Clement Ferrier
email: clement.ferrier@aphp.fr

Clémence Thébaut

Pierre Lévy

Sandrine Baffert

Bernard Asselain

Roman Rouzier

Delphine Hequet

Ferrier Clement

MD Thebaut Clémence

PhD Levy Pierre

PhD Baffert Sandrine

PhD Asselain Bernard

PhD Rouzier Roman

PhD Hequet Delphine

MD Clément Ferrier

Absenteeism and indirect costs during the year following the diagnosis of an operable breast cancer: A prospective multicentric cohort study

Keywords: Health economics, Breast cancer, Indirect costs, Absenteeism, Economic burden Breast Cancer FC: Friction costs

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

Introduction

Breast cancer (BC) is the most common cancer in French women with an estimated incidence of 54,062 new cases in 2015 (standardize incidence rate of 97.4 cases per 100,000 women per year). Usually, costs associated with health care interventions are split between direct costs referring to the resource utilization and indirect costs which represent the productivity lost or time cost due to illness. Different Health Technology Assessment (HTA) agencies developed guidelines including cost components to be included in economic evaluation, generally recommending exclusion of indirect costs for various reasons. The French Health Authority (HAS) alternatively suggested to consider production costs of health care interventions including the standard direct costs and time cost of patients for the delivery of care but excluding time cost due to the underlying condition [START_REF]Choix méthodologiques pour l'évaluation économique à la HAS[END_REF].

BC generates important direct costs for health care systems. A study conducted in France on the national public health insurance database concluded that BC was the most expensive, representing 18.5% of all the cancer expenditures (2). In the US, the estimated lifetime treatment costs ranged from $20,000 to $100,000 [START_REF] Campbell | The costs of treating breast cancer in the US: a synthesis of published evidence[END_REF]. Moreover, since BC is mostly prevalent in women of working age, it induces important indirect costs which should be consider to allow a more comprehensive approach of this disease in a societal perspective.

Methodology of indirect costs measurement raise several issues, especially the valuation of lost productivity related to the time lost due to illness. Defined by Rice, the human capital (HC) approach values the entire time lost, regardless of the duration of absence [START_REF] Rice | The economic costs of illness: A replication and update[END_REF]. To the contrary, in the friction costs (FC) approach, it is assumed that indirect costs only occur during the limited period before adjustment of firms to the workers absence defining a friction period [START_REF] Koopmanschap | Towards a new approach for estimating indirect costs of disease[END_REF]. Even though both may provide useful information, using one approach or the other leads to estimates which may differ dramatically especially when considering a lifetime horizon [START_REF] Koopmanschap | The friction cost method for measuring indirect costs of disease[END_REF][START_REF] Krol | How to estimate productivity costs in economic evaluations[END_REF][START_REF] Marcotte | Estimating the employment and earnings costs of mental illness: recent developments in the United States[END_REF].

Data over absenteeism and indirect costs are useful for decision makers when considering cost-of-illness studies or model-based economic evaluations on innovative treatments or screening strategies. Few studies in the literature focus on indirect costs of BC and absenteeism with estimates ranging from $8,068 [START_REF] Fu | Absenteeism and short-term disability associated with breast cancer[END_REF] to $21,086 per patient [START_REF] Lidgren | Resource use and costs associated with different states of breast cancer[END_REF], highlighting the importance of the methodology used and country of interest. In France, only one study reported indirect costs associated with adjuvant chemotherapy in BC [START_REF] Laas | Evaluation of the costs and resource use associated with adjuvant chemotherapy for breast cancer in France[END_REF]. There is also few information over individual characteristics driving the level of indirect costs. To maintain employment or early return at work could be justified in order to decrease economic burden of the disease from a societal perspective but also to limit its impact on patient's personal life (social environment, long term professional goals, etc.). In some countries, like France, it is considered as a public health priority [START_REF]Plan cancer 2014 -2019[END_REF][START_REF]Charte des 11 engagements[END_REF]. It could be promoted with multidisciplinary interventions and innovative treatments associated with less toxicity [START_REF] De Boer | Interventions to enhance return-to-work for cancer patients[END_REF].

The objective of this study was to describe the indirect costs of absenteeism and their determinants in the first year following the diagnosis of early BC in a French populationbased prospective cohort study, using both the HC and the FC approach.

