Factors associated with under-reporting of head and neck squamous cell carcinoma in cause-of-death records: A comparative study of two national databases in France from 2008 to 2012

Caroline Even; Luis Sagaon Teyssier; Yoann Pointreau; Stéphane Temam; Florence Huguet; Lionnel Geoffrois; Michaël Schwarzinger; on behalf of the EPICORL Study Group

doi:10.1371/journal.pone.0246252

. 2021 Feb 3;16(2):e0246252. doi: 10.1371/journal.pone.0246252

Factors associated with under-reporting of head and neck squamous cell carcinoma in cause-of-death records: A comparative study of two national databases in France from 2008 to 2012

Caroline Even ¹, Luis Sagaon Teyssier ^2,³, Yoann Pointreau ⁴, Stéphane Temam ¹, Florence Huguet ⁵, Lionnel Geoffrois ⁶, Michaël Schwarzinger ^3,^¤a,^¤b,^*; on behalf of the EPICORL Study Group^¶

Editor: Brecht Devleesschauwer⁷

¹Department of Surgical & Medical Head & Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France

²Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France

³Translational Health Economics Network (THEN), Paris, France

⁴Department of Radiation Oncology, ILC- Institut inter-régionaL de Cancérologie, Centre Jean Bernard-Clinique Victor Hugo, Le Mans, France

⁵Department of Radiation Oncology, Hôpital Tenon, AP-HP, Paris, France

⁶Department of Medical Oncology, Institut de cancérologie de Lorraine – Alexis Vautrin, Vandoeuvre Les Nancy, France

⁷Sciensano, BELGIUM

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr Caroline Even reports personal fees from Astra Zeneca, BMS, Innate Pharma, Merck and co, and Merck Serrono, outside and unrelated to the submitted work; Luis Sagaon-Teyssier was an employee of Translational Health Economics Network (THEN); Prof Françoise Huguet reports personal fees from BMS and Merck Serrono, outside and unrelated to the submitted work; Dr Michaël Schwarzinger was an employee of Translational Health Economics Network (THEN), Paris, France, that received a research grant from Merck Sharp & Dohme (MSD) France for the EPICORL study as well as research grants from Abbvie, Gilead and Novartis, outside and unrelated to the submitted work. Other authors have declared no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

^¤a

Current address: Department of Methodology and Innovation in Prevention, Bordeaux University Hospital, Bordeaux, France

^¤b

Current address: Université de Bordeaux, Isped, Inserm UMR 1219-Bordeaux Population Health, Bordeaux, France

¶ Membership of the EPICORL Study Group is provided in the Acknowledgments.

^✉

* E-mail: michael.schwarzinger@chu-bordeaux.fr

Roles

Caroline Even: Investigation, Validation, Writing – review & editing

Luis Sagaon Teyssier: Formal analysis, Methodology, Writing – review & editing

Yoann Pointreau: Investigation, Validation, Writing – review & editing

Stéphane Temam: Investigation, Validation, Writing – review & editing

Florence Huguet: Investigation, Validation, Writing – review & editing

Lionnel Geoffrois: Investigation, Validation, Writing – review & editing

Michaël Schwarzinger: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing

Brecht Devleesschauwer: Editor

PMCID: PMC7857613 PMID: 33534860

Abstract

Objective

To date, no study has evaluated the detection rate of head and neck squamous cell carcinoma (HNSCC) in cause-of-death records in Europe. Our objectives were to compare the number of deaths attributable to HNSCC from two national databases in France and to identify factors associated with under-reporting of HNSCC in cause-of-death records.

Methods

The national hospital discharge database and the national underlying cause-of-death records were compared for all HNSCC-attributable deaths in adult patients from 2008 to 2012 in France. Factors associated with under-reporting of HNSCC in cause-of-death records were assessed using multivariate Poisson regression.

Results

A total of 41,503 in-hospital deaths were attributable to HNSCC as compared to 25,647 deaths reported in national UCoD records (a detection rate of 62%). Demographics at death were similar in both databases with respect to gender (83% men), age (54% premature deaths at 25–64 years), and geographic distribution. In multivariate Poisson regression, under-reporting of HNSCC in cause-of-death records significantly increased in 2012 compared to 2010 (+7%) and was independently associated with a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, distant metastasis, palliative care, and death in hospitals other than comprehensive cancer care centers. The main study results were robust in a sensitivity analysis which also took into account deaths outside hospital (overall, 51,129 HNSCC-attributable deaths; a detection rate of 50%). For the year 2012, the age-standardized mortality rate for HNSCC derived from underlying cause-of-death records was less than half that derived from hospital discharge summaries (14.7 compared to 34.1 per 100,000 for men and 2.7 compared to 6.2 per 100,000 for women).

Conclusion

HNSCC is largely under-reported in cause-of-death records. This study documents the value of national hospital discharge databases as a complement to death certificates for ascertaining cancer deaths.

