Raphaelle Teysseire
email: raphaelle.teysseire@chu-bordeaux.fr

Manangama Guyguy

Isabelle Duki

Camille Baldi

Patrick Carles

Carole Brochard

Fleur Bedos

Delva

Raphaëlle Teysseire

Guyguy Manangama

Isabelle Baldi

Camille Carles

Patrick Brochard

Carole Bedos

Fleur Delva

Determinants of non-dietary exposure to agricultural pesticides in populations living close to fields: A systematic review

Keywords: Pesticides, Agriculture, Environmental exposure, Residents, Spray drift, Exposure determinants

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

Introduction

Individual exposure to pesticides may result from a combination of several potential sources:

1/agricultural and non-agricultural work associated with direct and/or indirect pesticide exposure, 2/contact with people occupationally exposed to pesticides, 3/household pesticide use, 4/dietary ingestion of contaminated food and water, and 5/environmental exposures related to pesticide application in fields or manufacturing (U.S. EPA, 2020). The relative contribution of each of these sources can be difficult to discern and human can be exposed through dermal, oral, or respiratory routes leading to short-term and chronic health impacts (Kim et al., 2017).

For people living close to agricultural areas, the agricultural drift pathway could contribute substantially to total exposure. Several studies have indeed demonstrated higher levels of pesticides in both biological and environmental matrices among agricultural communities compared to people residing away from agricultural land [START_REF] Dereumeaux | Pesticide exposures for residents living close to agricultural lands: A review[END_REF]. The agricultural drift pathway includes several transfer processes. Transfer of pesticides into the atmosphere can occur directly during pesticide application by spray drift from the fields which then forms deposits (primary drift). Aerial emissions can also arise for several days or weeks after application by volatilization of pesticides from soils and plants or by wind erosion (secondary drift) [START_REF] Bedos | Mass transfer of pesticides into the atmosphere by volatilization from soils and plants: overview[END_REF][START_REF] Focus | Pesticides in Air: Considerations for Exposure Assessment[END_REF]. These phenomena can result in the exposure of residents to pesticides via dermal, inhalation and ingestion routes [START_REF] Efsa | Guidance on the assessment of exposure of operators, workers, residents and bystanders in risk assessment for plant protection products[END_REF].

Associations between pesticide exposure and the onset of a variety of adverse health outcomes such as cancers, neurological diseases, and adverse effects on fertility or pregnancy in populations living close to agricultural crops have been reported in the scientific literature [START_REF] Teysseire | Assessment of residential exposures to agricultural pesticides: A scoping review[END_REF]. Improving knowledge of the factors that may influence pesticide exposure near treated fields is essential in order to design intervention strategies that reduce potential impacts on the population's health. We found two systematic reviews, by the same authors, on the determinants of non-dietary exposure to pesticides in agricultural areas. [START_REF] Deziel | A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas[END_REF] published a review on non-occupational pathways of pesticide exposure in women living in agricultural areas in North America, not involved in farm work: ten out of 35 publications (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013) reported significant or suggestive (p<0.1) associations between agricultural drift pathway and pesticides in house dust or biomarker levels. The authors found moderate evidence of the efficiency of hygiene behaviors in reducing exposure. The second review on the relative contribution of non-occupational pathways to pesticide levels in house dust was based on seven studies covering the period 1995-2015, and indicated that pesticide concentrations in house dust decreased sharply and non-linearly as the distance of the home from treated fields increased, the magnitude depending on the type of pesticides [START_REF] Deziel | Relative contributions of agricultural drift, paraoccupational, and residential use exposure pathways to house dust pesticide concentrations: Meta-regression of published data[END_REF]. These reviews focused on specific populations (women or children, often members of farming families), sample types (house dust mainly) and location (North America). We propose a broader systematic review to describe the existing literature on non-dietary determinants of exposure related to the drift pathway in populations living near treated fields, including spatial indicators related to agricultural activities, hygiene practices, behaviors and sociodemographic parameters.

Methods

General framework for the review

We conducted a systematic review driven by the following question: "What are the determinants of non-dietary exposure to agricultural pesticides in people living near treated fields?". We defined the determinants of exposure as the factors explored in the studies that could explain the levels of pesticide exposure as spatial indictors related to agricultural activities, hygiene parameters, behaviors, and sociodemographic data. This work has been reported following the PRISMA guidelines (Moher et al., 2009).

Literature Search

The search for articles relied on three online bibliographic databases chosen for their OR (residen*) OR ((agricultural OR rural) AND (communit* OR area*))). We added articles identified from websites or from the bibliographic references of the selected studies. The references were managed using Mendeley Reference Manager (Mendeley -Reference Management Software & Researcher Network).

Study Eligibility Criteria

To be included in our review, studies had to fulfill the following criteria:

1) original human studies published in English, French or Spanish.

2) studies referring to ground application of pesticides in agriculture. We excluded studies mentioning aircraft-mounted sprayers. The scale and speed of this kind of operation differ from ground spraying; the levels and profiles of exposure are a priori different for populations in the vicinity.

3) studies including a 'spatialized' definition of the term 'resident', e.g. studies providing numerical spatial indicators such as the residential distance from fields or the agricultural amounts of pesticides applied in the vicinity. We did not consider a maximum distance from the treated field. Indeed, there is no harmonized definition of the term "resident" in the scientific literature based on distance to fields. A qualitative definition such as "rural area"

was not considered as sufficient to define a resident but this information could have been studied as a potential determinant of exposure. As our main objective was to study exposure determinants linked to the agricultural drift pathway, we chose to exclude studies including exclusively farmworkers and/or their families. Indeed, previous reviews have demonstrated that it is difficult to disentangle the contribution of the agricultural drift pathway from other sources in these populations because of the major contribution of the take-home exposure route [START_REF] Deziel | A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas[END_REF]Hyland and Laribi, 2017). However, studies including famers' families and other people living near crops but not involved in agricultural work were retained.

4) non-experimental studies characterizing residents' exposure to pesticides using biomonitoring or environmental monitoring and which quantitatively assess the effect of potential exposure determinants.

No limitations on the date of publication or the geographical location were applied.

The relevant studies were selected by three reviewers (RT, GM, FD). For each article, the eligibility criteria were checked by two reviewers independently. A consensus was found between all the reviewers about inclusion/exclusion of the article in the event of disagreement.

Data collection and analysis

For each article, the following information was collected: study reference, location, time period, population, pesticides or metabolites searched for, matrices of exposure explored, determinants of exposure to the agricultural pesticides studied, methods of measuring these determinants, and key findings. The results were summarized in tables. We also collected information on the type of statistical analysis performed and the associations found by the authors, which we have presented in the appendices.

We presented results of multivariable tests rather than univariate statistical tests when both were available, focusing on the results on the determinants explaining the presence/absence of pesticides rather than the factors predicting the levels of pesticide exposure. When only univariate statistical tests were performed, this was specified in the presentation of the results.

We designed a specific reading grid to assess the adequacy of the selected publications to answer the research question presented above, based on the analysis of the potential bias of each study. Indeed, we did not find any validated grid to assess the quality of studies in the field of exposure science directly applicable to our subject. The grid detailing the score calculation method is available in a supplemental file (Appendix A). Briefly, five criteria were used: 1) population adequacy, 2) reliability of exposure measurement, 3) reliability of spatial determinants measurement, 4) reliability of non-spatial determinants measurement, 5) consideration of other sources of exposure for the pesticides under study. A score from 0 to 2 was calculated for each item when applicable, according to the criteria presented in the grid. The total score for an article was a mean of the score obtained for each relevant item expressed as a percentage of the maximal possible score. Publications were classified into four categories based on their adequacy score: A 'very good quality' (score above 75%), B

'good quality' (between 50 and 74%), C 'medium quality' (between 25 and 49%), D 'low quality' (less than 25%).

Results

Study selection

The search for articles in the selected databases was conducted on January 10, 2020. We included 27 publications in our review: 26 were identified through the databases and one was found in the grey literature (Figure 1). This document was a thesis. The main reasons for exclusion were: no mention of pesticides used in agriculture, no human population included, and inclusion of populations not considered as residents (workers or general population).

General characteristics of included studies

The 27 articles included in our review were published between 2002 and 2020. They were from North America (n=14, 51.9%), Europe (n=8, 29.6%), Asia (n=3, 11.1%), South America (n=1, 3.7%), and Australia (n=1, 3.7%). The description of the type of crops near the residence was often missing (n=13, 48.1%). When the information was available, the crops identified, sometimes in association, were fruit trees (n=9, 33.3%), arable crops (n=6, 22.2%), vineyards (n=4, 17.8%), vegetables (n=4, 14.8%), and flowers (n=3, 11.1%).