Material and methods

Population

We analyzed indirect costs in early BC, during the year following diagnosis. This study is part of a global research on BC pathways and burden of disease of the French prospective and multicentric study OPTISOINS01. The design of this prospective trial was previously described [START_REF] Baffert | The patient-breast cancer care pathway: how could it be optimized?[END_REF]. Patients were included in this cohort by 8 centers (three University hospitals, four local hospitals, one comprehensive cancer center) in three departments of the Ile-de-France region between 2014 and 2016. Patients included were female with a histologically confirmed, previously untreated and firstly operable BC (exclusion of metastatic, locally advanced or inflammatory BC as defined by the AJCC). Patients were prospectively followed during a year with a collection of information over three work packages: 1/resource utilization and costs of pathways, 2/patient satisfaction and work reintegration, 3/quality, coordination and access to innovation. Individual social and economic characteristics were also recorded at the beginning of the study.

From the initial cohort of OPTISOINS01, we included all patients reporting a paid activity at the moment of diagnosis. They were excluded if the data on wage or absenteeism were missing.

All components of absenteeism were included as part of indirect costs: sick days, parttime resumption, early retirement, mortality. Indirect costs related to presenteeism and unpaid work were excluded from the field of this study. A specific questioner in the second work package was used to assess time lost due to the disease during the year of survey: dates of work and absence from work during treatment, work arrangements, on-shift status (e.g., the recognition of disability at work, applications for disability allowance, retirement, and layoff).

We did not consider indirect costs of relatives.

Calculations methods for indirect costs

Periods of absenteeism were considered using both HC and FC approach, addressed separately. In the HC approach, we assumed that indirect costs were generated during the entire period of absenteeism [START_REF] Rice | The economic costs of illness: A replication and update[END_REF]. According to the FC approach (6), after a friction period, the level of productivity is restored because of the replacement of the sick individual and no indirect costs occurs. However, medium-term global macroeconomic consequences may arise in an international competitive labor market with an impact on macroeconomic indicators.

During the friction period and because of various parameters (diminishing returns to labour, internal labour reserve within firms, and delaying work after the absence period) the production losses are lower that estimates based on the HC approach. With the FC approach, we restricted indirect costs to the friction period and used a friction coefficient to reduce the value of lost production. We assumed insignificant medium-term macro-economic consequences for this cohort.

According to Koopmanschap's method, job vacancy duration estimates (i.e. length of recruitment processes) increased with 30 days of time lag (for the decision to recruit and the time between the recruitment and the first working day) were used as a proxy for the friction period's length [START_REF] Koopmanschap | The friction cost method for measuring indirect costs of disease[END_REF]. As job vacancy duration depends on professional categories, we stratified the estimation on this factor (managers vs. others). Data over jobs vacancy durations were scarce in the French literature (including the grey literature). The ofer survey conducted in 2005 by the labor department reported means of 56 days for managers and 28 days for other professional categories [START_REF]Offre d'emploi et recrutement (OFER) -2005[END_REF]. In 2017, Pole-emploi job offers were filled in 56 days for managers and 36 days for other categories [START_REF]Pole-emploi. Statistiques, études et évaluations. Enquête « besoin en main[END_REF]. Consequently, we assumed a friction period of 86 days for managers and 62 days for other professional categories. For the friction coefficient, we used a value of 0.8, initially computed by Koopmanschap et al. (using the estimated elasticity for annual labor time versus labor productivity) and never updated afterwards [START_REF] Koopmanschap | The friction cost method for measuring indirect costs of disease[END_REF].

Periods of absenteeism were recorded including days off (week end) in the patient's questioner and converted into Lost Working Days (LWD) for the analysis: five LWD for 7 sick days, 2.5 LWD for 7 days of part-time resumption, 251 LWD for a death or an early retirement (considering 5 working days per week during a year). Representing lost productivity, LWD were valued in euros by daily individual wages supplemented with employers and employee social contributions (computed with an online tool (18)). Wages were self-reported by the patients as their monthly net income. In the FC approach, if multiple periods of absenteeism were recorded, interspersed by work period, we assumed a new entire friction period for each period of absenteeism.

Statistical analysis

We performed different models of simple and multiple linear regressions using the Stata\IC 14.0 software (StataCorp, College Station, Texas). In the first model, the independent variable was the estimate number of LWD, with the HC approach. In the second model, the independent variable was the amount of indirect costs. As HC and FC approaches lead to different values, we performed two different statistical analyses. Dependent variables integrated in a simple linear regression were: marital status, professional category, cancer histology, surgical treatment, adjuvant treatment in the BC treatment. Factors correlated with the independent variable (with a p-value<.1) were integrated in the multiple linear regression.

A p-value < .05 was considered significant.

We conducted a univariate sensitivity analysis on estimated parameters of the FC approach (friction period length, friction coefficient) by applying them ±20% variation and constructed a Tornado diagram to illustrate the effect on indirect costs. This analysis was also conducted for subgroups: managers and other professional categories.

