more likely to be smokers compared with patients not exposed to these drugs. 1 Thus, it is likely that underestimation of tobacco smoking does not alter the association between IBD treatments and the protective effect observed. Acute arterial events identified during follow-up might be related to the first acute arterial event rather than to an authentic recurrence in patients among whom the subtype of acute arterial event at cohort entry and during follow-up were similar. However, sensitivity analyses assessing the impact of treatments according to the subtype of first and recurrent acute arterial events, and analyses with reduction of the time interval between the first acute arterial event and cohort entry, all provided consistent results.

As our data covered hospital discharge diagnoses, it was not possible to identify acute arterial events leading to sudden death outside of the hospital, so further studies are required to address this question. Finally, we were not able to differentiate disease control from an independent effect of thiopurines and anti-TNF by themselves, since disease activity is poorly captured in administrative healthcare databases. Further studies including clinical and biological data are required.

In summary, we observed that recurrent acute arterial events were substantial in patients with IBD and a previous history of such events. Both exposure to anti-TNF and thiopurines were associated with a protective effect on the risk of recurrent acute arterial events. This study provides new data for the benefit-risk assessment of anti-TNF and thiopurines in patients with IBD and a previous history of acute arterial event.

Chronic liver disease 572 (

IBD-related endoscopy

Lower gastrointestinal endoscopy HGQD002, HHAE001, HHEE001, HHFC001, HHFE001, HHFE002, HHFE004, HHFE005, HHFE006, HHGE002, HHJE001, HHLH001, HHNE001, HHNE002, HHNE003, HHNE004, HHQE002, HHQE003, HHQE004, HHQE005, HHSE001, HHSE002, HHSE003, HHSE004, HJQE001, HJQE002, HZQE900 Upper gastrointestinal endoscopy HEAE001, HEAE002, HEAE003, HEAH001, HEFE001, HEFE002, HEFE003, HEGE001, HEGE002, HEGE003, HEKE001, HELE002, HELE900, HELH001, HEME900, HENE001, HENE002, HENE004, HENE900, HEQE001, HEQE002, HEQE003, HEQE005, HESE002, HFAE001, HFAH001, HFLE001, HFLH001, HFLH002, HGFE005, HGGE001, HGKE001, HGLE001, HGNE001

Supplemental Methods

Sensitivity analyses

First, we performed sensitivity analyses restricted to patients identified with IBD after January 1, 2009 in order to have only patients with incident IBD diagnosis, restricted to patients untreated before inclusion in order to assess the impact in new users, and restricted to patients included three months after the first acute arterial event in order to have a homogeneous population for time duration since the first acute arterial event. Second, we excluded patients with heart failure (as anti-TNF are contraindicated in patients with moderate or severe heart failure). Third, we censored patients at initiation of other biologics or small molecules approved after anti-TNF marketing approval, including tofacitinib, vedolizumab, or ustekinumab. Fourth, since the three-month interval between the first acute arterial event diagnosis and the cohort entry was arbitrary defined, we performed analyses evaluating the risk of acute arterial events either different from or identical to the subtype of the previous event, and we also reduced the interval from three months to one month Lastly, we performed analyses with an additional time of three months for drug exposure estimates.

Statistical analysis

In this study, under the assumption of no unmeasured confounders, marginal structural models estimated causal effects of anti-TNF, thiopurines and combination therapy exposure periods compared to periods with absence of exposure to anti-TNF and thiopurines. 3 The follow-up time was arbitrary divided in 3-months intervals. At each time interval, patients were considered exposed to one treatment modality, that is exposed to anti-TNF, thiopurines, combination therapy, or unexposed. Time fixed covariates were evaluated at cohort entry and remained identical for all time intervals. Time dependent covariates were updated at each time interval. At the end of each time interval, occurrence of outcome or censorship (death or December 31, 2018) was evaluated. Follow-up continued until occurrence of outcome or censorship.

Time-varying inverse probability treatment weights (for both anti-TNF and thiopurines) and time-varying inverse probability censoring weights (to adjust for potential selection bias) were estimated. 4

Figure 1 :Figure 2 :

 12 Figure 1: Multivariable adjusted hazard ratios for recurrent acute arterial events according to medication exposure periods

TABLE LEGENDS Table 1 :

 LEGENDS1 Patients' characteristics at cohort entry according to subsequent treatment exposure during follow-up

Table 2 :

 2 Incidence of recurrent acute arterial events according to medication exposure a Patients exposed to more than one exposure group during follow-up were considered in each corresponding group. b Free access to healthcare for people with an annual income <50% of poverty threshold. c As registered within 6 months before cohort entry (except for corticosteroids and antiplatelet drugs [within 3 months]) and IBD assessment and complications [within 1 year]). Abbreviation: TNF, Tumor Necrosis Factor

Table 1 : Patients' characteristics at cohort entry according to subsequent treatment exposure during follow-up Characteristics Unexposed to anti- TNF and thiopurines (n = 22 496, 82.7%) Exposed to anti-TNF a (n = 2 578, 9.5%) Exposed to thiopurines a (n = 3 157, 11.6%) Total (n = 27 185) Age at cohort entry (years), mean (SD)

 1

	67.8 (13.7)	56.6 (14.1)	58.9 (14.1)	66.2 (14.2)

History of acute arterial event, n (%)

	Rheumatic disease
	Rheumatoid arthritis	528 (2.3)	136 (5.3)	49 (1.6)	693 (2.5)
	Ankylosing spondylitis	544 (2.4)	301 (11.7)	110 (3.5)	901 (3.3)
	Psoriatic arthritis	233 (1.0)	124 (4.8)	49 (1.6)	383 (1.4)
	Cancer	4 624 (20.6)	295 (11.4)	326 (10.3)	5 158 (19.0)
	Venous thromboembolism	1 491 (6.6)	197 (7.6)	235 (7.4)	1 857 (6.8)
	Serious infection	3 235 (14.4)	311 (12.1)	296 (9.4)	3 751 (13.8)
	Heart failure	3 294 (14.6)	195 (7.6)	278 (8.8)	3 703 (13.6)
	Atrial fibrillation	4 771 (21.2)	293 (11.4)	416 (13.2)	5 370 (19.8)
	Cardiomyopathy	1 452 (6.5)	112 (4.3)	145 (4.6)	1 673 (6.2)
	Cardiac or vascular prosthesis, implant or graft	1 579 (7.0)	90 (3.5)	102 (3.2)	1 744 (6.4)
	Atherosclerosis	3 503 (15.6)	283 (11.0)	394 (12.5)	4 075 (15.0)
	Ischaemic heart disease	15 079 (67.0)	1 552 (60.2)	2 011 (63.7)	18 007 (66.2)
	Cerebrovascular disease	6 031 (26.8)	748 (29.0)	843 (26.7)	7 311 (26.9)
	Peripheral artery disease	3 253 (14.5)	397 (15.4)	477 (15.1)	3 988 (14.7)
	Duration since first acute arterial event (years), mean (SD)	3.2 (5.0)	2.4 (4.0)	2.7 (4.5)	3.1 (4.9)
	Traditional cardiovascular risk factors, n (%)
	Arterial hypertension	19 773 (87.9)	1 960 (76.0)	2 525 (80.0)	23 490 (86.4)
	Dyslipidemia	17 041 (75.8)	1 671 (64.8)	2 223 (70.4)	20 258 (74.5)
	Diabetes	5 973 (26.6)	516 (20.0)	697 (22.1)	7 000 (25.7)
	Obesity	3 534 (15.7)	396 (15.4)	457 (14.5)	4 241 (15.6)
	Smoking behavior	4 852 (21.6)	797 (30.9)	840 (26.6)	6 171 (22.7)
	Chronic alcohol abuse	1 772 (7.9)	170 (6.6)	168 (5.3)	2 054 (7.6)
	Exposure to antiplatelet drugs, n (%) c	14 680 (65.3)	1 503 (58.3)	1 948 (61.7)	17 521 (64.5)
	Exposure to anticoagulants, n (%) c	4 829 (21.5)	503 (19.5)	622 (19.7)	5 775 (21.2)