In 13 studies (48.1%), pesticide exposure was assessed only by biomonitoring, mainly measurements of pesticides in urine samples (n=12, 44.4%), maternal blood, umbilical cord blood and placental tissue (n=1) [START_REF] Takser | Manganese levels during pregnancy and at birth: Relation to environmental factors and smoking in a Southwest Quebec population[END_REF]) and one study sampled prenatal dentin of shed teeth (n=1) [START_REF] Gunier | Determinants of manganese in prenatal dentin of shed teeth from CHAMACOS children living in an agricultural community[END_REF]. The publications covered mainly insecticides and their metabolites, such as organophosphates (OP) and their metabolites and notably Dialkyl phosphate (DAPs) (n=7), pyrethroids (PYR) and their metabolites (n=4) or imidacloprid and its metabolite (n=1). Two studies searched for herbicides and two for fungicides and their potential metabolites, such as ethylenethiourea (u-ETU). Finally, two searched for manganese (Mn) as an indirect measure of Mn-based fungicides such as maneb or mancozeb. The populations included in studies performing biomonitoring were children (n=7, 53.8%), pregnant or post-partum women (n=4, 30.8%) or families (n=2, 15.4%). The main results yielded by the biomonitoring studies regarding exposure determinants potentially related to the agricultural drift pathway are presented in Table 1. More details on these results (type of statistical analysis performed, associations found) are presented in Appendix B.

Pesticides were measured only in environmental matrices in 11 studies (40.7%). Nine sampled house dust (n=9, 33.3%). Occasionally, pesticides were measured in air or in surface deposition samples using passive air samplers (n=1, 3.7%) and silicone wristbands (n=1, 3.7%). Pesticides investigated in the environment were mainly insecticides including OP (n=6) and/or PYR compounds (n=2), followed by herbicides (n=3) and other pesticides (n=4). In studies conducting environmental monitoring, populations living in the dwellings were rarely described. Results of environmental studies are presented in Table 2 and Appendix B.

Finally, three studies explored both biological and environmental matrices (11.1%): two combined measurements in house dust and urines and one collected wipe samples from hands, feet, diverse surfaces in the home, and blood samples. Two of these three studies investigated OP pesticides and one PYR pesticides. Results of these studies are presented in Table 3 and Appendix B.

The quality of the studies was variable: seven articles were classified in category A (25.9%), eight in category B (29.6%), nine in category C (33.3%) and finally three in category D (11.1%). Details on the score calculated for each study are presented in a supplemental file (Appendix C).

In addition, 18 articles (66.7%) also investigated occupational and para-occupational determinants of exposure, 16 (59.3%) explored the contribution of factors related to the household use of pesticides, and 9 (33.3%) investigated dietary factors.

Spatial determinants of exposure

Place of residence (rural vs. urban)

Studies of various quality established a positive association between living in a rural area and the detection rate or levels of pesticides in urine samples [START_REF] Babina | Environmental exposure to organophosphorus and pyrethroid pesticides in South Australian preschool children: A cross sectional study[END_REF][START_REF] Chevrier | Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother-child cohort (France)[END_REF][START_REF] Dereumeaux | Urinary levels of pyrethroid pesticides and determinants in pregnant French women from the Elfe cohort[END_REF], silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF] and blood [START_REF] Takser | Manganese levels during pregnancy and at birth: Relation to environmental factors and smoking in a Southwest Quebec population[END_REF]. Two medium or low quality studies found, conversely, a positive association between living in an urban area and levels of OP, PYR and/or herbicide metabolites in urine samples [START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF][START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF].

Residential proximity to fields

Residential proximity to fields was the most common spatial determinant explored in the publications (n=16, 59.3%). A significant association between residential distance from the fields and pesticide measurements in different matrices was found in 12 of 16 studies (75%) of varying quality, seven being classified in category A or B and five in category C or D.

Seven studies showed a positive association between residential distance from fields within 100 meters and elevated detection rates or concentrations of pesticides in urine samples and house dust. Three of these studies found an association for OP insecticides or its metabolites (DAPs) [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF][START_REF] Butler-Dawson | Organophosphorus pesticide residue levels in homes located near orchards[END_REF]Hung et al., 2018), two for the herbicide Dimethyl tetrachloroterephthalate (DCPA) [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF][START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF] , one for a metabolite of fungicides (ETU) [START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF], and one for several herbicides [START_REF] Ward | Proximity to crops and residential to agricultural herbicides in Iowa[END_REF]. Three studies did not report any association with pesticide exposure indicators in urine samples [START_REF] Babina | Environmental exposure to organophosphorus and pyrethroid pesticides in South Australian preschool children: A cross sectional study[END_REF]Koch et al., 2002) or house dust (Hogenkamp et al., 2004) and living within 100 meters of fields. The pesticides explored were diverse, including insecticides, herbicides, and fungicides.

Six studies explored associations for greater distances. Of these, five showed a positive association between residential distance from fields less than 500 meters and elevated pesticide concentrations in urine samples or air for OP pesticides and its metabolites (n=4) [START_REF] Coronado | Organophosphate pesticide exposure and residential proximity to nearby fields: Evidence for the drift pathway[END_REF][START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF][START_REF] Gibbs | Passive sampling for indoor and outdoor exposures to chlorpyrifos, azinphos-methyl, and oxygen analogs in a rural agricultural community[END_REF][START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF] and for atrazine and triazine metabolites (n=1) [START_REF] Chevrier | Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother-child cohort (France)[END_REF]. One study found no association between distances less than 500 meters and levels of OP metabolites in urine samples [START_REF] Royster | A pilot study of global positioning system/geographical information system measurement of residential proximity to agricultural fields and urinary organophosphate metabolite concentrations in toddlerst[END_REF].

Crop acreage in one or several buffers around the home

Five publications studied the influence of crop acreage in one or more buffers around the home. In GIS, a buffer is a zone specified around a point or a line or a polygon area. In all the studies selected, this zone was a circular polygon with a center determined by the residential location. Three out of five studies (60%), considered to be of very good or good quality, found a positive association between areas of arable crops, vineyards and/or orchards within 500 to 1000 meters from the home and higher levels of pesticides in house dust [START_REF] Béranger | Environmental determinants of the indoor exposure to agricultural pesticides, in Testicular germ cell tumors : assessing the impact of occupational and environmental exposure to pesticides[END_REF][START_REF] Glorennec | Determinants of children's exposure to pyrethroid insecticides in western France[END_REF][START_REF] Ward | Proximity to crops and residential to agricultural herbicides in Iowa[END_REF]. Among these studies, one also found an association between the distance to the closest crop field and herbicide exposure; however, distance alone accounted for less of the variance than crop acreage [START_REF] Ward | Proximity to crops and residential to agricultural herbicides in Iowa[END_REF]. One very good quality study found no association between surface area of orchards and residential concentrations of pesticides [START_REF] Plascak | Evaluation of the relationship between residential orchard density and dimethyl organophosphate pesticide residues in house dust[END_REF]. One medium quality study showed no association between the number of fields in the vicinity and urinary DAPs levels [START_REF] Royster | A pilot study of global positioning system/geographical information system measurement of residential proximity to agricultural fields and urinary organophosphate metabolite concentrations in toddlerst[END_REF].

Amounts of pesticides applied around the dwelling

Four analyses conducted in California from the Pesticide Use Report (PUR) dataset explored the effect of the amounts of agricultural pesticides applied near the home on the presence of pesticides in several matrices. In California, all agricultural and non-agricultural pesticide uses are reported to the California Department of Pesticide Regulation. Information about crops, active substances, date and amount of pesticides applied, location of application, are compiled into the PUR data set with a resolution of 1.6 km (one mile) square sections (California Departement of Pesticide Regulation). Three studies found significant associations between pesticide amounts applied around the home (≤ 3,000 meters) and the presence in house dust of chlorpyrifos, iprodione, DCPA [START_REF] Gunier | Determinants of agricultural pesticide concentrations in carpet dust[END_REF][START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF], phosmet, simazine [START_REF] Gunier | Determinants of agricultural pesticide concentrations in carpet dust[END_REF] and manganese (Mn) [START_REF] Gunier | Determinants of manganese levels in house dust samples from the CHAMACOS cohort[END_REF].

One of these studies also searched for the influence of the distance to the nearest field and found an influence of this parameter for DCPA [START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF]. Higher Mn levels in prenatal dentin of shed teeth collected from a population of 7-year-old children were also associated with the use of Mn-based fungicides within 3000 meters of the maternal residence during pregnancy in a medium quality study [START_REF] Gunier | Determinants of manganese in prenatal dentin of shed teeth from CHAMACOS children living in an agricultural community[END_REF].