Introduction

National underlying cause-of-death (UCoD) records are a cornerstone of epidemiological research, health policy planning, and evaluation [1]. UCoD is certified by a physician using the coding rules and procedures of the WHO International Classification of Diseases (ICD), which is currently available in its tenth revision (ICD-10) [2]. However, many studies have identified misclassification problems in UCoD records, due to incomplete or inaccurate death certification [3, 4]. This was particularly the case for older decedents [5–7] and for certain specific UCoDs [7–9]. Despite coding rules and procedures which give priority to cancer over comorbidities as the UCoD [2], cancer deaths also present misclassification problems [10–12]. In particular, three U.S. studies conducted on population-based cancer registries have all identified low detection rates (around 60%) for head and neck squamous cell carcinoma (HNSCC) in UCoD records [10, 11, 13].

To our knowledge, the detection rate for HNSCC in UCoD records has not been studied in Europe. In several European countries, national hospital discharge records may be used to ascertain cancer deaths [14–17]. For instance, all hospital discharge records in France document diagnoses using standardized ICD-10 coding. In a recent French study linking death certificates with the last hospital admission in 2008 and 2009, the primary discharge diagnosis was similar to the UCoD for 54% of cancer deaths [18]. However, previous studies have relied only on the discharge records of the last acute hospital admission before death and, for this reason, may not fully capture the “chain of events leading directly to death” [14–18].

The objective of this study was to estimate the number of deaths attributable to HNSCC in France in 2008–2012 from all hospital discharge records in acute and post-acute care. This number was compared to national UCoD records for HNSCC in 2008–2012. In addition, we assessed factors associated with under-reporting of HNSCC in national UCoD records.

Materials and methods

Study design

Firstly, we conducted a retrospective longitudinal analysis of the French national hospital discharge database (Programme de Médicalisation des Systèmes d’Information; PMSI 2008–2013) to identify and characterize deaths attributable to HNSCC in 2008–2012. HNSCC was defined by the following ICD-10 codes: C00-C06; C09-C14; C30.0; C31; C32 [19]. The full coding dictionary used in the study is provided in S1 Table in S1 File. Secondly, we compared the number of HNSCC-attributable deaths identified in the national hospital discharge (PMSI) database to the number of deaths with HNSCC reported as the UCoD in national cause-of-death records, using the same definition of HNSCC, geographical area, and period. Finally, we assessed factors associated with under-reporting of HNSCC in national UCoD records, taking into account all patient characteristics available for analysis at the time of death.

Data sources

The national hospital discharge (PMSI) database contains discharge records for all acute hospital admissions and post-acute care in the public and private sectors. All hospital discharge records for a given patient are linked by a unique patient identification number [20, 21]. National UCoD records were obtained from the national mortality database (Epidemiological Center on Medical Causes of Death, CépiDc-INSERM 2008–2012).

Identification of HNSCC-attributable deaths in the national hospital discharge database

The study sample consisted of the 131,965 patients discharged with HNSCC in France between 2008 and 2012 (inclusive), of whom 46,463 (35.2%) died in hospital during the same period (S2 Table in S1 File). The set of rules to assess whether HNSCC was a probable/possible/unlikely cause of death was established by the medical experts of the study group in accordance with WHO coding rules and procedures prioritizing cancer as the UCoD over comorbidities [2, 22]. Accordingly, HNSCC was considered the probable cause of death in patients with distant metastases at initial treatment and in patients who relapsed at least six months after diagnosis. It was considered the possible cause of death in patients initially treated at a locally advanced stage. In all other situations, HNSCC was considered an unlikely cause of death.

Characterization of HNSCC-attributable deaths in the national hospital discharge database

A number of characteristics that may potentially be associated with misclassification in UCoD records were documented. These include patient demographics (gender, age at death, and region of residence), primary HSNCC site [10, 11, 13], distant metastasis after HNSCC diagnosis [13], multiple primary cancers [22]), comorbidities [22] and end-of-life characteristics.

The primary HNSCC site was identified from the primary diagnosis recorded on the hospital discharge summary for first HNSCC surgery or panendoscopy. Primary HNSCC sites were grouped into nine categories, namely nasal cavity/paranasal sinuses, nasopharynx, lip, tongue, oral cavity, oropharynx, hypopharynx, larynx and ill-defined HNSCC [19].

Multiple primary cancers were classified in four categories based on their expected frequency in HNSCC patients. Second primary HNSCC sites were classified as lung cancer, esophageal cancer or other primary cancers [23, 24]. WHO coding rules and procedures prioritize the first primary cancer as the UCoD over a second primary cancer [2, 22]. For this reason, multiple primary cancers were classified according to their temporal relationship to the primary HNSCC site. Six categories of multiple primary cancers were defined, namely history of HNSCC documented at diagnosis of HNSCC, second synchronous HNSCC, second metachronous HNSCC, history of non-HNSCC documented at diagnosis of HNSCC, second synchronous non-HNSCC and second metachronous non-HNSCC.