Table 2 : Incidence of recurrent acute arterial events according to medication exposure

 2 As patients could have been exposed successively to different treatment sequences, they could have therefore contributed follow-up time to more than one exposure classification. b Incidence rates per 1000 person-years Abbreviations: PY, person-years; TNF, Tumor Necrosis Factor

		Total 121 822 PY		Unexposed to anti-TNF and thiopurines* 106 732 PY	Exposed to anti-TNF a 7 435 PY	Exposed to thiopurines a 8 763 PY
		Events	IR b (95% CI)	Events	IR b (95% CI)	Events	IR b (95% CI)	Events	IR b (95% CI)
	All acute arterial events	6 865	56.4 (55.0-57.7)	6 221	58.3 (56.9-59.8)	291	39.1 (34.9-43.9)	396	45.2 (41.0-49.9)
	Ischaemic heart disease	3 894	32.0 (31.0-33.0)	3 507	32.9 (31.8-34.0)	178	23.9 (20.7-27.7)	234	26.7 (23.5-30.4)
	Cerebrovascular disease	1 416	11.6 (11.0-12.2)	1 312	12.3 (11.6-13.0)	47	6.3 (4.8-8.4)	65	7.4 (5.8-9.5)
	Peripheral artery disease	1 555	12.8 (12.1-13.4)	1 402	13.1 (12.5-13.8)	66	8.9 (7.0-11.3)	97	11.1 (9.1-13.5)

a

Figure 1 :

 1 Multivariable adjusted hazard ratios for recurrent acute arterial events according to medication exposure periods

Figure 2 :

 2 Multivariable adjusted hazard ratios for recurrent acute arterial events according to medication exposure periods: subgroup analyses according to IBD subtype, sex, and age

	Diabetes	E10, E11, E12, E13, E14, G59.0, G63.2, H28.0, H36.0, I79.2, M14.2, N08.3	A10
	Obesity	E66	A08AB, A08AX
	Smoking behavior	F17, J41, J42, T65.2, Z71.6, Z72.0	N07BA
	Chronic alcohol abuse	E24.4, F10, G31.2, G62.1, G72.1, I42.6, K29.2, K70, K85.2, K86.0, O35.4, T51, X45, X65, Y15, Z50.2, Z71.4	N07BB
			B01AC04, B01AC05,
			B01AC06, B01AC07,
	Exposure to antiplatelet drugs		B01AC16, B01AC17,
			B01AC22, B01AC24,
			B01AC25, B01AC30
	Exposure to anticoagulants		B01AA, B01AB, B01AF, B01AE03, B01AE07
	Abbreviation: CABG, Coronary Artery Bypass Graft Surgery

Table 4 : Patients' characteristics at cohort entry according to subsequent occurrence of acute arterial event

 4

		HEQH001, HEQH002, HGQH001,
	IBD-related imaging	HGQH002, HHQH001, ZCQH001, ZCQH002, ZCQJ004, ZCQJ005,
		ZCQK002, ZCQK004, ZCQK005,
		ZCQN001, ZCQN002
	Markers of IBD activity
	IBD-related hospitalization	K50, K51, K56, K60, K61, K62.4, K62.5, K63.0, K63.1, K63.2, K65.0, K92.2, R10
	IBD-related surgery
		HHFA002, HHFA004, HHFA005,
		HHFA006, HHFA008, HHFA009,
		HHFA010, HHFA014, HHFA017,
	Colectomy	HHFA018, HHFA021, HHFA022,
		HHFA023, HHFA024, HHFA026,
		HHFA028, HHFA029, HHFA030,
		HHFA031
	Intestinal resection	HGCA005, HGCC015, HGFA003, HGFA004, HGFA005, HGFA007,
		HGFC014, HGFC016, HGFC021
	Perineal surgery and minor
	digestive surgery	HGCA001, HGCA008, HGCC003,
		HGCC026, HGLA001, HHCA002,
		HHCA003, HHCC007, HHCC011,
		HKPA004, HKPA005, HKPA006,
		HKPA007, HKPA008, HPPA002,
		HPPC003, ZCJA001, ZCJA002,
		ZCJA004

a Free access to healthcare for people with an annual income of <50% of poverty threshold. b As registered within 6 months before cohort entry (except for corticosteroids and antiplatelet drugs [within 3 months] and IBD assessment and complications [within 1 year]). Abbreviation: TNF, Tumor Necrosis Factor Supplementary

History of acute arterial event, n (%)

	Ischaemic heart disease	12 979 (63.9)	5 028 (73.2)	18 007 (66.2)
	Cerebrovascular disease	6 076 (29.9)	1 235 (18.0)	7 311 (26.9)
	Peripheral artery disease	2 567 (12.6)	1 421 (20.7)	3 988 (14.7)
	Duration since first acute arterial event (years), mean (SD)	2.8 (4.7)	3.7 (5.4)	3.1 (4.9)
	Traditional cardiovascular risk factors, n (%)
	Arterial hypertension	17 178 (84.5)	6 312 (91.9)	23 490 (86.4)
	Dyslipidemia	14 542 (71.6)	5 716 (83.3)	20 258 (74.5)
	Diabetes	4 901 (24.1)	2 099 (30.6)	7 000 (25.7)
	Obesity	3 140 (15.5)	1 101 (16.0)	4 241 (15.6)
	Smoking behavior	4 515 (22.2)	1 656 (24.1)	6 171 (22.7)
	Chronic alcohol abuse	1 487 (7.3)	567 (8.3)	2 054 (7.6)
	Exposure to antiplatelet drugs, n (%) b	12 413 (61.1)	5 108 (74.4)	17 521 (64.5)
	Exposure to anticoagulants, n (%) b	4 408 (21.7)	1 367 (19.9)	5 775 (21.2)

all data relevant to the study are included in the article or uploaded as supplementary information.