Other spatial indicators

Two publications found positive associations between proximity of school or child care to fields and the insecticide levels in children's urines and/or house dust [START_REF] Glorennec | Determinants of children's exposure to pyrethroid insecticides in western France[END_REF][START_REF] Tao | Characteristics of neonicotinoid imidacloprid in urine following exposure of humans to orchards in China[END_REF] while two others did not find any association with urinary concentrations of several fungicides or insecticide metabolites [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF][START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF].

The observation by subjects of pesticide spraying from home showed no influence on the measure of pesticides in silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF]. These results were inconsistent with those in another lower quality publication reporting a positive association for pesticide spraying less than 1 km away [START_REF] Takser | Manganese levels during pregnancy and at birth: Relation to environmental factors and smoking in a Southwest Quebec population[END_REF].

Meteorological and topographical determinants of exposure

Season

The effect of season was investigated in seven studies. Four showed a significant increase in the urinary levels of OP metabolites [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]Koch et al., 2002;[START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF] and chlormequat [START_REF] Galea | Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land[END_REF] during spraying season compared with the agricultural low-season, and two studies found higher urinary concentrations of atrazine and chlorpyrifos during winter [START_REF] Chevrier | Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother-child cohort (France)[END_REF][START_REF] Galea | Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land[END_REF]. Variations of carbaryl concentrations in house dust were found in one study: levels were higher in fall than summer, spring, and winter [START_REF] Gunier | Determinants of agricultural pesticide concentrations in carpet dust[END_REF]. One Asian study found no difference in pesticide concentrations in indoor and outdoor dust according to the season considered (warm/cold) (Hung et al., 2018).

Meteorological and topographical determinants of exposure

All studies that included meteorological and topographical parameters were considered to be of very good or good quality.

The influence of daily rainfall prior to sampling yielded contradictory results. In two studies, an increase in precipitation on sampling days or in the month before sampling was associated with lower levels in urine samples and house dust for some OP pesticides [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF][START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF], and with higher levels for other OP pesticides [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]. One publication found no association between precipitations during the last 4 and 8 weeks before sampling and Mn levels in house dust [START_REF] Gunier | Determinants of manganese levels in house dust samples from the CHAMACOS cohort[END_REF].

The effect of temperature was studied in only one publication: increased temperatures on days prior to sampling were only associated with higher DCPA levels [START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF].

The influence of wind direction on pesticide exposure was taken into account through the prevailing wind into the models did not improve the prediction of urinary herbicide concentrations much. Finally, one study showed that the presence of vegetative barriers between fields and homes, determined using GIS, reduced the presence and concentration of pesticides in house dust [START_REF] Béranger | Environmental determinants of the indoor exposure to agricultural pesticides, in Testicular germ cell tumors : assessing the impact of occupational and environmental exposure to pesticides[END_REF].

Sociodemographic determinants of exposure

Age, gender and weight

In children, a study observed that associations between determinants of pesticide exposure and urinary levels of insecticide metabolites differed by age when this parameter was considered as an interaction term in the models [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]. Two studies describe an inverse relationship among older children going to kindergarten or school [START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF][START_REF] Tao | Characteristics of neonicotinoid imidacloprid in urine following exposure of humans to orchards in China[END_REF]. Three studies found no influence of age on exposure [START_REF] Galea | Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land[END_REF]Koch et al., 2002;[START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF]. Results for the effect of gender were also inconsistent: DAP levels in children's urines were higher in boys in one publication (Koch et al., 2002) and in girls in another [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF], while three studies observed no association [START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF][START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF][START_REF] Tao | Characteristics of neonicotinoid imidacloprid in urine following exposure of humans to orchards in China[END_REF].

In adults, one study found higher pesticide exposure in younger adults [START_REF] Dereumeaux | Urinary levels of pyrethroid pesticides and determinants in pregnant French women from the Elfe cohort[END_REF], whereas five found no association [START_REF] Chevrier | Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother-child cohort (France)[END_REF][START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF][START_REF] Galea | Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land[END_REF][START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF][START_REF] Takser | Manganese levels during pregnancy and at birth: Relation to environmental factors and smoking in a Southwest Quebec population[END_REF]. The effect of gender was investigated in a single study which found that ETU concentration in urine samples was not associated with gender [START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF]. A higher body mass index or weight was associated with lower pesticide levels (PYR, OP and herbicides) in one study [START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF] but was not found to be a determinant of pesticide exposure in two publications with a better quality score [START_REF] Dereumeaux | Urinary levels of pyrethroid pesticides and determinants in pregnant French women from the Elfe cohort[END_REF][START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF].

Other sociodemographic parameters

No association was found between pesticide indicators of exposure and the educational level or the household income of subjects [START_REF] Chevrier | Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother-child cohort (France)[END_REF][START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF][START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF][START_REF] Takser | Manganese levels during pregnancy and at birth: Relation to environmental factors and smoking in a Southwest Quebec population[END_REF]. Results were contradictory regarding the house density metrics [START_REF] Béranger | Environmental determinants of the indoor exposure to agricultural pesticides, in Testicular germ cell tumors : assessing the impact of occupational and environmental exposure to pesticides[END_REF][START_REF] Gunier | Determinants of manganese levels in house dust samples from the CHAMACOS cohort[END_REF][START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF].

Hygiene factors

Housekeeping

Three studies with a high level of confidence found that the more frequently the house was cleaned, the lower the presence or concentrations of several pesticides in urine samples [START_REF] Glorennec | Determinants of children's exposure to pyrethroid insecticides in western France[END_REF], house dust [START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF], and silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF]. These associations were not reported for all the pesticides studied, and two publications considered to be of very good or good quality observed no association between the frequency or the quality of house cleaning and pesticide contamination [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF][START_REF] Butler-Dawson | Organophosphorus pesticide residue levels in homes located near orchards[END_REF].

Increased time or frequency of window opening was associated with higher concentrations of certain pesticides only, i.e. p-nitrophenol in urine samples [START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF] and esfenvalerate in silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF]. Two studies found no association at all [START_REF] Butler-Dawson | Organophosphorus pesticide residue levels in homes located near orchards[END_REF][START_REF] Siriwat | Exposure of chlorpyrifos in toddlers living in an agricultural area in Sakon Nakhon province, North-East Thailand[END_REF]. Similarly, results regarding the influence of a ventilation system on OP pesticide exposure were inconsistent [START_REF] Butler-Dawson | Organophosphorus pesticide residue levels in homes located near orchards[END_REF][START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF].

Other hygiene factors

Personal hygiene practices were studied in a single medium quality publication where frequent hand washing was associated with lower concentrations of chlorpyrifos residue on feet [START_REF] Siriwat | Exposure of chlorpyrifos in toddlers living in an agricultural area in Sakon Nakhon province, North-East Thailand[END_REF].

Three high quality studies found no influence of the presence of pets in the dwelling on urinary concentrations of DAPs [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF] or on the pesticides' presence or concentrations in indoor dust [START_REF] Béranger | Environmental determinants of the indoor exposure to agricultural pesticides, in Testicular germ cell tumors : assessing the impact of occupational and environmental exposure to pesticides[END_REF] or in silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF].

Finally, the presence of carpeting in homes was associated only with the presence of DCPA in silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF]; this parameter showed no influence on the urinary concentrations of DAPs [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]. The presence of doormats was associated with a lower presence of permethrin and piperonyl butoxide, a synergist compound of pesticide products, in silicone wristbands [START_REF] Harley | Determinants of pesticide concentrations in silicone wristbands worn by Latina adolescent girls in a California farmworker community: The COSECHA youth participatory action study[END_REF] and with lower Mn in house dust [START_REF] Gunier | Determinants of manganese levels in house dust samples from the CHAMACOS cohort[END_REF].

Activities of the occupants

Activities and behaviors of persons residing near agricultural fields were not extensively investigated. In one study, pesticide exposure was not associated with child behavior indicators [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]. Duration of play or sitting on the floor was associated with lower concentrations of chlorpyrifos on hands and feet in one study [START_REF] Siriwat | Exposure of chlorpyrifos in toddlers living in an agricultural area in Sakon Nakhon province, North-East Thailand[END_REF].

Time spent inside and outside a building located near agricultural activities was not associated with pesticide levels in urine samples [START_REF] Galea | Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land[END_REF][START_REF] Sammartano | Levels of Ethylenethiourea (u-ETU) in a Population Living Near Vineyards[END_REF], except for one study of a child population [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]. Four studies found no influence of smoking on pesticide levels in urine samples [START_REF] Chevrier | Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother-child cohort (France)[END_REF][START_REF] Fernandez | Biomonitoring of non-persistent pesticides in urine from lactating mothers: Exposure and risk assessment[END_REF][START_REF] Galea | Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land[END_REF][START_REF] Takser | Manganese levels during pregnancy and at birth: Relation to environmental factors and smoking in a Southwest Quebec population[END_REF], while one observed an association between the concentrations of pyrethroids in pregnant women's urines and their smoking habits [START_REF] Dereumeaux | Urinary levels of pyrethroid pesticides and determinants in pregnant French women from the Elfe cohort[END_REF]. One publication found lower Mn levels in the deciduous teeth of children whose mothers smoked during pregnancy [START_REF] Gunier | Determinants of manganese in prenatal dentin of shed teeth from CHAMACOS children living in an agricultural community[END_REF].