WHO coding rules specify that HIV/AIDS should be considered as the UCoD in HNSCC patients [2, 22, 25]. However, other comorbidities are frequent competing causes of death in patients with HNSCC [26, 27]. The Charlson comorbidity index is widely used in HNSCC care [26, 28] and we documented each comorbidity of the index using a validated ICD-10 coding algorithm for the national hospital discharge (PMSI) database [29, 30]. In addition, we documented depression and suicide attempts, both of which are frequently reported in HNSCC patients [31].

Finally, with respect to end-of-life characteristics, we documented palliative care provided by non-cancer specialists and the place of death (comprehensive cancer care center, public teaching hospital, private clinic, or public local hospital). These are two factors which may be associated with a lower degree of cancer specialization of the certifying physician and thus potentially more misclassification in UCoD records.

Identification of HNSCC-attributable deaths in national cause-of-death records

National UCoD records are available by ICD-10 code and stratified by year of death (from 2008 to 2012), gender, age at death (eight categories: 25–34; 35–44; 45–54; 55–64; 65–74; 75–84; 85–94; 95+) and region of residency (22 regions). We selected UCoD records using the same HNSCC definition as for the national hospital discharge (PMSI) database. These were grouped into the same nine categories of primary HNSCC sites. Because of small sample sizes at extreme ages and in some regions, age at death was grouped into six categories (25–44, 45–54, 55–64, 65–74, 75–84 and 85+ years) and regions into five categories (Greater Paris region, North-West, North-East, South-West and South-East).

Study outcome

The primary outcome of the analysis was the number of HNSCC-attributable deaths identified in the two national databases. In the national hospital discharge (PMSI) database, attributable deaths were defined as HNSCC identified as a probable/possible cause of in-hospital death. In the National UCoD records, they were identified as deaths with the UCoD reported as HNSCC. This number was compared between the two databases, both overall and stratified by the variables common to both datasets (year of death, gender, age category, region of residence, primary HNSCC site).

Statistical analysis

The number of deaths attributable to HNSCC was compared for each of the 2,700 profiles defined by all possible combinations of the variables common to both databases. We studied under-reporting of HNSCC in UCoD records by selecting all profiles for which HNSCC-attributable deaths identified in the national hospital discharge (PMSI) database exceeded those identified in national UCoD records. A multivariate Poisson regression model was conducted in order to identify independent factors associated with under-reporting. All variables were entered in the initial model, which was then iterated with stepwise selection of variables (p<0.10 for entry and p<0.05 for retention). Variables common to both databases were included in all selection models. For these variables, exponents of Poisson coefficients correspond to relative risks (RR) of under-reporting. An RR>1 indicates an increased risk of under-reporting for a given category as compared to the reference category, and an RR <1 indicating a decreased risk.

For variables only identifiable in the national hospital discharge (PMSI) database, the number of in-hospital deaths was counted for each profile and the counts log-transformed. Log-transformation made it possible both to control data dispersion and to interpret Poisson coefficients as elasticities. Accordingly, an elasticity>0 (<0) indicates the percentage increase (decrease) in the number of records under-reported given an increase of 1% in the number of deaths for the variable.

Since only in-hospital deaths are recorded in the national hospital discharge (PMSI) database, we conducted a sensitivity analysis with overall deaths after imputing deaths outside hospital [32]. Imputation was based on the analysis of multiple determinants of death for all patients discharged with HNSCC in 2008 and for whom vital status was known at the end of 2008. A multivariate logistic regression was then used to estimate the probability of dying outside hospital for each patient lost to follow-up from 2008 to 2012 (further details on imputation method are provided in S1 Methods in S1 File).

From the overall number of HNSCC-attributable deaths in the most recent year (2012), we computed age-standardized mortality rates (ASMR) by gender and region after standardization to the new European Standard Population [33]. All statistical analyses were carried out using the R software for records (version 3.2.0; R Foundation for Statistical Computing, Vienna, Austria).

Ethics and consent

The EPICORL (EPIdémiologie des Cancers ORL) study was approved by the French National Commission for Data Protection (CNIL DE-2015-025) who granted access to the national hospital discharge (PMSI) database for the years 2008 to 2013. The requirement for informed consent was waived because the study used de–identified data.

Results

Deaths attributable to HNSCC in the national hospital discharge database

Of the 46,463 patients discharged with HNSCC and dying in hospital in 2008–2012, 41,503 (89.3%) deaths were attributable to HNSCC as a probable (28,254 [68.1%]) or possible (13,249 [31.9%]) cause of death, and 4,960 (10.7%) deaths were not attributable to HNSCC (Table 1). These data were left-censored on January 1^st 2008, when the national hospital discharge (PMSI) database first became available. For this reason, identification of relapses requiring at least six months of follow-up after diagnosis (a criterion for attribution of HNSCC as a probable cause of death) was incomplete for the year 2008. The proportion of the study sample fulfilling this criterion increased from 2008 (9.8%) up until 2010 (44.0%) and remained stable thereafter (51.1% in 2012) (S3 Table in S1 File). The proportion of deaths with HNSCC as a probable cause thus also increased over time, from 51.1% in 2008 to 70.9% in 2010 and 74.4% in 2012 (S3 Table in S1 File).