 5: Multivariable adjusted hazard ratios for recurrent acute arterial events according to medication exposure periods in sensitivity analyses Supplementary Figure 1: Graphical visualization of cohort study design based on methods developed by Schneeweiss et al. [1] Supplementary Figure 2: Cumulative incidences of all recurrent acute arterial events, ischaemic heart disease, cerebrovascular disease, and peripheral artery disease in the overall cohort Supplementary Figure 3: Cumulative incidences of all recurrent acute arterial events, ischaemic heart disease, cerebrovascular disease, and peripheral artery disease, for patients included into the cohort three months after the first acute arterial event Supplementary Figure 4: Multivariable adjusted hazard ratios for recurrent acute arterial events according to subtype of first and subtype of recurrent event, and according to medication exposure periods Serious infection A00-A08, A15-A28, A31, A32, A34-A40, A41.0-A41.8, A42-A49, A51-A56, A60, A65-A69, A75-A89, A92-A96, A98, A99, B00.1-B00.9, B01, B02, B05, B06, B08, B09, B15, B17, B25-B83, B95-B97, B99, G00-G02, G04.0-G04.2, G05-G07, H00, H03.0, H03.1, H06.1, H13.1, H19.1, H19.2, H60.0-H60.3, H65.1, H66, H68.0, H70, I30.1, I33.0, J39.0, J39.1, I98.0, J01-J22, J36, J85, J86, K11.3, K12.2, K23.0, K23.80, K23.81, K67.3, K75.0, K80.0, K80.3, K80.4, K81.0, K83.0, K87.00, K93.0, K93.820, L00-L08, L30.3, M00, M01, M49.0, M60.0, M72.6, M86, M90.0, N10, N30.0, N33.0, N39.0, N41.0, N41. Supplementary Figure 2: Cumulative incidences of all recurrent acute arterial events, ischaemic heart disease, cerebrovascular disease, and peripheral artery disease in the overall cohort* Supplementary Figure 3: Cumulative incidences of all recurrent acute arterial events, ischaemic heart disease, cerebrovascular disease, and peripheral artery disease, for patients included into the cohort three months after the first acute arterial event* Supplementary Figure 4: Multivariable adjusted hazard ratios for recurrent acute arterial events according to subtype of first and subtype of recurrent event, and according to medication exposure periods

Supplemental Methods

Binomial logistic regression models were used to estimate the conditional probability terms for the numerators and denominators for stabilized weights. 5 Stabilized weights from the exposure selection model were calculated as follows: the numerator was the probability of receiving the treatment actually received during follow-up conditional on baseline covariates and past treatment history. The denominator was the predicted probability of receiving the treatment actually received after treatment modification conditional on baseline covariates, past treatment history and time-varying covariates.

Stabilized weights from the censoring model were calculated as follows: the numerator was the probability of being censored conditional on baseline covariates and past treatment history. The denominator was the predicted probability of being censored conditional on baseline covariates, past treatment history and time-varying covariates.

The stabilized weights were the product of the weights from the exposure selection and the censoring models, updated at each time interval. They allowed to achieve balance between treatment groups not only at baseline but also during follow-up.

After calculation, the stabilized weights were truncated at 5th and 95th percentiles to minimize the impact of extreme weights and improve precision. 4,6 After truncation, mean (SD) of the weights were 1.12 (0.39). There was no tendency for the mean to deviate from 1 after a long period of follow-up, which supported the positivity assumption.

The outcome model was adjusted for baseline covariates. An interaction term between anti-TNF and thiopurines exposures was introduced in the outcome model. 5 Robust variance estimators were used to estimate conservative 95% confidence intervals.

Consistency and correct specified model were admitted. Exchangeability was admitted under the assumption of no unmeasured confounders.


Gabriel Vasile
email: gabriel.vasile@grenoble-inp.fr

Marco Congedo
email: marco.congedo@grenoble-inp.fr

COMPARATIVE ANALYSIS OF ICA BASED INCOHERENT TARGET DECOMPOSITIONS FOR POLSAR DATA

Keywords: Incoherent Target Decomposition, ICA, PolSAR, data analysis

The Independent Component Analysis (ICA) has been recently introduced as a reliable alternative to identify canonical scattering mechanisms within PolSAR images. This paper addresses an overview of the most important aspects for applying such methods on real data. A new geometric classification algorithm is proposed by combining the polar decomposition and by adjusting the conventional k-means mean and distance with their counterpart on the Riemannian manifold. This algorithm is tested using P-band airborne PolSAR data acquired for the ESA campaign TropiSAR campaign.

INTRODUCTION

Polarimetric Synthetic Aperture Radar (SAR) images can be used for several applications, for example for land cover classification. With current SAR sensors being able to emit or receive two orthogonal polarizations, the polarimetric target decompositions are PolSAR image interpretation techniques relying on the study of the interaction between the targeted area and the transmitted waveform. In this context, the Incoherent Target Decomposition (ICTD) theory assumes that the scattering process is a combination of coherent speckle and random vector scattering effects [START_REF] Cloude | A review of target decomposition theorems in radar polarimetry[END_REF][START_REF] Touzi | Speckle effect on polarimetric target scattering decomposition of SAR imagery[END_REF]. Polarimetric target decomposition is a PolSAR image interpretation technique that relies on the analysis of the interaction between the illuminated area and the transmitted waveform, considering each polarimetric state of the latter. More specifically, it enables the description of an image cell as a sum of canonical scattering mechanisms (also called as target vectors) making it more intuitive to understand the behavior of the clutter and therefore to analyze it [START_REF] Cloude | A review of target decomposition theorems in radar polarimetry[END_REF].

In the remaining parts of this paper, Section 2 is dedicated to a short review of the ICA-ICTD framework and to the introduction of a new classification algorithm, while Section 3 Thanks to the French Aerospace Lab for providing the PolSAR data.

presents results obtained using real PolSAR data. Lastly, Section 4 provides some directions for further investigation.

INCOHERENT TARGET DECOMPOSITION TECHNIQUES FOR POLSAR DATA

ICTD algorithms can be split in two stages: the decomposition of an image pixel into basic target vectors and the correct retrieval of quantitative information from them (parametrization). In this paper, we propose a comparative analysis of three ICTD techniques: Cloude and Pottier's H/α, Touzi's TSVM and ICA based ICTD. The combined use of the Eigenvector approach with Cloude and Pottier's parametrisation gave rise to one of the most employed and most traditional classification schemes in PolSAR data analysis, the H/α feature space [START_REF] Cloude | An entropy based classification scheme for land applications of polarimetric SAR[END_REF]. The entropy, H, measures the degree of randomness of the scattering phenomenon, given as a function of the eigenvalues of the coherence matrix. Each eigenvector correspond to a scattering mechanism within the image cell and therefore each one will provide a different α angle. The authors in [START_REF] Cloude | An entropy based classification scheme for land applications of polarimetric SAR[END_REF] state that the best estimate of such parameter to represent the image cell is an weighted average based on the eigenvalues of the coherence matrix.