To facilitate the use of our data in other medico-economic analysis, we estimated average indirect costs in subgroups, according to the care pathway and the occupational activity.

This study was approved by the French National ethics committee (CCTIRS Authorization n°14.602 and CNIL DR-2014-167) and covers research at all participating hospitals. This study was registered with ClinicalTrials.gov (Identifier: NCT02813317).

Results

On the 617 screened patients, 604 were included in the OPTISOINS01 cohort. Some patients were excluded from our study either due to the absence of paid activity during the study period (n=307) or due to missing data (wages for 42 patients and length of absenteeism for 87 patients). Finally, 168 patients were included in the analysis (figure 1). Patients characteristics are presented in table 1.

Eleven patients did not have any period of absenteeism. One hundred fifty six patients (93%) had at least one period of sick leave, with on average 2 period and 186 days of sick leave (i.e. 133 LWD). Forty patients (24%) had a part-time resumption after their sick leave periods, during 114 days on average (i.e. 41 LWD). Five patients did request for early retirement but procedures were still pending at the end of the follow-up. No death was declared during the study period. On average, managers declared less sick leave days than other professional categories (146 and 172, respectively) but longer period of part time recovery (33 and 24, respectively). Using the HC approach, we recorded a total of 20 973 LWD (mean: 125 LWD per patient). Then, using the FC approach, we computed a total of 8 297 LWD (mean: 49 LWD per patient). For 66 patients (38%), there were no differences in the computed number of LWD using on approach or the other. Patients in this subgroup had significantly less mastectomy (11%), less axillary lymph node dissection (5%) and less chemotherapy (27%) than the whole sample.

As a consequence, using the HC approach, the total estimated indirect costs in the cohort were three times those estimated with the FC approach : 3,817,000.00 € vs. 1,298,000.00 €. Respectively, this represented 22,722.00 € and 7,724.00 € of indirect costs, per patient, during the first year after diagnosis. In both approaches, the main driver of lost productivity and indirect costs was sick leave days, representing 90% of the total amount. Part-time resumption only accounted for 10% of the total of these costs (figure 2). Indirect costs were higher for managers than other professional categories: 11,044 €/patient vs. 5,353 €/patient with the FC approach, despite less sick leave days in this group. This result is explained by highest incomes.

In the multiple linear regression model, factors associated with the number of LWD were: the invasive nature of the tumor (+65 LWD, p=.043), a mastectomy (+40 LWD, p=.038), a surgery revision (+48LWD, p=.002), a chemotherapy (+35 LWD, p=.027), being a manager (-33LWD, p=.025) or a craftsman (-113LWD, p=.005) (compared to being a paid employee). With both approaches, in the simple linear regression model, individual indirect costs were correlated with the invasive nature of the tumor, characteristics of the treatment (mastectomy, axillary lymph node dissection, chemotherapy) and socio-economic characteristics (high educated vs. low educated, being manager vs. being a paid employee) (see Table 2. For details and differences between HC and FC approach). In the HC approach, factors significantly associated with indirect costs in the multiple linear regression model were: a mastectomy (p=.046), a revision surgery (p=.003) and being a craftsman (p=.023).

Being a manager, the invasive nature of the tumor or receiving a chemotherapy increased indirect costs in the model but with less degree of statistical signification. In the FC approach, being a manager was the only significant factor associated with indirect costs in the multiple linear regression model (p<.001) (Table 2).

In the univariate sensitivity analysis for the FC approach, the variation of friction coefficient (benchmark: 0.8; +/-20%) impacted the most the amount of indirect costs from 6,179 €/patient to 9269 €/patient (basis: 7,724€/patient) (Figure 3). In the subgroup analysis, indirect costs for managers were much more sensitive to a variation on estimated parameters than other professional categories.

Tables with estimated average indirect costs by care pathway and occupational activities are published in the supplementary data.

Discussion

Breast cancer associated direct costs are already well-documented in the literature.