Table 1. Deaths attributable to HNSCC in the national hospital discharge database (2008–2012).

Stage at initial treatment	Relapse during follow-up	Deaths attributable to HNSCC	Main analysis (in-hospital deaths only)	Sensitivity analysis (overall deaths)^a
Distant metastasis stage	–	Probable	10,882 (23.4)	13,199 (22.4)
Locally advanced stage	Yes	Probable	14,218 (30.6)	17,183 (29.2)
Locally advanced stage	No	Possible	13,249 (28.5)	16,933 (28.7)
Early stage	Yes	Probable	3,154 (6.8)	3,814 (6.5)
Early stage	No	Unlikely	4,960 (10.7)	7,801 (13.2)
Total deaths attributable to HNSCC			41,503 (89.3)	51,129 (86.8)
Total deaths			46,463 (100)	58,930 (100)

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^a In-hospital deaths or deaths imputed outside hospital in patients lost to follow-up after hospital discharge.

In a sensitivity analysis which also took into account deaths outside hospital in the 131,965 patients discharged with HNSCC in 2008–2012, overall all-cause mortality was estimated to be 44.7% (58,930 deaths) in 2008–2012 (S1 Methods in S1 File). Of these, 51,129 deaths (86.8%) were attributable to HNSCC, either as a probable (34,196 cases; 66.9%) or possible (16,933 cases; 30.1%) cause of death.

Comparison of HNSCC-attributable deaths between the national hospital discharge database and national UCoD records

In the national UCoD records, 25,647 deaths were attributable to HNSCC over the 2008–2012 period. Accordingly, the detection rate of HNSCC-attributable deaths (as identified in the national hospital discharge database) in national UCoD records was 62% in the main analysis (41,503 in-hospital deaths) and 50% in the sensitivity analysis (51,129 overall deaths). Although the number of HNSCC-attributable deaths identified in the national hospital discharge (PMSI) database increased from 2008 to 2012, the number of HNSCC in national UCoD records remained relatively stable. In consequence, the detection rate decreased from 70% in 2008 to 56% in 2012 in the main analysis (from 57% to 43% in the sensitivity analysis) (Fig 1).

Fig 1 — Percentages indicate the proportion of HNSCC-attributable deaths in the national hospital discharge (PMSI) database for which HNSCC is the certified underlying cause of death. Data are presented by year of death for both the main analysis and the sensitivity analysis.

Apart from year of death, four characteristics of HNSCC-attributable deaths could be compared between the two national databases (Table 2). Demographics at death were similar in both databases regarding gender (83% men), age (54% premature deaths at 25–64 years), and geographic distribution. However, higher proportions of primary larynx cancers (24% vs. 19%) and ill-defined HNSCC (12% vs. 5%) were documented in national UCoD records than in the national hospital discharge (PMSI) database.

Table 2. Comparison of characteristics of HNSCC attributable-deaths according to the source of information (2008–2012).

Characteristics of HNSCC-attributable deaths	National hospital discharge (PMSI) database		National UCoD records
	Main analysis (in-hospital deaths)	Sensitivity analysis (overall deaths)^a
	N = 41,503	N = 51,129	N = 25,647
Year of death
2008	7,251 (17.5)	8,887 (17.4)	5,094 (19.9)
2009	8,106 (19.5)	9,886 (19.3)	5,095 (19.9)
2010	8,598 (20.7)	10,309 (20.2)	5,263 (20.5)
2011	8,738 (21.1)	10,673 (20.9)	5,276 (20.6)
2012	8,810 (21.2)	11,374 (22.2)	4,919 (19.2)
Men	34,315 (82.7)	42,133 (82.4)	21,100 (82.3)
Age at death
25–44	934 (2.2)	1,164 (2.3)	502 (1.7)
45–54	7,158 (17.3)	8,670 (17.0)	4,289 (16.7)
55–64	14,296 (34.5)	17,432 (34.1)	8,572 (33.4)
65–74	9,687 (23.3)	11,935 (23.3)	5,605 (21.9)
75–84	7,196 (17.3)	8,968 (17.5)	4,682 (18.3)
≥85	2,232 (5.4)	2,960 (5.8)	1,997 (7.8)
Region
Greater Paris region	6,449 (15.5)	7,778 (15.2)	3,657 (14.3)
North-West	10,968 (26.4)	13,381 (26.2)	6,767 (26.4)
North-East	11,237 (27.1)	13,769 (26.9)	7,033 (27.4)
South-West	3,812 (9.2)	4,819 (9.4)	2,516 (9.8)
South-East	9,037 (21.8)	11,382 (22.3)	5,674 (22.1)
Primary HNSCC site
Nasal cavity/paranasal sinuses	1,861 (4.5)	2,277 (4.5)	1,004 (3.9)
Nasopharynx	1,212 (2.9)	1,619 (3.2)	612 (2.4)
Lip	346 (0.8)	468 (0.9)	170 (0.7)
Tongue	6,160 (14.8)	7,558 (14.8)	4,213 (16.4)
Oral cavity	6,177 (14.9)	7,439 (14.5)	2,977 (11.6)
Oropharynx	8,771 (21.1)	10,793 (21.1)	4,363 (17.0)
Hypopharynx	6,935 (16.7)	8,435 (16.5)	3,217 (12.5)
Larynx	7,864 (18.9)	9,860 (19.3)	6,064 (23.6)
Ill-defined HNSCC	2,177 (5.2)	2,680 (5.2)	3,027 (11.8)