Smoking habits could lead to pesticide exposure, not only through the consumption of pesticide-treated tobacco leaves [START_REF] Cai | Determination of pyrethroid residues in tobacco and cigarette smoke by capillary gas chromatography[END_REF], but also because smoking is likely to increase hand-to-mouth carrying [START_REF] Dereumeaux | Urinary levels of pyrethroid pesticides and determinants in pregnant French women from the Elfe cohort[END_REF]. None of the studies incorporating smoking habits was considered to be of good quality.

Discussion

The main objective of this systematic review was to identify the non-dietary determinants of exposure to agricultural pesticides in populations living near treated fields. Twenty-seven relevant studies were analyzed and provided consistent evidence about the role of the drift pathway in the overall pesticide exposure of people residing in agricultural areas, which is expected to be linked with atmospheric dispersion at the local range. Spatial indicators, reflecting agricultural activities, were the determinants studied most frequently and were found to be associated to pesticide levels or presence in urine samples or house dust in a majority of studies, including high quality publications. Indicators of exposure were more frequently associated with the amounts of pesticides applied in the vicinity than other metrics such as crop acreage around the home or residential proximity to fields. Studies that explored several indicators confirmed that the amount of pesticide used locally better explained the level of exposure observed [START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF][START_REF] Ward | Proximity to crops and residential to agricultural herbicides in Iowa[END_REF]. The studies reviewed here also found frequently increased urinary levels of pesticides during the treatment season compared with the non-spraying period, which is an additional argument in favor of the contribution of the agricultural drift pathway in exposure. These findings are in line with those from previous reviews conducted in other populations (farmworkers and their families, or other agricultural communities) which also identified many studies that concluded that people living near agricultural lands were more exposed to pesticides than people living elsewhere [START_REF] Dereumeaux | Pesticide exposures for residents living close to agricultural lands: A review[END_REF][START_REF] Deziel | Relative contributions of agricultural drift, paraoccupational, and residential use exposure pathways to house dust pesticide concentrations: Meta-regression of published data[END_REF][START_REF] Deziel | A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas[END_REF].

However, although these results may support the importance of the agricultural drift pathway overall, they remain inconsistent from one study to another, even for the same family of pesticides. The values of the spatial indicators associated with a significant effect on pesticide exposure varied greatly between publications. They ranged between 30 and 750 meters for the residential distance from the fields. The indicators based on crop surfaces and amounts of pesticides applied, associated with exposure, had buffer radii ranging between 500 and 3,000 meters. The disparities observed could be due to the large variations in study protocols. Sampling strategies were indeed very diverse regarding the matrix considered, the choice of exposure marker, the population followed, the temporality of measurements, and the analysis techniques. Moreover, in the scientific literature, several parameters have been identified as influencing the emission and dispersion of agricultural pesticides in ambient air, including the physico-chemical characteristics of compounds, the type of vegetation treated, the spraying equipment used [START_REF] Focus | Pesticides in Air: Considerations for Exposure Assessment[END_REF]. The values of these parameters were highly variable in the reviewed studies and could partially explain the differences observed in the results. Meteorological conditions during and after spraying also play a role in the emission and transport of pesticides [START_REF] Focus | Pesticides in Air: Considerations for Exposure Assessment[END_REF]. High temperatures, or elevated wind velocity generally enhance the volatilization rate from plant and soils and consequently increase pesticide losses into the atmosphere [START_REF] Bedos | Mass transfer of pesticides into the atmosphere by volatilization from soils and plants: overview[END_REF][START_REF] Focus | Pesticides in Air: Considerations for Exposure Assessment[END_REF]. Some of the studies we reviewed showed an influence of several of these variables on pesticide levels in urine samples or house dust but the results could sometimes be contradictory depending on the substance considered [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF][START_REF] Harnly | Pesticides in dust from homes in an systematic reviews and meta-analyses: The PRISMA statement[END_REF]. Controlling some of the parameters linked to pesticides and their conditions of application could be a relevant way to reduce exposure among people living near treated fields and prevent adverse health effects.

Sammartano et al. ( 2019) observed a significant reduction of u-ETU in adults and children after local stakeholders banned the use of mancozeb on vineyards. Other mitigation measures could also reduce residents' pesticide exposure, such as applying pesticides under favorable weather conditions, using drift reduction techniques or installing windbreaks at the edges of fields. The delimitation of no-spray buffer zones could also be proposed [START_REF] Focus | Landscape And Mitigation Factors In Aquatic Risk Assessment. Volume 1. Extended 35 Summary and Recommendations[END_REF]. As argued by [START_REF] Gunier | Will buffer zones around schools in agricultural areas be adequate to protect children from the potential adverse effects of pesticide exposure?[END_REF], determining a safe distance or buffer should be based on the published literature about health effects related to pesticide exposure. However, the authors estimated that the scientific data was still limited to identify the correct distance that would protect public's health and that more research is needed in this field.

Exposure to pesticides also seems to depend on some sociodemographic parameters. In children, half of the studies investigating an effect of age showed that this was a possible determinant of exposure. In toddlers, some authors observed elevated levels of pesticides at 12 and 24 months compared to 6-month-old children and they related these to changes in behaviors and diet [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF]. After three years old, publications found an inverse relation between age and insecticide levels in urine samples. The authors argued that the higher concentrations found in younger children could be due to their smaller body size or their immature metabolism which might lead to longer pesticide half-lives in their body, but could also be related to specific behaviors (e.g., mouthing activity, hygiene habits, time spent on the floor) [START_REF] Munoz-Quezada | Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile[END_REF][START_REF] Tao | Characteristics of neonicotinoid imidacloprid in urine following exposure of humans to orchards in China[END_REF]. Some studies confirmed a possible effect of children's behaviors on their exposure to OP pesticides. Sitting on the floor, playing periods and time spent in child care have been associated with urinary levels of DAPs [START_REF] Bradman | Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community[END_REF][START_REF] Siriwat | Exposure of chlorpyrifos in toddlers living in an agricultural area in Sakon Nakhon province, North-East Thailand[END_REF]. The effect of gender on the level of pesticide exposure remains inconsistent since two studies described as being of good or medium quality found opposite results, whereas the rest of the publications did not find any association. One article speculates that some differences in behavioral and/or activity patterns between boys and girls could cause exposure disparities. Boys may be more exposed because of a higher frequency of hand-to-mouth activity or strenuous physical activities (Koch et al., 2002). Finally, the effect of parental socioeconomic status has not been extensively studied. Parental education was investigated in a single publication and was not related to children's pesticide exposure. No conclusion can be drawn from this single study. The relationships between socioeconomic status and chemical levels of exposure in biological matrices can be very complex and give heterogeneous results according to the pollutant considered; higher exposures are not always found in poor and minority communities [START_REF] Morrens | Social distribution of internal exposure to environmental pollution in Flemish adolescents[END_REF][START_REF] Tyrrell | Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001-2010[END_REF]. In the case of pesticide exposure driven by the agricultural drift pathway, it would be difficult to hypothesize the effect of socioeconomic status on exposure and this question needs to be explored in future studies.

In adults, the results extracted from the selected studies do not favor an effect of age and gender on pesticide exposure, but information is still limited and comes from a study considered to be of lower quality. However, some biological factors could cause physical and metabolic disparities between men and women. Some behavioral differences could also lead to differentiate results according to gender. Women spend in general more time in a residential setting than men [START_REF] Schweizer | Indoor timemicroenvironment-activity patterns in seven regions of Europe[END_REF] and could be more exposed to pesticides by the agricultural drift pathway. Effects of behaviors and activities have not been investigated in the reviewed studies, except for smoking habits, which showed poor evidence for predicting the levels of pesticides in urine samples. Nor is it possible to distinguish the contribution of hand-to-mouth contact that could be linked to contamination of homes located near agricultural fields by the consumption of pesticide-treated tobacco leaves.

The effects of age, gender, socioeconomic status and behaviors have been only rarely explored in adults and children and the trends observed need to be confirmed in further studies. Indeed, they are not usually investigated as determinants for exposure but are frequently used as a priori variables of adjustments in statistical modelling. By improving knowledge of these determinants, it could be possible to design targeted effective interventions in order to reduce exposure.