Determinants of the indirect costs are less known. Studying the OPTISOINS cohort, Arfi et al. [START_REF] Arfi | Determinants of return at work of breast cancer patients: results from the OPTISOINS01 French prospective study[END_REF] estimated the average daily allowances for sick leave costs (i.e. indirect medical costs) around 8 841 € per patients for the first year from diagnosis. In the same cohort, we showed that BC often cause sick leave periods and part-times recoveries in the year following diagnosis leading to important indirect costs even in the absence of mortality. However, the utilization of two different approaches conducted to a gap in the estimated indirect costs per patient: 22,722.00 € for the HC approach and 7,724.00 € for the FC approach. Factors were correlated to the number of LWD and the amount of indirect costs in the HC approach: the invasive nature of the tumor, receiving a mastectomy, a revised surgery, a chemotherapy, being a manager or a craftsman. Estimated indirect costs in the FC approach were mostly led by the occupational status since managers present higher wages and higher friction periods. BC mean age of diagnosis matches with the mean age of retirement in industrialized countries (62 years old in France) [START_REF]Les cancers en France[END_REF]. Moreover the age of retirement is nowadays being delayed in many countries, following the increase of life expectancy [START_REF]Mutual Information System on Social Protection[END_REF]. Thus, absenteeism, indirect costs and more generally work consequences associated with this disease are concerns for decision makers. In the OPTISOINS01 initial cohort, half of the patients had a paid activity during the study period. On average, these patients spent almost half the year after diagnosis in sick leave and 24% of the patients returned to work in part-time resumption for a mean period of 114 days. A mean of 125 LWD was recorded for each patient and 26 patients were absent from work during the entire year of analysis, highlighting the impact of BC on paid work. Only few studies report such data. Two US retrospective cohort studies found that working patients with BC had significantly higher length of absenteeism in comparison with "control" patients (without BC) [START_REF] Fu | Absenteeism and short-term disability associated with breast cancer[END_REF][START_REF] Wan | Indirect costs associated with metastatic breast cancer[END_REF]. However, using a HC approach in the year following diagnosis, they found shorter period of absenteeism: about 10 days of sick leave and between 25 and 45 days of short-term disability (according to the severity of the disease). In Sweden, patients in the first year after a primary BC declared on average 271 working hours lost in the last 3 months before their interview [START_REF] Lidgren | Resource use and costs associated with different states of breast cancer[END_REF]. In accordance with our results, mortality and early retirement were rare in the first year following diagnosis.

We conducted the first prospective cohort study focusing on cost of absenteeism related to BC. The large initial sample size of OPTISOINS01 allowed us to exclude working patients with missing data which could have affected the quality of the analysis. Due to the geographical design of the study, most patient in this cohort reside near Paris and may have different socio-economic characteristics than the national population. Indeed, we noticed that the proportion of managers in our sample was larger than in the French active population (41.6% vs. 17.1%), as well as the average wage (2,214€ vs.1,926€) (governmental data) (23).

The time frame was limited to one year after diagnosis but most indirect costs related to BC occurs during this first year, except when the disease progresses to a metastatic stage or a recurrence [START_REF] Lidgren | Resource use and costs associated with different states of breast cancer[END_REF][START_REF] Gordon | Exploring the economic impact of breast cancers during the 18 months following diagnosis[END_REF].

We only considered in this study indirect costs due to absenteeism. There is a growing interest for presenteeism, i.e. workers being at job with reduced capacity and productivity due to illness, and unpaid work, which generate indirect costs [START_REF] Hemp | Presenteeism: at work--but out of it[END_REF]. Exploring those phenomena require suitable tools (iMTA Productivity Cost Questionnaire [START_REF] Bouwmans | The iMTA Productivity Cost Questionnaire: A Standardized Instrument for Measuring and Valuing Health-Related Productivity Losses[END_REF], Valuation of Lost Productivity ( 27)) which weren't used on our cohort. As a consequence, this component was excluded from our analysis. Even though few studies suggest substantial indirect costs associated with presenteeism and unpaid work [START_REF] Gordon | Exploring the economic impact of breast cancers during the 18 months following diagnosis[END_REF][START_REF] Łyszczarz | Productivity losses and public finance burden attributable to breast cancer in Poland, 2010-2014[END_REF][START_REF] Tachi | The impact of side effects from outpatient chemotherapy on presenteeism in breast cancer patients: a prospective analysis[END_REF], there is no recommendation on their integration. Usually, authors refer to unique method for the calculation of the lost productivity value, the HC approach being the most commonly employed. For the FC approach, authors use friction periods initially estimated by Koopmanschap et al. (2.8-3.2 months (6)), or other values but without justification on their sources [START_REF] Kigozi | Estimating productivity costs using the friction cost approach in practice: a systematic review[END_REF]. Nevertheless, Koopmanschap's estimation is based on outdated data (1988)(1989)(1990)) and restricted to the Dutch labor market.