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^a In-hospital deaths or deaths imputed outside hospital in patients lost to follow-up after hospital discharge.

Note: Results are presented as n (%).

Other characteristics of HNSCC-attributable deaths could only be identified in the national hospital discharge (PMSI) database. Of the patients who died, 13% were recorded with multiple primary HNSCC, 43% with a primary cancer other than HNSCC (16% lung cancer, 8% esophageal cancer, and 20% other cancer; 10% former primary cancer, 22% second synchronous cancer, and 11% second metachronous cancer), 47% with distant metastasis after HNSCC diagnosis and 64% with comorbidities, including 0.5% with HIV/AIDS and 11% with depression (S4 Table in S1 File). Two-thirds of patients who died received palliative care and less than 6% died in a comprehensive cancer care center. Similar proportions were found in the sensitivity analysis which also took into account deaths outside hospital (S4 Table in S1 File).

Independent factors associated with under-reporting of HNSCC in UCoD records

National UCoD records for HNSCC were available for 2,700 profiles at death, defined by all possible combinations of year of death, gender, age group, region and primary HNSCC site. For 1,790 (66.3%) profiles, the number of HNSCC-attributable deaths at hospital was under-reported in UCoD records. These profiles corresponded to 37,789 individual deaths, of which 17,474 were not identified as HNSCC-attributable in the UCoD records. Independent factors associated with under-reporting of these HNSCC-attributable deaths were evaluated in multivariate Poisson regression.

Under-reporting was significantly higher in 2012 compared to 2010 (+7%) and was independently associated with intermediate ages (45–74 years), a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, any record of distant metastasis after HNSCC diagnosis, HIV/AIDS, depression, palliative care, and death in hospitals other than a comprehensive cancer care center (Table 3). In contrast, primary esophageal cancer was independently associated with less under-reporting compared to cancer of the larynx.

Table 3. Variables associated with under-reporting of HNSCC in national UCoD records in multivariate Poisson regression (2008–2012).