Residential exposure to pesticides could be modified by hygiene factors. Three of the studies we reviewed showed a positive impact of an elevated frequency or quality of house cleaning in the reduction of pesticides for several matrices (house dust, silicone wristbands and urines). These findings are consistent with those obtained in the environment of farmworkers and their families [START_REF] Deziel | A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas[END_REF][START_REF] Quandt | Workplace, household, and personal predictors of pesticide exposure for farmworkers[END_REF]. Improving cleaning practices could be an effective leverage for reducing pesticide exposure. However, previous interventions promoting hygiene practices in farmworkers' homes gave mixed results [START_REF] Griffith | Application of improved approach to evaluate a community intervention to reduce exposure of young children living in farmworker households to organophosphate pesticides[END_REF][START_REF] Salvatore | Home-based community health worker intervention to reduce pesticide exposures to farmworkers' children: A randomized-controlled trial[END_REF][START_REF] Thompson | Para niños saludables: A community intervention trial to reduce organophosphate pesticide exposure in children of farmworkers[END_REF]. Two publications showing a positive effect of interventions on reducing pesticide exposure provided limited information about which behaviors or combination of behaviors and what level of compliance would most effectively prevent residential pesticide contamination [START_REF] Griffith | Application of improved approach to evaluate a community intervention to reduce exposure of young children living in farmworker households to organophosphate pesticides[END_REF][START_REF] Salvatore | Home-based community health worker intervention to reduce pesticide exposures to farmworkers' children: A randomized-controlled trial[END_REF]. Other hygiene factors were less explored: personal hygiene in children, and presence of a doormat were associated with lower indicators of exposure, whereas open windows seem related to higher exposure values. The presence of pets in the house and carpets on the floor were not associated with the pesticides measured in the environment. Hygiene factors should be investigated further in order to identify potential leverage to reduce residents' exposure to agricultural pesticides.

To our knowledge, this study is the first qualitative systematic review exploring the state of knowledge about non-dietary determinants of exposure conducted in a non-specific population of residents. It can be compared with previous work carried out in other populations (children, women living in agricultural areas). This work has been reported using the PRISMA Guidelines. In addition, we created a subject-specific evaluation grid to interpret the biases of the studies from the perspective of our research question. However, there are limitations to this review. Few of the publications we selected were specifically designed to answer our research question. The populations selected in the reviewed publications could be very heterogeneous and frequently included farmworkers or their families. The contribution of the agricultural drift pathway may therefore be difficult to distinguish from other routes, such as the take-home or the residential exposure pathways. Indeed, some previous studies have shown that these routes could contribute substantially to overall exposure [START_REF] Deziel | A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas[END_REF]Hyland and Laribi, 2017;[START_REF] Quandt | Workplace, household, and personal predictors of pesticide exposure for farmworkers[END_REF]. Although the selected studies performed adjustments to the statistical modeling, some potential confounding factors could remain. Finally, the review we conducted was perhaps not totally exhaustive. Using a definition of "residents" based on spatial indicators, we may have wrongly considered some people living near treated fields as "general population". Studies conducted by scientific institutions as part of environmental health policy are not usually published in the databases we consulted, and could probably not be identified despite consulting the grey literature. We might also have missed studies published in other languages than English, French or Spanish.

The results provided by this review are still too limited to comprehensively identify the determinants contributing substantially to the pesticide exposure linked to the drift pathway and they should be interpreted with caution. Future studies are needed to confirm the trends observed and acquire data on the poorly or insufficiently studied determinants. These studies should be specially designed to assess drift exposure. In their review published in 2020, [START_REF] Dereumeaux | Pesticide exposures for residents living close to agricultural lands: A review[END_REF] developed a list of study characteristics to accurately measure spray-drift exposure in residents, and this could be used as a framework reference. It is indeed essential to improve knowledge of the determinants of exposure in order to design 20 appropriate interventions and thus reduce exposure and prevent health effects related to agricultural pesticides in populations at risk.

Conclusion

A majority of the studies we selected in our systematic review provided robust evidence for the contribution of the agricultural drift pathway in overall pesticide exposure in people living near fields. Several spatial indicators reflecting pesticide use around residences have been associated with elevated concentrations of agricultural pesticides in both biological and environmental matrices in residents. Other potential determinants of exposure such as sociodemographic characteristics, behaviors and hygiene practices have been less extensively studied. It is hoped that our knowledge of determinants of pesticide exposure could be improved from future studies specifically designed to explore this research question.

Improving knowledge of the determinant of pesticide exposure due to the agricultural drift Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., Altman, D., Antes, G., Atkins, D., Barbour, V., Barrowman, N., Berlin, J.A., Clark, J., Clarke, M., Cook, D., D'Amico, R., Deeks, J.J., Devereaux, P.J., Dickersin, K., Egger, M., Ernst, E., Gøtzsche, P.C., Grimshaw, J., Guyatt, G., Higgins, J., Ioannidis, J.P.A., Kleijnen, J., Lang, T., Magrini, N.

  calculation of spatial indicators. Chevrier et al. (2014) developed a wind-weighted score for residential proximity to corn, while Béranger et al. (2014) investigated the influence of the crop acreage around the home for different buffer sizes, wind-weighted. Both studies found a positive association between these indicators and pesticide levels in biological and environmental matrices. Béranger et al. (2014) et al. found that the use of a wind-weighted indicator provided additional information compared with acreage alone and significantly improved the models used, whereas Chevrier et al. (2014) concluded that adding the

Figure

  Figure 1 -Flow Diagram of study selection

  pathway is essential in order to design efficient and proportionate interventions and thus prevent the onset of adverse health effects in populations living near treated fields.

	agricultural	area.	Environ.	Sci.	Technol.	43,	8767-8774.
	https://doi.org/10.1021/es9020958.
	Hogenkamp, A., Vaal, M., Heederik, D., 2004. Pesticide exposure in dwellings near bulb
	growing fields in the Netherlands: An explorative study. Ann. Agric. Environ. Med. 11,
	149-153.
	Hung, C.-C., Huang, F.-J., Yang, Y.-Q., Hsieh, C.-J., Tseng, C.-C., Yiin, L.-M., 2018.
	Pesticides in indoor and outdoor residential dust: a pilot study in a rural county of
	Taiwan. Environ. Sci. Pollut. Res. 25, 23349-23356. https://doi.org/10.1007/s11356-
	018-2413-4.
	Hyland, C., Laribi, O., 2017. Review of take-home pesticide exposure pathway in children
	living	in	agricultural	areas.	Environ.	Res.	156,	559-570.
	health		effects.	Sci.	Total	Environ.	575,	525-535.
	https://doi.org/10.1016/j.scitotenv.2016.09.009.
	Koch, D., Lu, C., Fisker-Andersen, J., Jolley, L., Fenske, R.A., 2002. Temporal association of
	children's pesticide exposure and agricultural spraying: Report of a longitudinal
	biological		monitoring	study.	Environ.	Health	Perspect.	110,	829-833.
	https://doi.org/10.1289/ehp.02110829.
	Mendeley.	Reference	Management	Software	&	Researcher	Network.
	https://www.mendeley.com/ (accessed 7.31.19).

https://doi.org/10.1016/j.envres.2017.04.017. Kim, K.-H., Kabir, E., Jahan, S.A., 2017. Exposure to pesticides and the associated human

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Spatial indicators


I Mandoul

F Boulay-Coletta

Nicolas Curros-Doyon

P Molinari

Ingrid Taourel

Millet
email: millet@chu-montpellier.fr.

B Monsonis

M Zins

C Orliac

MD Ingrid Millet

Retrospective case-control study to predict a potential underlying appendiceal tumor in an acute appendicitis context based on a CT

Keywords: positive likelihood ratio NLR: negative likelihood ratio SE: sensitivity SP: specificity LAMN: low appendiceal mucinous tumor multidetector computed tomography, appendicitis, appendiceal neoplasms

Introduction

The appendiceal tumor incidence on appendectomy specimens from patients presenting with acute appendicitis ranges from 0.9% to 1.7% [START_REF] Connor | Appendiceal tumors: retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies[END_REF][START_REF] Marudanayagam | Review of the pathological results of 2660 appendicectomy specimens[END_REF]. Acute appendicitis is the initial clinical presentation of primary neoplasms of the appendix in about 40-50% of cases, generally due to occlusion of the appendiceal lumen by the tumor [START_REF] Connor | Appendiceal tumors: retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies[END_REF][START_REF] Pickhardt | Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature[END_REF].