The time to fill job vacancies (i.e. the length of recruitment processes) increased by four weeks of time lag (decision to recruit and time between the recruitment and the first working day) was used to approximate the friction period. Therefore, the friction period's length is strongly correlated with the unemployment rate and the economic environment. It varies over time and across countries. It also has to be stratified on the socio professional category, since the recruitment process is longer for managers than for employees [START_REF] Kigozi | Valuing productivity costs using the friction-cost approach: Estimating friction-period estimates by occupational classifications for the UK[END_REF]. In the absence of guidelines, we preferred to use both approaches and used French grey literature sources to estimate friction periods length, following the Koopmanschap's method. Compared to his results, our estimation was similar for managers but much shorter for other socio professional categories (62 vs. 86 days), highlighting the importance of using proper data for the FC approach. Nevertheless, our sensitivity analysis focused on the importance of the friction coefficient estimate on the amount of indirect costs. In order to improve the robustness of our results, we would need to proceed on our own estimation for France, which unfortunately was not possible here as it requires unavailable micro economic data at the firm level. Friction period duration and friction coefficient values should then be regularly estimated and updated to facilitate the application of the FC approach.

As mentioned above, the necessity to account for indirect costs related to productivity losses in economic studies is not clearly established. Health Technology Assessment agencies provide different guidelines. Those focusing on payer perspective recommend to exclude those costs from the evaluation [START_REF] Nice | Guide to the methods of technology appraisal[END_REF][START_REF]A format for submission of clinical and economic evidence in support of formulary consideration[END_REF]. By contrast, other agencies adopting a collective or societal perspective, including the World Health Organization, propose to include indirect costs, sometimes in a separate analysis [START_REF] Who | Guide for standardization of economic evaluations of immunization programmes[END_REF][START_REF] Ces | Actualisation partielle du guide méthodologique pour l'évaluation économique des stratégies de santé[END_REF][START_REF] Wellpoint | Health technology assessment guidelines. Drug submission guidelines for new products, new indications, and new formulations[END_REF]. Besides the methodological challenge to measure indirect costs, ethical objection are often mentioned [START_REF] Drummond | Cost-of-illness studies: a major headache?[END_REF]. Indeed, if decision makers use those studies to plan resource allocations, working age people would be favored over young or elderly, and any other unemployed population. Moreover, authors discuss the risk of double counting in cost-effectiveness evaluation when including productivity loss. The question is to determine whether individuals take into account the impact of disease would have on their income and career when they assess its impact on quality of life, which is included in the denominator of the incremental cost-effectiveness ratio (ICER) [START_REF] Tilling | The impact of losses in income due to ill health: does the EQ-5D reflect lost earnings?[END_REF][START_REF] Lensberg | Challenges in measuring and valuing productivity costs, and their relevance in mood disorders[END_REF]. By presenting direct and indirect costs in separate analysis, authors allow decision-makers to take a stand regarding these scientific and equity issues in healthcare resource utilization. Furthermore, the relationship between disease and work should be more precisely studied to limit the consequences of being sick on occupational activity. The low proportion of early retirement procedures and the absence of dismissal in our cohort will reassure BC patients on their future capacity to work and motivate them to use part time recovery when needed. Another study showed a good readjustment to the workplace for patient after a BC [START_REF] Maunsell | Work situation after breast cancer: results from a population-based study[END_REF].

Conclusion

We believe crucial to report absenteeism, productivity losses and indirect costs.

Moreover, accurate data on type and length of absenteeism are fundamental, particularly for economic studies based on simulated models and using a societal perspective. and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

Figure 1 .

 1 Figure 1. Flow-chart.

Figure 2 .

 2 Figure 2. Indirect costs per patient.

Figure 3 .

 3 Figure 3. Tornado diagram for the univariate sensitivity analysis.

  Figure legends:

Figure 2 :

 2 Figure 2: Tch: Human Capital Approach. Tcf: Friction Costs Approach.

Figure 3 :

 3 Figure 3: Horizontal axis: cost (€) / patient. SPC: socio professional category. For the subgroup analysis, the variation is applied only for the patients in the subgroup.

Acknowledgements

The authors acknowledge the French National Cancer Institute.

Funding

This study was supported by a grant from the French National Cancer Institute, dedicated to economic studies of innovative techniques (PRME-K-2013). The funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval

This study was approved by the French National ethics committee (CCTIRS Authorization n°14.602 and CNIL DR-2014-167) and covers research at all participating hospitals. This study was registered with ClinicalTrials.gov (Identifier: NCT02813317).

Ethics, consent to participate

All individuals included in this study consented to participate after a complete information.

Consent for publication

A written consent for publication was obtained from all individuals included in this study.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

CF, RR and DH contributed to the acquisition of data. CF, CT, PL, SB, BA, RR and DH contributed in (1) the conception and design of the study, or acquisition of data, or analysis