Characteristics at death	Main analysis (N = 17,474 in-hospital deaths)^a			Sensitivity analysis (N = 26,489 overall deaths)^b
Characteristics available in both databases	Relative risk (95% CI)	P-value	Relative risk (95% CI)	P-value
Year of death (ref. 2010)
2008	0.94 (0.88 to 1.01)	0.079	0.91 (0.86 to 0.96)	<0.001
2009	1.00 (0.95 to 1.05)	0.95	0.98 (0.94 to 1.02)	0.38
2011	0.99 (0.95 to 1.04)	0.81	1.00 (0.96 to 1.04)	0.95
2012	1.07 (1.02 to 1.12)	0.008	1.10 (1.05 to 1.14)	<0.001
Men (ref. women)	1.00 (0.94 to 1.07)	0.91	1.07 (1.01 to 1.13)	0.015
Age at death (ref. 55–64)
25–44	0.93 (0.82 to 1.06)	0.28	0.81 (0.73 to 0.90)	<0.001
45–54	1.11 (1.05 to 1.17)	<0.001	1.05 (1.01 to 1.10)	0.025
65–74	1.10 (1.04 to 1.15)	<0.001	1.07 (1.03 to 1.11)	<0.001
75–84	1.04 (0.98 to 1.11)	0.22	1.02 (0.97 to 1.08)	0.42
≥85	0.84 (0.75 to 0.94)	0.003	0.81 (0.74 to 0.88)	<0.001
Region (ref. Greater Paris region)
North-West	0.95 (0.90 to 1.01)	0.11	0.97 (0.93 to 1.02)	0.29
North-East	0.94 (0.89 to 1.00)	0.059	0.96 (0.91 to 1.01)	0.083
South-West	1.00 (0.93 to 1.08)	0.98	0.97 (0.91 to 1.03)	0.26
South-East	0.95 (0.90 to 1.00)	0.060	0.99 (0.94 to 1.03)	0.55
Primary HNSCC site (ref. Larynx)
Nasal cavity/paranasal sinuses	1.71 (1.55 to 1.89)	<0.001	1.30 (1.21 to 1.41)	<0.001
Nasopharynx	1.76 (1.58 to 1.97)	<0.001	1.37 (1.25 to 1.49)	<0.001
Lip	1.50 (1.27 to 1.76)	<0.001	1.06 (0.93 to 1.21)	0.38
Tongue	1.42 (1.33 to 1.52)	<0.001	1.23 (1.17 to 1.30)	<0.001
Oral cavity	2.04 (1.92 to 2.17)	<0.001	1.60 (1.53 to 1.68)	<0.001
Oropharynx	1.89 (1.79 to 2.01)	<0.001	1.54 (1.47 to 1.60)	<0.001
Hypopharynx	2.03 (1.91 to 2.16)	<0.001	1.59 (1.52 to 1.67)	<0.001
Ill-defined HNSCC	1.27 (1.09 to 1.47)	0.002	0.93 (0.84 to 1.04)	0.22
Characteristics only identified in the national hospital discharge database	Elasticity (95% CI)	P-value	Elasticity (95% CI)	P-value
Cancer characteristics
Any esophageal cancer	-0.06 (-0.12 to -0.00)	0.041	-0.06 (-0.10 to -0.01)	0.013
Former primary cancer other than HNSCC	0.06 (0.01 to 0.10)	0.023	0.02 (-0.02 to 0.06)	0.25
Second synchronous cancer other than HNSCC	0.10 (0.03 to 0.17)	0.004	0.04 (-0.01 to 0.10)	0.15
Second metachronous cancer other than HNSCC	0.02 (-0.03 to 0.06)	0.49	-0.01 (-0.05 to 0.03)	0.68
Any distant metastasis after HNSCC diagnosis	0.15 (0.06 to 0.24)	<0.001	0.16 (0.08 to 0.23)	<0.001
Comorbidities
HIV/AIDS	0.10 (0.01 to 0.19)	0.037	0.05 (-0.01 to 0.12)	0.11
Depression	0.06 (0.01 to 0.11)	0.014	0.04 (0.00 to 0.08)	0.038
End-of-life characteristics
Palliative care	0.17 (0.05 to 0.29)	0.005	0.21 (0.12 to 0.30)	<0.001
Place of death:
Comprehensive cancer care center	0.03 (-0.01 to 0.08)	0.15	0.01 (-0.03 to 0.05)	0.65
Public teaching hospital	0.20 (0.14 to 0.25)	<0.001	0.12 (0.07 to 0.16)	<0.001
Private clinic	0.17 (0.11 to 0.24)	<0.001	0.14 (0.09 to 0.18)	<0.001
Public local hospital	0.36 (0.27 to 0.46)	<0.001	0.28 (0.21 to 0.36)	<0.001
Home (death imputed outside hospital)	—		0.25 (0.20 to 0.29)	<0.001

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^a Overdispersion test: z = -1.18, p-value = 0.88.

^b In-hospital deaths or deaths imputed outside hospital in patients lost to follow-up after hospital discharge. Overdispersion test: z = 4.62, p-value = 1.

A relative risk >1 corresponds to an increased risk of under-reporting in a given category as compared to the reference category; a relative risk <1 corresponds to a decreased risk. An elasticity>0 indicates the percentage increase in the number of records under-reported given a 1% increase in the number of deaths for the variable; an elasticity<0 indicates the percentage decrease in the number of records under-reported.

UCoD: underlying cause-of-death; HNSCC: head and neck squamous cell carcinoma; HIV: Human Immunodeficiency Virus infection; AIDS: Acquired Immune Deficiency Syndrome; ref.: reference; CI 95%: confidence intervals at 95%.

In the sensitivity analysis, adding HNSCC-attributable deaths outside hospital was associated with more under-reporting of HNSCC-attributable deaths in the UCoD records. This was the case for 2,054 (76.1%) of the 2,700 profiles, corresponding to 48,688 individual HNSCC-attributable deaths of which 26,489 were not identified as HNSCC-attributable in the UCoD records.

In the sensitivity analysis, the same factors associated with under-reporting were identified by multivariate Poisson regression as in the main analysis (Table 3). However, the strengths of these associations were generally lower than in the main analysis, except for the year of death (+10% in 2012 as compared to 2010) and gender (+7% in men as compared to women). In addition, under-reporting was independently associated with dying at home, which, together with public local hospitals, was the place of death associated with the highest rate of under-reporting.

Age-standardized mortality rate of HNSCC in France in 2012

For the year 2012, the age-standardized mortality rate for HNSCC derived from underlying cause-of-death records was less than half that derived from hospital discharge summaries (14.7 compared to 34.1 per 100,000 for men and 2.7 compared to 6.2 per 100,000 for women) (Figs 2–5).

Fig 2 — Age-Standardized Mortality Rates (ASMR) were standardized to the new European Standard Population (ESP 2011–2030).

Fig 5 — Age-Standardized Mortality Rates (ASMR) were standardized to the new European Standard Population (ESP 2011–2030).

Fig 3 — Age-Standardized Mortality Rates (ASMR) were standardized to the new European Standard Population (ESP 2011–2030).