Appendiceal tumors can be benign or malignant (4) and classified in two main groups: epithelial and neuroendocrine tumors (NET). A recent review of the literature (5) revealed that the neoplasm rate may range from 10% to 29% in patients presenting with complicated appendicitis (phlegmon or abscess). The ideal treatment approach in that context is still controversial. There are, for instance, proposals for indirect non-surgical treatment (percutaneous drainage and antibiotics). When conservative treatments have a positive initial outcome, there is often a dilemma as to whether or not to perform an interval appendectomy or maintain a nonoperative approach. Yet not subjecting the appendix to histological analysis is the main disadvantage of the latter. Mällinen et al. [START_REF] Mällinen | Risk of Appendiceal Neoplasm in Periappendicular Abscess in Patients Treated With Interval Appendectomy vs Follow-up With Magnetic Resonance Imaging: 1-Year Outcomes of the Peri-Appendicitis Acuta Randomized Clinical Trial[END_REF] argued in favor of routine interval appendectomy in this setting given the high rate of underlying neoplasm (20%) they found in their randomized trial comparing interval appendectomy and MRI follow up. Nonoperative management is also a therapeutic alternative to surgery when the patient presents with uncomplicated appendicitis [START_REF] Salminen | Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial[END_REF]. It is thus of paramount importance to forewarn the surgeon when there is suspicion of an underlying tumor so as to accurately target the treatment [START_REF] Mccutcheon | Long-Term Outcomes of Patients with Non-Surgically Managed Uncomplicated Appendicitis[END_REF]. A major virtue of preoperative detection of an appendiceal tumor is that-instead of having to manage the situation under emergency conditions-it provides an opportunity to schedule surgery during working hours when a trained oncological surgeon may be available.

Forewarning the surgeon is especially crucial in such cases to avoid peroperative perforation of the appendix, which could affect the prognosis by increasing the risk of recurrence. The quality of the primary excision (including mesoappendix resection) and the absence of mucin in the abdominal cavity at the end of the surgery are the main prognostic factors (4, [START_REF] Clift | Goblet cell carcinomas of the appendix: rare but aggressive neoplasms with challenging management[END_REF][START_REF] Shaib | Appendiceal Mucinous Neoplasms: Diagnosis and Management[END_REF][START_REF] Bartlett | Mucinous appendiceal neoplasms: classification, imaging, and HIPEC[END_REF].

Preoperative diagnosis of an appendicular tumor in an appendicitis context is quite challenging for both the surgeon and radiologist [START_REF] Bhangu | Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management[END_REF][START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF]. In the literature, there is no case -control study assessing predictive values of CT features for diagnosing potential underlying appendiceal tumor.

Our study was thus focused on assessing exhaustive CT signs to be able to discriminate an appendiceal tumor versus a non-tumoral appendix in an acute appendicitis context. We aimed to build a predictive diagnostic scoring system to be able to forewarn surgeons on the likelihood of an underlying tumor.

II. Materials and methods

A. Patient selection

This retrospective bicentric study was approved, and informed consent was waived, by our institutional review board (IRB) (N°2018_IRB-MTP_04-07).

We "perforation", "perforated", "gangrenous", "abscess" or "phlegmon".

B. Imaging techniques

CT scans were performed at the two centers using a 64-detector row machine (Lightspeed VCT 64; General Electric Medical Systems, Milwaukee, Wis) with 1.375 pitch, 0.7 ms tube rotation time, 120 kVp and dose-modulation software to determine the milliampere-second value on the basis of body weight (noise index, 20; 130-700 mA).

Images were acquired from the dome of the liver through the pubis with inframillimetric slices (0.675 mm) to enable multiplanar reconstruction. CT images were also reconstructed at 3-mm section thickness in the axial, coronal and sagittal planes.

All CT scans were performed with intravenous iodinated contrast agent, i.e.

Iobitridol (Xenetix 300, Guerbet, Aulnay-sous Bois, France), Iomeprol (Iomeron 300, Bracco Imaging, France), or Iopromide (Ultravist 300, Bayer Healthcare, Lerverkusen, Germany) administered with a power injector at 2-3 mL/s during the portal venous phase (70-80 s delay). Unenhanced CTs were also available for 60 patients (29%). Few CT scans were acquired with colorectal enema (n=11 (5%)). No oral contrast was given.

C. Imaging review

CTs were reviewed independently by two blinded readers who are senior radiologists specialized in emergency radiology (CO, MD with 7 years of experience and PT, MD with 30 years of experience) on a dedicated picture archiving and communication system unit (Centricity PACS, General Electric Healthcare). Multiplanar reconstructions were available in the axial, coronal and sagittal planes. We provided guidelines for the readers reviewing the CT scans to help them understand all of the radiologic signs based on scans from five patients who were not included in the final study. The readers were blinded to the surgical and pathological outcomes but they were aware that all CT examinations involved patients with appendicitis. The readers were finally asked to answer the question: Do you think there could be an underlying tumor? They were asked to grade their answer from 1 to 5 (1: no, there's no tumor, 2: it is unlikely, 3: I don't know, 4: it is likely, and 5: yes, there's an underlying tumor).

D. Statistical analysis

Interobserver agreement for qualitative CT findings was determined with the κ statistic and classified as follows: κ=0-0. We used the bootstrap method to internally validate the score by sampling with replacement for 1,000 iterations. We compared the obtained diagnostic score AUC with that of each of the readers' subjective scores using the DeLong test.

III. Results

A.

Population

A total of 208 patients (94 females (45%), 114 males (55%)) were included in the study.

The mean age of the population was 51 years (SD=21 y) with a median of 52 years (range = 18-94) and an interquartile range (IQR) = [34-66].

The tumor group (n=52) included 10 adenocarcinomas (19%), 26 mucinous lesions (50%) (16 LAMN, 4 serrated polyps and 6 non-neoplastic appendiceal mucinous lesions), 13 neuroendocrine tumors (25%), 2 goblet cell tumors (4%) and 1 lymphoma (2%).

Size of the tumor was not reported on all the pathology reports (35 missing data).

Among the available data (N=17, 33%), mean size of adenocarcinomas was 18 mm (N=4), of mucinous lesion (LAMN) was 62 mm (N=3), of neuroendocrine tumors was 10.6 mm (N=9) and of goblet cell tumor was 15 mm (N=1).

The surgical findings are reported in Table 1. Among the 13 patients (25%) in the tumor group that had an additional surgery, 8 (61%) had undergone a right hemicolectomy.

B. Univariate comparison of CT findings between the tumor and non-tumor groups

Comparison and diagnostic performances of the CT signs between the tumor and nontumor groups are reported in Tables 2 and3.

Mural calcification and appendiceal mass were the two leading CT signs that predicted an underlying appendiceal tumor, with PLR=13.5 (95% CI, 3-60) and PLR=18 (95% CI, 5.86-61), respectively. We noted mural calcifications in 7/38 (18%) of our epithelial tumors, accounting for 78% (7/9) of all of the appendiceal tumors with calcifications. The other two patients with mural calcifications had neuroendocrine tumors.

Some CT signs such as malignant peritoneal involvement was not significant (p=1).

Only one subject from the non-tumor group presented with this sign unrelated to acute appendicitis but to a known left colon cancer. In our cohort, no patients from the tumor group showed malignant peritoneal involvement.

Focal asymmetric wall abnormality of the appendix and/or a mass were detected respectively in 9/10 (90%) and 7/10 (70%) of adenocarcinoma cases, 11/26 (42%) and 6/26 (23%) of the mucinous lesions while both signs were found in 5/13 (38%) of the NET cases.

C. Inter-observers' agreement

All the reproducibility results were reported in Table 2.

The concordance between the two blinded readers was excellent for most of the defined CT signs, especially for the six signs included in our diagnostic score, with kappa statistic ranging from 0.75 to 1 (substantial to almost perfect agreement).

IV. Discussion

Our results suggested that CT is a reliable technique for predicting underlying tumors of the appendix in an inflammatory appendiceal setting. We developed an accurate CT diagnostic score that outperformed readers' subjective assessments using six reliable CT findings (mural calcification, mass, focal asymmetric wall abnormality, appendix diameter ≥ 15 mm, fat stranding and appendicolith), while achieving a high diagnostic performance (AUC=0.88) and high positive likelihood ratio (PLR=13.5), implying that it could have a substantial impact with regard to clinical decisions. When the score is greater or equal to 1, the radiologist should warn the surgeon for performing an appropriate resection including especially the whole mesoappendix, and at times a cecotomy or even a hemicolectomy. The option between an open surgery vs. a laparoscopy should be discussed in that context.