The parameters H and α are plotted in a plane, originating the so called H/α feature space. Upon the introduction of the aforementioned method, Cloude and Pottier suggested the partitioning of the plane in 9 regions, based on the polarimetric behavior of known type of natural phenomenons. Therefore, once the H and the average α parameters are extracted from the target polarimetric signature, it is straightforward to classify it as one of the corresponding type of scattering mechanisms. Many works are based on such method, from geophysical parameters inversion algorithms (in varied regions from the globe) to detection and classification algorithms. Having a remarkable correspondence to ground truth, the usage of this unsupervised technique has had very few improvements since its conception. It has been shown in [START_REF] Pralon | Evaluation of the new information in the H/α feature space provided by ICA in PolSAR data analysis[END_REF] that the Independent Component Analysis (ICA) provides additional information: unconstrained by the orthogonality condi-tion between the estimated scattering mechanisms that compose the PolSAR clutter under analysis, ICA is not subject to the unfeasible region in the H/α plane, increasing the range of possible natural phenomenons depicted in this feature space.

In [START_REF] Besic | Polarimetric incoherent target decomposition by means of independent component analysis[END_REF], a novel strategy to polarimetric ICTD was introduced by selecting the Independent Component Analysis (ICA) to identify the canonical scattering mechanisms within an image cell. The proposed ICA was able to retrieve non-orthogonal scatterer types [START_REF] Pralon | Evaluation of ICA-based ICTD for PolSAR data analysis using a sliding window approach: convergence rate, gaussian sources, and spatial correlation[END_REF][START_REF] Pralon | Evaluation of the new information in the H/α feature space provided by ICA in PolSAR data analysis[END_REF]. This ICA-ICTD decomposition can be applied either locally (inside a sliding neighborhood) or globally (using a redefined classification map).

In the local approach, by applying the MMSE filter [START_REF] Lee | Polarimetric SAR speckle filtering and the extended sigma filter[END_REF] on each of the ICA derived rotation invariant scattering vectors, we have shown in [START_REF] Vasile | Independent component analysis based incoherent target decompositions for polarimetric SAR data -practical aspects[END_REF] that spatial resolution can be better preserved with respect to the conventional PolSAR boxcar speckle filter.

The ICA based ICTD decomposition is based on the estimation of the mixing matrix A (Eq. 1). There are several criteria for determining the elements of A in order to ensure the mutual independence of the sources in s. The common factor for all the applied methods is the assumption that at most one of the sources is Gaussian.

k c (i, j) =   A c 11 A c 12 A c 13 A c 21 A c 22 A c 23 A c 31 A c 32 A c 33   •   s c 1 (i, j) s c 2 (i, j) s c 3 (i, j)   = A c s c (i, j) (1)
The selected Complex Fast-ICA algorithm is based on a bottom-up approach: emphasizing the non-gaussanity of the sources by maximizing an arbitrary nonlinear contrast function (Eq. 2) whose extrema coincides with the independent component.

J G (w) = E{G(|w H x| 2 )} (2)
The performances of the algorithm depend strongly on the choice of the nonlinear function G(y), which is supposed to be suited to the particular application. Therefore, here we have used the kurtosis criterion in deriving independent target vectors:

G 1 (y) = 1 2 y 2 . (3)
In this case, the contrast functions becomes essentially a measure of the fourth statistical moment of the source. As its value in case of the Gaussian variable equals zero, by maximizing the kurtosis of each of the sources, we ensure their independence.

The result of the incoherent target decomposition is the set of target vectors representing elementary scatterers and a set of scalars, providing their proportion in the total scattering. In our case, the target vectors of the independent scatterers are the columns of the estimated mixing matrix A = W H . The contribution to the total backscattering (m) is computed as a square root of the maximal eigenvalue of the derived Graves matrix.

Being based on Kennaugh-Huynen condiagonalization projected onto the Pauli basis, the TSVM [START_REF] Touzi | Target scattering decomposition in terms of roll-invariant target parameters[END_REF] allows parametrization of the target vector in terms of rotation angle (ψ), maximum amplitude (m), target helicity (τ m ), symmetric scattering type magnitude (α s ) and symmetric scattering type phase (Φ αs ), among which the last four are roll-invariant: Using these parameters, it is eventually possible to represent the obtained independent target vectors on either symmetric or non-symmetric target Poincaré sphere. In the ICA case, they do not necessarily form an orthogonal basis.

Global approach: classification on the Riemannian manifold using the polar decomposition

In the global approach, one may think to classify directly the mixing matrices derived by the Fast-ICA, however there is not a well established metric for the general linear group. Instead we propose here to consider the polar decomposition of the original 2 × 2 scattering matrices, following [START_REF] Souyris | Polarimetric analysis of bistatic SAR images from polar decomposition: A quaternion approach[END_REF].

The right polar decomposition of scatter matrix S is given by: S = UP,

where U is a unitary matrix and S = √ S H S is a Hermitian matrix. The unitary factor is unique if S is non-singular, which is the practical case of PolSAR data due to the presence of speckle and thermal noise in the scattering matrices.

Further on, we concentrate on the Hermitian factor P and we discard the unitary factor from Eq. 5. Therefore, each pixel of the PolSAR image yields a Hermitian matrix P i lying on the Riemannian manifold of positive matrices [START_REF] Bhatia | Riemannian geometry and matrix geometric means[END_REF].

Exploiting this geometry, we first replace the complex multilooking by computing the Riemannian barycenter within a local neighborhood of the current pixel in order to remove the speckle. Second, we cluster the pixels using, for example, a modified k-means algorithm, where the mean and distance are replaced by their counterpart on the Riemannian manifold of positive definite matrices.

Specifically, in this manifold we adopt the widely used affine-invariant metric for two tangent vectors V and W, defined by ⟨V, W⟩ P = T r(P -1 VP -1 W).

It follows the distance between two points on the manifold (positive definite matrices), given by

d 2 (X, Y) = ||log(X -1/2 YX 1/2 || 2 F , (7)
and the barycenter (geometric mean) of a set of points, which is the unique solution of

B = argmin G i d 2 (X i , G). (8)

POLSAR EXPERIMENTAL RESULTS

The Finally, we illustrate in Fig. 4-(c) the classification map, in slant range, obtained using the proposed modified k-means classifier with random initialization and N = 8 classes. This can be re-sampled in ground range as proposed in [START_REF] Julea | Simulation of SAR images and radar coding of georeferenced information for temperate glacier monitoring[END_REF].

CONCLUSION

This paper presented an overview of the most important aspects for applying ICA based incoherent target decompositions on real PolSAR data. Based on the coupling between the polar decomposition and the Riemanian k-means clustering, we have proposed a new classification algorithm for the global analysis of such data. Results have been illustrated using P band airborne PolSAR data over forested areas.

Further developments will be addressed to take into account also the left polar decomposition and to combine it in the final classification result.

Fig. 1 .