Fig 4 — Age-Standardized Mortality Rates (ASMR) were standardized to the new European Standard Population (ESP 2011–2030).

Discussion

This study showed significant under-reporting of deaths attributable to HNSCC in national UCoD records as compared to the national hospital discharge (PMSI) database in France. Under-reporting was multi-factorial and has increased over recent years. For the year 2012, the age-standardized mortality rate of HNSCC derived from national UCoD records was less than half of the corresponding figure derived from the national hospital discharge database.

Misclassification problems in national UCoD records have been identified in many studies [3, 4, 6, 8, 9], including studies conducted in the French healthcare setting [5, 7, 12, 34]. The most commonly cited reasons for misclassification include physician inexperience in death certification and lack of appropriate training. In addition, retrospective determination of the “chain of events leading directly to death” may be problematic if the certifying physician was not involved in the care of the patient or has only limited access to the patient’s medical records. This situation seems particularly critical for HNSCC-attributable deaths, since exposure to tobacco and alcohol are major risk factors for HNSCC and may be responsible for multiple other causes of death declared on death certificates [35–37].

Previous studies on misclassification of HNSCC in UCoD records have all been conducted using U.S. population-based cancer registries. These have described a detection rate for HNSCC-attributable deaths in UCoD records of around 60% [10, 11, 13]. Our results are consistent with these findings, with a detection rate of HNSCC-attributable deaths at hospital in French UCoD records of 62% when considering only in-hospital death records (main analysis) and even lower (50%) when considering overall deaths in a sensitivity analysis. We also found that primary larynx cancer (19%) was significantly more likely to be reported in UCoD records compared to all other primary HNSCC sites [10, 11]. We also found that any distant metastasis recorded after HNSCC diagnosis (47%) was associated with an increased risk of HNSCC being under-reported in UCoD records [13]. These findings suggest that certifying physicians may be less attentive about specifying primary HNSCC sites associated with poor prognosis in death certificates [19].

This study using data from the national hospital discharge (PMSI) database provides new information on the frequency and nature of competing causes of death in patients with HNSCC. Previous studies have been conducted in cancer registries which do not usually record comorbidities and have excluded multiple primary cancers from the analysis [10, 11, 13]. For the deaths considered to be HNSCC-attributable from the national hospital discharge (PMSI) database, the presence of competing causes of death was the rule rather than the exception: 64% of HNSCC-attributable deaths were associated with comorbidities, 13% with multiple HNSCC and 43% with a primary cancer other than HNSCC. WHO coding rules and procedures prioritize cancer as the UCoD over comorbidities, with the exception of HIV/AIDS [2, 22]. Consistent with these recommendations, we did not find that comorbidities were associated with under-reporting of HNSCC in UCoD records (except for HIV/AIDS and depression).

Regarding multiple primary cancers, WHO coding rules and procedures prioritize reporting of the first primary cancer as the UCoD over a second primary cancer [2, 22]. We found that another primary cancer treated before HNSCC (10%) was significantly associated with under-reporting of HNSCC in the UCoD records. Nonetheless, primary esophageal cancer (8%) was significantly associated with better reporting of HNSCC. This may suggest that certifying physicians are more careful about specifying the primary HNSCC site as the UCoD when multiple cancers of the same body system are present, and supports recoding practices considering the first primary HNSCC site as the UCoD rather than esophageal cancer [22]. We found that a second synchronous cancer other than HNSCC was associated with under-reporting of HNSCC in UCoD records. Since lung cancer was the most frequent second primary cancer (16.1%), and may arise from metastatic spread of HNSCC [2], our findings suggest that certifying physicians usually simplify the “chain of events leading directly to death” by reporting lung cancer as the UCoD rather than the primary HNSCC site.

Finally, our findings suggest that the cancer specialization of the certifying physician is important for accurately identifying a primary HNSCC site as the UCoD. Of 41,503 individuals dying in hospital in 2008–2012, 69% received palliative care provided by non-cancer specialists and 56% died in public local hospitals where cancer specialists are under-represented. In agreement with a previous study on the misclassification of uterine cancers in French UCoD records [38], we found that both markers of a lower cancer specialization of the certifying physician were strongly associated with under-reporting of HNSCC in UCoD records. Similarly, death certification at home is generally not performed by a cancer specialist in France and we found that death certification outside hospital (19% of overall deaths in the sensitivity analysis) was associated with a similar degree of under-reporting.

The study has a number of strengths and limitations, which are frequently interrelated. An important strength is the fact that the study is based on a nationwide sample of all patients discharged with HNSCC, for whom a full medical history could be reconstituted from all hospital discharge records from January 1^st, 2008, until death in 2008–2012. The use of an algorithm to identify all HNSCC-attributable deaths in the national hospital discharge (PMSI) database avoids problems of subjectivity such as those associated with the judgment of the certifying physician in the UCoD records. On the other hand, the accuracy of the algorithm is critical for the robustness of the findings. The performance of the algorithm had not been externally validated prior to the study. Nonetheless, we found that HNSCC was identified as a probable/possible cause of death in more than 85% of cases within a short interval after diagnosis of HNSCC. This is consistent with data from French cancer registries indicating that HNSCC was the initial cause of death in 93% of deaths recorded within five years after diagnosis [39].