This was the first study to our knowledge to assess diagnostic values of CT findings for an appendix tumor in an acute appendicular setting while including a control group. Pickhardt et al. [START_REF] Pickhardt | Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature[END_REF], in a series of 22 appendiceal tumors revealed by appendicitis and screened by preoperative CT, did not include a control group (i.e. inflamed appendix without tumor), which is essential for calculating predictive values. Moreover, their results were not based on predictive statistics but rather on subjective assessments and the CT readers were aware that each patient had a proven appendiceal tumor, thus biasing the CT analysis. Given the low prevalence of appendiceal tumors in an appendicitis context (less than 2% 1,2), the fact that a high number of patients with a neoplastic appendix were included was a major feature of our study. Indeed, there were half as many patients (17 and 22 patients, respectively) in the retrospective cohorts of appendix tumors [START_REF] Pickhardt | Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature[END_REF][START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF] that were explored by CT in an appendicitis setting, and all other studies just dealt with appendectomy cohorts regardless of the clinical symptoms. We opted to include non-neoplastic appendiceal mucinous lesions (i.e. mucoceles) in the tumor group because they must be resected to ensure the absence of underlying serrated polyps or dysplasia [START_REF] Marotta | Predicting Underlying Neoplasms in Appendiceal Mucoceles at CT: Focal Versus Diffuse Luminal Dilatation[END_REF][START_REF] Wang | Appendiceal Mucocele: A Diagnostic Dilemma in Differentiating Malignant From Benign Lesions With CT[END_REF]. Mucoceles result from chronic luminal obstruction and, like other appendicular tumors, require cautious and careful surgical care to avoid per-operative perforation.

Appendiceal neoplasms are a challenge for radiologists as they mimic acute appendicitis, so it is crucial to provide radiologists with simple tools that could reveal the potential presence of a tumor. Non-operative treatment is now the standard care in many acute infectious abdominal pathologies (cholecystitis, perforated diverticulitis, tubo-ovarian abscess, etc.) that were previously treated surgically. This decreased frequency of surgery raises concern since fewer incidental and early-stage cancers will be diagnosed. Although many appendiceal tumors can have an indolent course, there is still a risk of peritoneal dissemination and cancer-related mortality [START_REF] Overman | Improving the AJCC/TNM staging for adenocarcinomas of the appendix: the prognostic impact of histological grade[END_REF]. The tumor location, depth, dimensions and possible invasion of the mesoappendiceal region are key factors for calculating the disease recurrence or progression rate [START_REF] Alexandraki | Appendiceal neuroendocrine neoplasms: diagnosis and management[END_REF]. In our study, 25% of patients in the tumor group required further surgery, including 61% of whom required a right colectomy. It is therefore crucial to forewarn surgeons to enable them to perform a complete mesoappendiceal resection with simultaneous full examination of the small bowel and peritoneal cavity, thus avoiding the need for subsequent exploratory surgery to detect peritoneal tumor extension [START_REF] Pape | ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas[END_REF].

Predicting the occurrence of an adverse event or outcome is a major issue in clinical medicine. Clinical prediction models and associated points-based risk-scoring systems are popular statistical methods for describing the relationship between a multivariable set of patient risk factors and the risk of occurrence of an adverse event, which can facilitate medical decision making. We developed a diagnostic score based on CT findings as CT is the first-line imaging technology used most widely to investigate suspicion of appendicitis in adults. We performed a paired-study on age and gender in order to assess the independent relationship between the CT aspect of appendicitis and the risk of an underlying neoplasm regardless the patient age. Interestingly, we did not corroborate the association between complicated appendicitis and an underlying neoplasm as the complication rate was similar in the two groups (17.3% in the tumor group and 25.6% in the non-tumor group). The positive likelihood ratio of a tumor in a complicated appendicitis setting was very low (0.87) in our study, which is much too low to alone indicate the need for specific care. Age is clearly a confounding factor with regard to the risk of an underlying tumor in a complicated appendicitis context, as pointed out by Mällinen et al. [START_REF] Mällinen | Risk of Appendiceal Neoplasm in Periappendicular Abscess in Patients Treated With Interval Appendectomy vs Follow-up With Magnetic Resonance Imaging: 1-Year Outcomes of the Peri-Appendicitis Acuta Randomized Clinical Trial[END_REF] and Loftus et al. [START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF]. The worrisome prevalence of an underlying tumor found in previous study conducted to assess the risk of a hidden malignant tumor in a complicated appendicitis setting was probably due to the higher rate of complicated appendicitis in older patients, which prompted the authors to include a high number of advanced age patients (5). They thus found a very high tumor rate, but regardless the age, a complicated appendicitis has an equal chance of being tumorous or not. Hence it is crucial to look for other CT findings predictive of a neoplasm.

Among the significant CT findings with regard to our diagnostic score, we corroborated the relevance of the 15 mm diameter cut-off for suspicion of an underlying appendiceal tumor, as previously reported by Pickhardt et al. [START_REF] Pickhardt | Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature[END_REF]. One point was assigned to this CT finding with our diagnostic score, that is sufficient to consider an underlying appendix neoplasm but if this sign is associated with an appendicolith then the total score is no longer suspicious for an underlying neoplasm. The PLR of an underlying tumor when there is an appendicolith was shown to be at 0.33 in our study, indicating that a patient with an appendicolith was approximately 3-fold less likely to have an appendiceal neoplasm than a patient without an appendicolith. An appendicolith causes appendiceal obstruction, leading to mucus stasis, appendix distension and infection whereas when no appendicolith is present a tumor is more likely to be the cause of the lumen obstruction leading to appendicitis. Furthermore, Marotta et al. [START_REF] Marotta | Predicting Underlying Neoplasms in Appendiceal Mucoceles at CT: Focal Versus Diffuse Luminal Dilatation[END_REF] in their retrospective study including only mucoceles but not in an inflammatory context, showed that distal dilatation of the appendix with a normal segment of the appendix between the base of the appendix and the beginning of the mucocele, without appendicolith, was more related to an underlying neoplasia (87% at histopathology) than to non-neoplastic mucocele.

Unsurprisingly, mural calcifications were closely associated with an appendix neoplasm (OR=47.6). Mural calcifications arise from fibrous reorganization or tumoral necrosis. Mural calcifications are not specific to any kinds of appendicular tumor, although they seem to be more frequent in epithelial tumors (7/9 in our series), especially in well-differentiating mucinous neoplasms (LAMN). Sagebiel et al. [START_REF] Sagebiel | Utility of Appendiceal Calcifications Detected on Computed Tomography as a Predictor for an Underlying Appendiceal Epithelial Neoplasm[END_REF] showed that 31.9% of their patients with epithelial tumors had wall calcifications, with the majority being peripheral eggshell calcifications, i.e. a pattern that differs from coarse calcifications that can potentially be mistaken for a luminal stercolith.

Furthermore, we found that an appendicular mass was associated with an underlying tumor with an OR=7.1, which was consistent with the findings of previous study [START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF], as well as with a focal asymmetric wall abnormality (OR = 4.86). In our study, 70% of adenocarcinomas displayed as a mass and 90% of them had a focal asymmetric wall abnormality, suggesting that these patterns are more likely to be associated with malignant epithelial tumors. Moreover, adenocarcinomas in other intestinal locations display similar features and the CT diagnosis is based on the presence of irregular asymmetric bowel wall thickening or masses with exoluminal growth.

Our study had several limitations. The first one was related to its retrospective design, which can bias diagnostic performance assessment as retrospective reads have been shown to be more accurate than prospective reads [START_REF] Sheedy | CT of small-bowel ischemia associated with obstruction in emergency department patients: diagnostic performance evaluation[END_REF]. We performed a retrospective study because of the low appendiceal neoplasm prevalence, which precludes prospective inclusion. The tumor prevalence (4.4%) in our whole eligible population was slightly higher than in other series (1-2,26), probably due to the exclusion of pediatric patients, consequently boosting the appendiceal tumor rate. This latter may also have been biased by the inclusion of patients explored by CT, potentially more severe than those explored by ultrasound. In our practice, ultrasound remains the primary imaging tool in cases of suspected appendicitis for young non-obese patients with low biologic inflammatory signs and for pregnant women. For the other cases or when there are atypical findings or signs of complicated appendicitis using ultrasound, we usually perform directly an abdominal and pelvic CT. The retrospective design allowed us to increase the number of patients in the tumor group and thus the statistical power, but at the cost of a large number of missing data especially regarding the CT images availability (more than 50% of the eligible patients had not undergone a preoperative CT and were thus excluded). Nevertheless, patients in our tumor group had a median age of 52 years (IQR=34-66), which was in line with that reported in a similar published study where a median age of 53 years (IQR=35-61) was reported [START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF].

Second, some groups of appendicular tumors were underrepresented. For example, we included only one lymphoma and two goblet cell tumors. However, the proportion of each tumor type was similar to the proportions reported in previous studies [START_REF] Pickhardt | Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature[END_REF][START_REF] Dupre | Diverticular disease of the vermiform appendix: a diagnostic clue to underlying appendiceal neoplasm[END_REF], with a majority of epithelial and neuroendocrine tumors, along with a few other types.

Third, the tumor prevalence was artificially raised to 25% in our study cohort as we matched three control subjects to one tumorous appendix. We therefore decided to report likelihood ratios and not predictive values as diagnostic performance measures are independent of the disease prevalence.