 1 Fig. 1. Paracou P-band airborne dataset, TSVM parameters after PCA boxcar speckle filtering: (a) entropy, (b) symmetric scattering type magnitude, (c) helicity and (d) symmetric scattering type phase. As an example, we propose to analyse the results by representing the derived TSVM parameters of symmetric targets on the Poincaré sphere (helicity equal 0). It can be observed in Fig. 3-(a),(b) that the second and the third most dominant mechanism (represented in blue and green, respectively) occupy different position onto the sphere, thus meaning that the non-orthogonality of ICA will produce different mechanisms, indeed.Regarding the global approach, we propose in Fig.4a comparison between complex multilooking and Riemanian barycenter as an estimate of the local 2 × 2 Hermitian factor of scattering matrix. The size of the local neighborhood is 7 × 7. One can observe in Fig.4-(b) that derived result is more robust to the inherent speckle noise.

Fig. 2 .Fig. 3 .Fig. 4 .

 234 Fig. 2. Paracou P-band airborne dataset, TSVM parameters after ICA MMSE speckle filtering: (a) entropy, (b) symmetric scattering type magnitude, (c) helicity and (d) symmetric scattering type phase.


Céline Bouteleux

Sylvain Fass

Laurence Mathieu

Influence of chlorine discontinuities on the bacteria present in biofilm and water of a drinking water distribution system

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

Introduction

Water distribution networks seldom function in stationary conditions. According to many parameters (quality of the resource, chlorine rate applied, technical interventions...), networks are constantly subjected to hydraulic, biological as physicochemical discontinuities. This study concerned disinfectant discontinuities (bleach). Few works already published on this topic and limited to discontinuities "all-or-nothing", have thus identified a risk of unsteadiness of the distributed water quality. To our knowledge, no published data exists on discontinuities with a "high and low" sequence of chlorine concentration and none have explored their impact on the bacterial communities.

Characteristics of the drinking water at in inlet of the distribution system

Objective

The objective is to appreciate, in drinking water and biofilm, the impact of chlorine discontinuities (changing from 0.1 to 0.4 then 0.1 mg Cl 2 /L of residual chlorine) on:

-the total number of bacteria, -the viability of bacteria (membrane integrity and culturability), -the phylogenetic composition of bacteria (α, β et γ-proteobacteria).

Effect of the chlorine discontinuity on the bacterial quality of water

Effect of the chlorine discontinuity on the biofilm The increase of the residual chlorine concentration in distributed drinking water from 0.1 to 0.4 mg Cl 2 /L : -alters the culturability of biofilm bacteria (CFU ÷ 3 after discontinuity), no modification of the total number of bacteria.

-changes the phylogenetic composition of biofilms: of the β-and γ-proteobacteria and of the α-proteobacteria.

This effect is temporary because the signals are reversed when the Cl 2 concentration is again brought back to 0.1 mg Cl 2 /L : -the culturable bacteria increased by a factor 5 after discontinuity.

-the proportions of α-, β-and γ-proteobacteria find their initial level gradually. 33.1 ± 12.3%

1.9 ± 0.3% 64.7 ± 12.3% 0.3 ± 2.2% (18d after discontinuity 2)

36.4 ± 15.8% 61.2 ± 15.4% 0.5 ± 0.2% 1.9 ± 0.6% α-proteobacteria γ-proteobacteria β-proteobacteria Other Eubacteria

(

  average of the 3 periods) Methods This work was completed within the framework of a research program coordinated by the International Center of Water (NanCIE) and funded by the Agence de l'Eau Seine-Normandie, Véolia Eau / Anjou-Recherche, le Syndicat des Eaux d'Ile de France, la Communauté Urbaine du Grand Nancy et le NanCIE. Continuous feeding with re-chlorinated drinking water in order to reach 0.1 or 0.4 mg Cl 2 /L in the water at the outlet of of bacteria (Syto 9 staining) -Viable bacteria (with a membrane integrity) (kit BacLight) -Culturable bacteria (PCA, 22°C, 15days) Phylogenetic composition (FISH) : (adapted from Batté et al., 2003)-Eubacteria (probe EUB338) -α-proteobacteria (probe ALF1b) -β-proteobacteria (probe BET42a) -γ-proteobacteria (probe GAM42a)

  ± 0.1% 37.5 ± 9.4% 60.8 ± 9.6% 1.6 ± 0.7%1.1 ± 0.8% (64d after discontinuity 1) 70.2 ± 8.8% 3.3 ± 2.9% 25.4 ± 7.5% (56d after discontinuity 2) 38.2 ± 7.6% 0.3 ± 0.1% 1.1 ± 0.2% 60.4 ± 7.8%Only the culturability of bacteria is modified during chlorine discontinuities:-CFU ÷ 4 when [ Cl 2 ] increased from 0.1 to 0.4 mg/L -CFU × 4 when [ Cl 2 ] decreased from 0.4 to 0.1 mg/L Seasonal variations of the water quality masking the possible effect of chlorine discontinuities.

  , Mathieu L., Laurent P. and Prévost M. (2003) Influence of phosphate and disinfection on the composition of biofilms produced from drinking water, as measured by fluorescence in situ hybridization. Can. J. Microbiol., 49: 741-753.• Regular analysis of water during the three periods • Punctual analysis of biofilm:-before discontinuity 1 -24d and 64d after discontinuity 1 -18d and 54d after discontinuity 2While remaining a minority sub-group, the proportion of γ-proteobacteria, including many bacteria of sanitary interest (coliforms, Legionella, Pseudomonas,

  Etudes et de Recherches en Environnement et Santé, Faculté de médecine, 9 av. de la forêt de Haye, B.P. 184, 54505 Vandoeuvre-lès-Nancy cedex, 2 Centre International de l'Eau, 149 rue Gabriel Péri, B.P. 290, 54500 Vandoeuvre-lès-Nancy, 3 Ecole Pratique des Hautes Etudes, D.E.S.P., Faculté de médecine, 9 av. de la forêt de Haye, 54505 Vandoeuvre-lès-Nancy cedex

1 , Fass S. 2 et Mathieu L. 3 1 Service d'


A Thomere

N Barreau

N Stephant

C Guillot-Deudon

E Gautron

M T Caldes

A Lafond

Formation of Cu(In,Ga)S 2 chalcopyrite thin films following a 3-stage co-evaporation process

Keywords: Cu(In, Ga)S 2, thin film, co-evaporation, solar cell

The study aims to investigate the origin of the crystalline and compositional bilayered structure of CuIn 1-x Ga x S 2 (CIGS) films we previously observed for samples deposited following the 3-stage process. Therefore, the growth of films of different gallium contents (i.e. x) was interrupted at key steps of the 3-stage, namely at the end of the first stage, after half of the second stage and at the end of third stage. Compositional, morphological and structural differences at each stage were characterized by X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Scanning Transmission Electron Microscopy (S/TEM) and Energy Dispersive X-Ray Spectroscopy (EDX). From these investigations, we propose a model attributing composition plateaus to the formation of diverse Cu-poor crystalline phases during the second stage of the growth process.

INTRODUCTION

Solar cells based on polycrystalline Cu(In,Ga)(S,Se) 2 thin films have reached a record conversion efficiency of 23.35 % [START_REF] Nakamura | Cd-Free Cu(In,Ga)(Se,S) 2 Thin-Film Solar Cell With Record Efficiency of 23.35%[END_REF]. This outstanding performance results from a device based on a chalcopyrite absorber containing both selenium and sulfur. The elemental distribution throughout the layer has been optimized for single junction photovoltaic application. While a pure selenide absorber layer demonstrated 22.6 % record efficiency [START_REF] Jackson | Effects of heavy alkali elements in Cu(In,Ga)Se 2 solar cells with efficiencies up to 22.6%[END_REF], devices based on pure sulfides remains lower with a 15.5 % record efficiency achieved using an absorber with a bandgap below 1.6 eV [START_REF] Hiroi | New World-Record Efficiency for Pure-Sulfide Cu(In,Ga)S 2 Thin-Film Solar Cell With Cd-Free Buffer Layer via KCN-Free Process[END_REF]. Nevertheless, by combining both improved material properties and growth process understanding, several groups have shown improved performance launching pure sulfide based devices towards much higher efficiency [START_REF] Shukla | Over 15% efficient wide-band-gap Cu(In,Ga)S 2 solar cell: Suppressing bulk and interface recombination through composition engineering[END_REF][START_REF] Hamtaei | Dominant Processing Factors in Two-Step Fabrication of Pure Sulfide CIGS Absorbers[END_REF]. Moreover, the bandgap of CuIn 1-x Ga x S 2 can be tuned between 1.5 eV and 2.4 eV by increasing x from 0 through 1 [START_REF] Bär | Determination of the band gap depth profile of the penternary Cu(In (1-X) Ga X )(S Y Se (1-Y) ) 2 chalcopyrite from its composition gradient[END_REF]. This bandgap energy range offers a large variety of applications such as building integrated photovoltaic (BIPV) and photoelectrochemistry (PEC) [START_REF] Shukla | Recent advancement in BIPV product technologies: A review[END_REF][START_REF] Mathews | Technology and Market Perspective for Indoor Photovoltaic Cells[END_REF][START_REF] Deangelis | Wide Band Gap CuGa(S,Se) 2 Thin Films on Transparent Conductive Fluorinated Tin Oxide Substrates as Photocathode Candidates for Tandem Water Splitting Devices[END_REF]; in particular, CuIn 0.7 Ga 0.3 S 2 (E g  1.7 eV) stands among the most suitable absorbers to act as top cell in tandem structures with c-Si technology [START_REF] Bremner | Analysis of tandem solar cell efficiencies under AM1.5G spectrum using a rapid flux calculation method[END_REF].

Recently, we have demonstrated that 14.2 % efficiency can be achieved from a structure based on a Cu(In,Ga)S 2 /CdS heterojunction, showing a photon absorption threshold of about 1.65 eV [START_REF] Barreau | High efficiency solar cell based on Cu(In,Ga)S 2 thin film grown by 3-stage process[END_REF]. The device absorber was grown by the co-evaporation of elemental copper, indium, gallium and sulphur following a sequential 3-stage process, originally developed for pure selenide layers [START_REF] Noufi | Method of fabricating high-efficiency Cu(In,Ga)(SeS) 2 thin films for solar cells[END_REF]. However, in contrast to pure selenide films, the resulting absorber consists of a bi-layered structure with high gallium content close to the rear contact and high indium content close to the surface. With the goal of better understanding the origin of such group III elemental distributions, the material evolution during the co-evaporation process is investigated. The co-evaporation process was interrupted at three key steps of the deposition process and the resulting layers investigated by X-Ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Scanning Transmission Electron Microscopy (S/TEM) and Energy Dispersive X-Ray Spectroscopy (EDX). A model based on crystalline phase stability is finally proposed to interpret the formation of such bi-plateau chemical compositions.

EXPERIMENTAL DETAILS

Absorber growth

Cu(In,Ga)S 2 (CIGS) thin films were deposited from the co-evaporation of elemental Cu (99.999%), In (99.999%), Ga (99.9999%) and S (99.99%) following the 3-stage process.

During the first stage, Mo-covered soda-lime glass (SLG) substrates were heated by infrared lamps at 300°C; In and Ga were evaporated simultaneously under excess S flux. For the series of samples investigated herein, the targeted gallium to group III ratio (i.e. GGI) was either 0.2, 0.35, 0.5 or 0.6. Samples removed at the end of this first step are labeled "layer A".

During the second stage, the substrate temperature is increased to 570°C. Cu is supplied until the composition of the growing layer turns Cu-rich (i.e. copper to group III ratio (CGI) > 1). The samples removed before the end of the second stage are labeled "layer B".

Finally, during the third stage In and Ga are supplied again until the film turns Cu-poor (CGI < 1); the In and Ga fluxes are similar to those of first stage. Cu-poor/Cu-rich/Cu-poor transitions were followed using the end-point-detection method as for selenide absorbers [START_REF] Barreau | High efficiency solar cell based on Cu(In,Ga)S 2 thin film grown by 3-stage process[END_REF][START_REF] Noufi | Method of fabricating high-efficiency Cu(In,Ga)(SeS) 2 thin films for solar cells[END_REF][START_REF] Kessler | Rapid Cu(In,Ga)Se 2 growth using "end point detection[END_REF]. The samples that have undergone the whole growth process are labeled "layer C".

The evolution of the substrate temperature, element-supply sequence and the output power of the heater during representative process time are plotted in Fig. 1. This figure identifies key steps where the process was interrupted, corresponding to samples labeled layer A, B and C.

We assume the co-evaporation process to be sufficiently reproducible. Numerous growths conducted with similar parameters yielded layers with similar physico-chemical properties.

Note that alkali species are not intentionally supplied during or after the deposition; spontaneous diffusion from the soda-lime glass (SLG) substrates into the growing layer is the exclusive alkali source.

Sample characterization

All CIGS thin films were investigated by X-Ray diffraction (XRD) on a D8 Bruker diffractometer ( = 1.540598 Å) and scanning electron microscope (SEM) (JEOL JSM 7600F). Compositions were determined by energy dispersive X-ray (EDX) spectroscopy using a different SEM (JEOL JSM 5800LV) equipped with a SAMx SDD energy dispersive spectrometer to evaluate the mean

CGI (i.e. [Cu]/([Ga]+[In]) and GGI (i.e. [Ga]/([Ga]+[In]). EDX mapping was performed by sampling

34 EDX spectra along the cross section of the layers stack. The acquisition area of each spectrum stretched as a "fishbone" perpendicular to this line on either side. These spectra were extracted from a hyperspectral mapping acquired at 7 kV and quantified with a library of standard compounds. The accelerating voltage was chosen because it was strong enough to ionize the elements studied but weak enough to obtain a good spatial resolution in this material.