Finally, our diagnostic performance estimates may have been biased since we used the same data to come up with the thresholds. The AUC was also estimated from the same data used to develop the model, and was likely an optimistic estimate. These findings thus need to be validated in future studies on other external samples.

V. Conclusion

We developed a reliable scoring system based on CT findings, which was highly predictive of an underlying appendiceal neoplasm in an appendicitis context. The surgeon should be warned as to the positive likelihood of an underlying appendiceal tumor when the CT score is equal to or greater than 1, thus providing an opportunity for appropriate care. Final histology corroborated the absence of an appendiceal tumor.

  Interpretation discrepancies were resolved by consensus by a senior emergency radiology specialist (IM, MD with 12 years of experience) for the purpose of the statistical analyses. The two readers assessed the CT images for the following signs: (a) appendix maximal transversal diameter; (b) periappendiceal fat stranding; (c) appendicolith; (d) appendix mural curvilinear calcification (15); (e) appendix content (air, liquid or mixed); (f) ileocaecal lymph nodes with a short axis diameter > 8 mm; (g) focal asymmetricalwall abnormality involving either a focal wall irregularity or a focal hyper-enhancement (Fig.2); (h) appendix mass characterized by an enlargement of the appendix with complete loss of its normal tubular shape (16) (Fig.2); (i) appendix diverticulum viewed as a rounded, para-appendicular outpouching; (j) local complications such as perforation (free intraperitoneal gas or loss of appendix wall enhancement) or abscess (Fig.2); (k) wall thickening of the cecum and/or the ileum with a wall thickness > 3 mm; (l) CT signs of peritonitis reflected by a thickened and enhanced peritoneal layer; (m) intraperitoneal free fluid; or (n) malignant peritoneal involvement reflected by enhanced nodes suggesting peritoneal carcinomatosis.

  Statistical significance for all tests was set at p<0.05. SAS version 9.4.4 software (SAS Institute, Cary, NC, USA) and R version 3.4.4 software (R Foundation for Statistical Computing, Vienna, Austria, 2018) were used to perform the statistical analyses.

Figure 5 :

 5 Figure 5: A perforated appendicitis in a 56-year-old patient with a CT diagnostic score < 1, thus ruling out an underlying neoplasm. Axial oblique plane and portal phase. The appendix (arrow) has a diameter greater than 15 mm (arrowhead) counting for 1 point and a peripheral fat stranding counting for -1 point, thus the total score is equal to zero.

Fig 1 :

 1 Fig 1: Flow chart of patients included in the tumor group (n=52 patients)

  Disagreements for categorical variables between the two readers were resolved by consensus. Consensual data were then used for the final statistical analysis.

	Reproducibility between continuous variables was assessed using the intra-class
	correlation coefficient. Average of the measurements between the two readers was
	used for final statistical analysis.
	We compared CT signs between patients with an appendiceal tumor (tumor group)
	and those without tumor (non-tumor group). Pearson Chi square or Fisher tests were
	used for comparison of categorical variables, and Student t test or Wilcoxon rank-sum
	test for comparison of continuous variables, as appropriate. The diagnostic
	performances (sensitivity, specificity, likelihood ratio) of each CT finding were also

2, slight agreement; κ=0.21-0.4, fair agreement; κ=0.41-0.6, moderate agreement; κ=0.61-0.8, substantial agreement; and κ=0.81-1, almost perfect agreement

[START_REF] Landis | The measurement of observer agreement for categorical data[END_REF]

. calculated. Cutoffs for significant continuous variables were identified by plotting receiver operating characteristic (ROC) curves and computing the Youden index to ensure relevance for input in a multivariate model.

All CT findings with a univariate p value ≤ 0.2 were input in a multivariate logistic regression model to gauge their independent association with an appendiceal tumor. A stepwise procedure was used to select the final model. We established a diagnostic score using the Beta/Sullivan technique to assign a rounded up numerical value to each of the significant CT findings included in the final prediction model, in relation to their β parameter (logistic regression estimates)

[START_REF] Sullivan | Presentation of multivariate data for clinical use: The Framingham Study risk score functions[END_REF][START_REF] Mehta | Regression coefficient-based scoring system should be used to assign weights to the risk index[END_REF]

. Then, for each patient, we were able to calculate a score corresponding to the sum of the number assigned to each variable present in the model. A ROC curve was plotted to estimate the best cut-off of this model for differentiating tumor group from non-tumor group, and its diagnostic performances.

Table 1 :

 1

	Tumor group	Non tumor group
	N = 52 (%)	N = 156 (%)

* A complicated appendicitis includes perforation of the appendix, empyema or abscess formation.

The authors declare that they have no conflicts of interest.

IRB statement:

The institutional review board of Lapeyronie University Hospital (Montpellier, France) approved this bicentric retrospective study.

The mean appendix diameter of the 208 patients was 14.3 mm (±7.8). In the tumor group (n=52), the median appendix diameter was 15 mm (range = 7 -63) with an interquartile range (IQR) = [START_REF] Bartlett | Mucinous appendiceal neoplasms: classification, imaging, and HIPEC[END_REF][START_REF] Bhangu | Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management[END_REF][START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF][START_REF] Schulz | Case-control studies: research in reverse[END_REF][START_REF] Sagebiel | Utility of Appendiceal Calcifications Detected on Computed Tomography as a Predictor for an Underlying Appendiceal Epithelial Neoplasm[END_REF][START_REF] Lee | Goblet cell carcinoid neoplasm of the appendix: clinical and CT features[END_REF][START_REF] Landis | The measurement of observer agreement for categorical data[END_REF][START_REF] Sullivan | Presentation of multivariate data for clinical use: The Framingham Study risk score functions[END_REF][START_REF] Mehta | Regression coefficient-based scoring system should be used to assign weights to the risk index[END_REF][START_REF] Marotta | Predicting Underlying Neoplasms in Appendiceal Mucoceles at CT: Focal Versus Diffuse Luminal Dilatation[END_REF][START_REF] Wang | Appendiceal Mucocele: A Diagnostic Dilemma in Differentiating Malignant From Benign Lesions With CT[END_REF][START_REF] Overman | Improving the AJCC/TNM staging for adenocarcinomas of the appendix: the prognostic impact of histological grade[END_REF][START_REF] Alexandraki | Appendiceal neuroendocrine neoplasms: diagnosis and management[END_REF][START_REF] Pape | ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas[END_REF][START_REF] Sheedy | CT of small-bowel ischemia associated with obstruction in emergency department patients: diagnostic performance evaluation[END_REF][START_REF] Lietzén | Appendiceal neoplasm risk associated with complicated acute appendicitis-a population based study[END_REF][START_REF] Dupre | Diverticular disease of the vermiform appendix: a diagnostic clue to underlying appendiceal neoplasm[END_REF], whereas in the non-tumor group (n=156), the median appendix diameter was 12 mm (range = 6 -24) with an IQR = [START_REF] Shaib | Appendiceal Mucinous Neoplasms: Diagnosis and Management[END_REF][START_REF] Bartlett | Mucinous appendiceal neoplasms: classification, imaging, and HIPEC[END_REF][START_REF] Bhangu | Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management[END_REF][START_REF] Loftus | Predicting appendiceal tumors among patients with appendicitis[END_REF][START_REF] Schulz | Case-control studies: research in reverse[END_REF] (p<0.0001). Using the ROC curve, the best cutoff for discriminating a tumorous vs. a non-tumorous appendix was set at 15 mm.

A.

Multivariate analysis and diagnostic score

All the multivariate analysis results are reported in Table 4.

Fat stranding and the presence of an appendicolith emerged as protective factors of appendiceal neoplasm, with OR=0.28 (p=0.0228) and OR=0.22 (p=0.144), respectively.

Four other CT signs remained positive predictive factors of an underlying tumor, including two major signs, i.e. mural calcification (OR=47.05; p=0,0001) and appendiceal mass (OR=7.1; p=0.0082).

The mathematical cutoff leading to the best diagnostic performance was found to be at 0.5. Consequently, a score of ≥ 1 would suggest the possible presence of an underlying appendiceal tumor (Fig. 3). The ROC curve plotted on the basis of our scoring system showed an AUC of 0.88 (95% CI, 0.83-0.93) (Fig. 4).

Using a cutoff ≥ 1, our score had 69% sensitivity (95% CI, 57-82), 95% specificity (95% CI, 91-98), 13.5 PLR (95% CI, 6.7-27.1) and 0.3 NLR (95% CI, 0.2-1) in our cohort (Fig. 5). The internal bootstrap validation of our score gave an AUC of 0.87 (95% CI, 0.82-0.93).

B. Subjective diagnostic performances of the blinded readers

The analysis of the two blinded readers' answers to the question "Do you think there could be an underlying tumor?" showed that the AUC for Readers 1 and 2 were 0.759