Scanning Transmission Electron Microscopy (S/TEM) characterization was performed on a Csprobe corrected Themis Z G3 (Thermo Fisher Scientific) operating at 300 kV accelerating voltage. High Angle Annular Dark Field (HAADF) images were acquired with a 21.4 mrad convergence angle and 63-200 mrad collection angles and Energy Dispersive X-ray Spectroscopy (EDX) maps collected with 4 windowless silicon drift detectors (Super-X system).

RESULTS

3.1.

Layer A

These layers correspond to the status of the films at the end of the first stage, i.e. after the deposition of In, Ga and S onto the SLG/Mo substrates heated at 300 °C.

The compositions of layers A have been measured from the top (electron beam perpendicular to the layers). This setup leads to average compositions within the thickness of the layer. The measured compositions, in terms of the so-called GGI ratio

(GGI = [Ga]/([In]+[Ga]
)), are compared to the targeted values in Table I.

Table I: Targeted and experimental GGI ratio ([Ga]/([In]+[Ga])) of layer A measured by EDX. The experimental GGI values are the mean of analyses performed at five different locations of each

sample.

Samples A #1 #2 #3 #4
Targeted GGI 0.20 0.35 0.50 0.60 Experimental GGI 0.19 0.34 0.47 0.60

These layers were also investigated by XRD to determine their crystalline characteristics and whether GGI variations could imply important phase evolution. Selected angle area XRD patterns are presented in the Fig. 2a; 5°-95° angle range patterns are shown as supplementary material (Fig. SM-A). Accordingly, (In,Ga) 2 S 3 phase with cubic spinel structure (space group Fd-3m) is formed in the case of the lowest GGI. Increasing GGI yields a shift of the main (111) peak towards larger angles, which suggests a decrease of the lattice parameter with increasing gallium content. Furthermore, this peak widens while GGI increases, which can be due to narrower crystallite size as proposed in [START_REF] Sanz | Gallium indium sulfide layers obtained by modulated flux deposition[END_REF]. Although a definitive conclusion would demand further investigations, for GGI = 0.6 a peak appears at 11.36°. This can be assigned to the (011)

of Ga doped β-In2S3 (space group I4 1 /amd), or to the (004) of a InGaS 3 -like lamellar phase (space group P6 3 mc).

Finally, the morphology of the films is depicted through SEM cross sectional images in Fig. 2b. All layers A are about 1.1 µm thick, compact and very smooth. They all appear to be made of grains whose microstructure is hardly distinguishable from these SEM images. Only columnar grains are discernable for the lowest GGI.

Layer B

As a reminder, the layer B correspond to the status of the growing absorber after roughly half of the total copper amount is supplied, and substrate temperature has reached 570°C (see Fig. 1).

These films were investigated by SEM and images of representative cross sections are depicted in Fig. 3b. Although less obvious in the case of GGI = 0.19, these images show layers B consist of two stacked sub-layers of different grains morphologies. In addition, these images suggest that the interface between the sub-layers is planar and parallel to the plane of the substrate. To recently investigated family of lamellar trigonal phases (CIGS n ) [START_REF] Caldes | Layered Quaternary Compounds in the Cu 2 S-In 2 S 3 -Ga 2 S 3 system[END_REF]. Note that these phases were also identified within the frame of investigations on bulk materials [START_REF] Thomere | Chemical crystallographic investigation on Cu 2 S-In 2 S 3 -Ga 2 S 3 ternary system[END_REF]. Interestingly, in contrast to layer A, all peaks angle positions are independent of GGI; only their relative intensities appear influenced. This observation suggests the crystalline phases constituting layer B have similar lattice constants and the main impact of GGI increase is their relative amount within layer B.

By combining all these results, one may propose all layer B consist of a high gallium containing tetragonal phase as the rear sub-layer, covered with high indium containing 1-5-8 spinel like cubic phase. The additional trigonal phase detected by XRD is probably located at the interface of these two sub-layers. These results suggest the phase separation/segregation occurs as soon as copper starts being supplied. The gallium content of layers A appears to primarily influence the amount/thickness of one phase/sub-layer relative to the other.

Layer C

Layers C correspond to the status of the completed films, meaning after they underwent all Cupoor/Cu-rich/Cu-poor transitions (see Fig. 1). All layers were investigated by XRD (see Fig. 6a for selected angle area and Fig. SM-C in supplementary material for 5°-95°) and SEM (Fig. 6b).

The XRD patterns show two main features. The first one is that all films are made exclusively of chalcopyrite materials; secondary phases are no longer detected. Secondly, the shape of the reflections suggests two dominant contributions: one corresponding to a GGI ranging between 0.2 and 0.3, which is weakly dependent on A layer characteristics, and a second one attributed to higher GGI, ranging from 0.4 up to 0.9 with increasing GGI of layer A. Contributions assignable to intermediate GGI are visible as a continuum of compositions in between the two main reflections, suggesting steep graded GGI between the compositional plateaus.

According to our previous studies [START_REF] Barreau | High efficiency solar cell based on Cu(In,Ga)S 2 thin film grown by 3-stage process[END_REF], the chalcopyrite with the lowest GGI is located at the top of the layer, whereas that with the highest GGI is at the rear side of the film. The reasons for such a GGI evolution throughout the layer, which assuredly results from multi-phased layer B structure, are still not clear but could be explained by the higher sulfur amount available at the surface of the films while it grows.

Discussion

The investigated Cu(In,Ga)S 2 films were grown following the 3-stage process, known to result in the highest device performances for pure selenide absorbers (Cu(In,Ga)Se 2 ). Amongst the reasons mentioned for the superiority of the 3-stage process, one may highlight (i) the recrystallization of the growing film during Cu-poor/Cu-rich transition which decreases the density of detrimental extended crystalline defects [START_REF] Shukla | Over 15% efficient wide-band-gap Cu(In,Ga)S 2 solar cell: Suppressing bulk and interface recombination through composition engineering[END_REF][START_REF] Raghuwanshi | Influence of grain boundary modification on limited performance of wide bandgap Cu(In,Ga)Se 2 solar cells[END_REF][START_REF] Lomuscio | Phonon coupling and shallow defects in CuInS 2[END_REF], and (ii) the bandgap variation throughout the layer, evolving along with GGI V-shaped gradient [START_REF] Siebentritt | The electronic structure of chalcopyritesbands, point defects and grain boundaries[END_REF][START_REF] Niki | CIGS absorbers and processes[END_REF][START_REF] Lomuscio | Influence of stoichiometry and temperature on quasi Fermi level splitting of sulfide CIS absorber layers[END_REF]. This latter GGI gradient results from different diffusion coefficients of indium and gallium within the growing Cu(In,Ga)Se 2 layer. Such a mechanism is enabled thanks to stability of the tetragonal structure within a large range of Cu-contents, from 1-5-8 up to stoichiometric 1-1-2 compositions [START_REF] Caballero | Investigation of Cu(In,Ga)Se 2 thin-film formation during the multi-stage co-evaporation process: CIGSe thin-film formation multi-stage co-evaporation process[END_REF].

The location of the Ga-notch as well as gradient shapes are strongly dependent on both the deposition conditions (i.e. substrate temperature, selenium flux, …) and the amount of alkali elements (i.e. sodium) present while the film grows.

The experimental results presented suggest the mechanisms involved in the formation of GGI gradients for pure sulfide films differ from those for pure selenide films. GGI evolution throughout completed CIGS is rather made of two plateaus than a V-shaped gradient. Similarly to selenides, GGI profiles are set during the second stage, while copper is supplied to react with the (In,Ga) 2 S 3 or InGaS 3 resulting from the 1 st -stage. As reported in [START_REF] Thomere | Chemical crystallographic investigation on Cu 2 S-In 2 S 3 -Ga 2 S 3 ternary system[END_REF], the pseudo-ternary phase diagram of Cu 2 S-In 2 S 3 -Ga 2 S 3 indicates the Cu-poor CIGS is no single phased, the structure separates into two main crystalline phases corresponding to the cubic CuIn 5 S 8 -like (possibly with very low gallium content) and the Cu-poor Cu 0.8 (In 0.2 Ga 0.8 ) 1.06 S 2 tetragonal phase. These two phases are not miscible as long as the nominal composition of the film remains Cu-poor.

Surprisingly, this phase separation does not result in a homogenous narrow-crystals blending, but in a bilayered structure showing an abrupt planar interface parallel to that of the substrate.

It appears that the top of the Cu-poor CIGS layer is always In-rich and the bottom always Garich. This distribution of the group III elements remains so, even after the layer turned Cu-rich, inducing the formation of the two GGI plateaus. This mechanism is similar within the investigated range of layer A GGI ratios (i.e. from 0.19 through 0.60). Interestingly, the GGI of the top layer is independent of layer A GGI, which contrasts with that of the bottom layer, whose GGI strongly increases with layer A composition.

CONCLUSIONS

In the present study, Cu(In,Ga)S 2 thin films deposited by co-evaporation following the so-called 3-stage process were investigated. The absorbers synthesized by this process achieved solar cell efficiencies above 14 % but were still limited by a V oc -deficit. The original goal of the investigations presented herein is to provide a fundamental understanding of the mechanisms yielding the observed structural, compositional and morphological bi-layered structure in the absorbers. Absorber growth was intentionally interrupted at key steps of the sequential process and the layers characterized. The interpretation we propose is based on the relative stability of the numerous Cu-poor phases formed during the second stage. In contrast to pure selenide phases, there are many crystalline Cu-poor sulfides phases that are strongly dependent on the relative amounts of group III elements, namely the ratio between indium and gallium (i.e. GGI).

In particular, the model we propose explains the lowered gallium content of absorbers surfaces independent of the amount supplied during the first stage. As a consequence, although high efficiencies result from absorbers with bandgaps between 1.5 eV and 1.6 eV, the investigated 3stage process does not appear to be a suitable process to fabricate 1.7 eV band gap Cu(In,Ga)S 2 -based devices regardless of heterojunction partners. (c) Evolution of CGI, GGI and S/Metals through the sample.

18

  further explore the nature of these sub-layers, EDX cross sectional mappings were performed on Layers B with GGI = 0.47 and 0.19. The respective qualitative elemental distributions of In, Ga and Cu are shown in Fig.4. These mappings suggest that even in the case of the lowest GGI investigated, the top sub-layer contains more In and less Cu and Ga than the bottom. In addition, Fig.4cdisplays the superimposition of the SEM image (for GGI = 0.47) with the quantitative evolution of GGI and CGI measured by EDX. This figure confirms that the bilayered morphology corresponds with the two compositional plateaus: GGI top < 0.1 with 0.2 < CGI top < 0.3 and GGI bottom  0.8 with CGI bottom > 0.8. Nevertheless, the quantitative reliability of these EDX mappings remains poor because of overlapping signals at interfaces, in particular at the top/bottom layer interface. To gain accuracy, EDX mapping was performed using TEM on layer prepared by mechanical scratching. Fig.5ashows elemental EDX mappings of Cu, In and Ga in the case of the highest GGI (i.e. 0.6). This result strengthens the hypothesis that a majority of the gallium and copper atoms are located within the bottom sub-layer, while indium dwells at the top. Fig.5bplots the atomic fraction profiles of Cu, In, Ga and S through the investigated structure and Fig.5cplots GGI, CGI and S/Metals evolutions. These quantitative plots highlight at least three important features. Firstly, the composition of the bottom sub-layer (~900 nmthick for this sample) corresponds to Cu 1- In 0.1 Ga 0.9 S 2 , with 0.1 <  < 0.2. Secondly, the compositional transition at bottom/top sublayers interface corresponds to a strong increase in sulphur content, up to S/Metal ~ 1.3. This suggests that the top-sublayer near the interface has a composition close to Cu(In 0.9 Ga 0.1 ) 5 S 8 . Finally, for a high GGI layer B, the top sublayer composition evolves towards the surface with a moderate increase in GGI (< 0.2) and CGI and a decrease of relative sulphur content. Unfortunately, electron diffraction patterns could not be achieved on this sample because of its preparation procedure yielding too thick fragment. XRD patterns shown in Fig.3aand Fig.SM Bshow that all layers B are multiphased, as could be expected from compositional mapping. Additionally, for all GGI the patterns show peaks identified as (i) cubic CuIn 5 S 8 -like phase, (ii) tetragonal Cu-poor and Ga-rich phase, and (iii) a

FIGURESFigure 1 :

 1 FIGURES

Figure 2 :

 2 Figure 2: Layer A (a) XRD patterns in the angle range [10°-40°] of the layers at the end of the first stage for varying GGI. The peak marked with a * may be assigned to the InGaS 3 phase. (b) SEM cross sections of the layer A for varying GGI.

Figure 3 :

 3 Figure 3: Layer B (a) XRD patterns in the angle range [5°-40°] of the layers after half of total copper amount is supplied for varying GGI. (b) SEM cross sections of the layer B for varying GGI.

Figure 4 :

 4 Figure 4: Layers B Qualitative EDX mappings of the cross sections of layers with (a) GGI = 0.47 and (b) GGI = 0.19. (c) Quantitative evolution of GGI and CGI throughout Layer B with GGI = 0.47 calculated from EDX mapping.

Figure 5 :

 5 Figure 5: Layers B (a) Qualitative TEM-EDX mappings of the cross sections of layers with GGI = 0.60. (b) Quantitative evolution of elements through the sample deduced from TEM-EDX mapping.

Figure 6 :

 6 Figure 6: Layers C (a) XRD patterns around (112) reflections of the completed layers for varying GGI. (b) SEM cross sections of the layers.

Acknowledgment

The authors would like to thank E. Palmiotti for proof reading the article.

They also acknowledge the CIMEN Electron Microscopy Center in Nantes for the access to facilities.

Funding source

This work was supported by the French Contrat lan tat-gion and the uropean egional Development Fund of Pays de la Loire.