The detection of HNSCC-attributable deaths by the algorithm was logically sensitive to the length of follow-up at death due to left-censoring of the national hospital discharge (PMSI) database on January 1^st, 2008. Overall, we found that identification of a relapse in the follow-up was the main criterion by which HNSCC was determined as the probable cause of death (S3 Table in S1 File). In consequence, HNSCC was identified as the probable cause of death in 51% of HNSCC-attributable deaths in 2008 (all decedents had less than one year of follow-up) as compared to 74% in 2012 (decedents may have up to five years of follow-up). In this regard, our study results for the year 2012 are the most reliable and suggest that the detection rate of HNSCC in UCoD records may be as low as 43% (Fig 1).

Since follow-up was right-censored at last hospital discharge in 2008–2012, we conducted a sensitivity analysis to assess death outside hospital in patients who were lost to follow-up after hospital discharge (S1 Methods in S1 File). Of 51,129 HNSCC-attributable deaths estimated overall, 41,503 (81.2%) occurred in hospital, which is consistent with the proportion (73%) of cancer deaths in death certificates in which the hospital is given as the place of death [40]. These limitations due to censoring in the national hospital discharge (PMSI) database may be overcome in the future, as a result of ongoing efforts to facilitate broader access to the last ten years of the national hospital discharge database with information on vital status on December 31^st of the last study year [41]. In addition, possible linkage of the national hospital discharge (PMSI) database to the national database of multiple causes of death would provide more specific information on whether HNSCC was simply not mentioned on the death certificate [18] or, as may be more likely, misclassified as an associated cause of death rather than the UCoD [12].

Conclusions

HNSCC is largely under-reported in cause-of-death records in France. This study documents the value of national hospital discharge databases as a complement to death certificates for ascertaining cancer deaths in general and HNSCC-attributable deaths in particular.

Supporting information

S1 File

(DOCX)

Click here for additional data file.^{(117.3KB, docx)}

Acknowledgments

The EPICORL (EPIdémiologie des Cancers ORL) Study Group includes: Sylvain Baillot, MSc, Translational Health Economics Network (THEN), Paris, France; Mélina Bec, MSc, Health Economics & Outcomes Research department, MSD France; Lynda Benmahammed, MD, Medical Advisor Oncology, MSD France; Caroline Even, MD, PhD, Department of Head & Neck Surgical & Medical Oncology, Institut de cancérologie Gustave Roussy, Villejuif, France; Lionnel Geoffrois, MD, PhD, Department of Medical Oncology, Institut de cancérologie de Lorraine–Alexis Vautrin, Vandoeuvre Les Nancy, France; Florence Huguet, MD, PhD, Department of Radiation Oncology, Hôpital Tenon, AP-HP, France; Béatrice Le Vu, MD, MSc, Stratégie et Gestion Hospitalière, UNICANCER Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France & Translational Health Economics Network (THEN), Paris, France; Laurie Lévy-Bachelot, PhD, Health Economics & Outcomes Research department, MSD France; Stéphane Luchini, PhD, CNRS, GREQAM-IDEP, Marseille, France & Translational Health Economics Network (THEN), Paris, France; Yoann Pointreau, MD, PhD, Department of Radiation Oncology, ILC- Institut inter-régionaL de Cancérologie, Centre Jean Bernard-Clinique Victor Hugo, Le Mans, France; Camille Robert, PharmD, Health Economics & Outcomes Research department, MSD France; Luis Sagaon Teyssier, PhD, AMU/Inserm/IRD, UMR 912, Marseille, France & Translational Health Economics Network (THEN), Paris, France; Antoine Schernberg, MD, MPH, Department of Radiation Oncology, Hôpital Tenon, AP-HP, Paris, France; Michaël Schwarzinger, MD, PhD, Translational Health Economics Network (THEN), Paris, France; Stéphane Temam, MD, PhD, Department of Head & Neck Surgical & Medical Oncology, Institut de cancérologie Gustave Roussy, Villejuif, France.

Data Availability

French UCoD statistics are publicly available from the Epidemiological Center on Medical Causes of Death (CépiDc-INSERM) at https://www.cepidc.inserm.fr/causes-medicales-de-deces/interroger-les-donnees-de-mortalite. De-identified data from the 2008-2013 French national hospital discharge (PMSI) database are available from the Agence Technique de l’Information sur l’Hospitalisation (ATIH) at https://www.atih.sante.fr/bases-de-donnees/commande-de-bases.

Funding Statement

The EPICORL study was supported by a research grant from Merck Sharp & Dohme (MSD) France. Translational Health Economics (THEN) was responsible for data collection, preparation, and statistical analysis. THEN received payment from Merck Sharp & Dohme (MSD) France for these research activities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0246252.r001

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Underlying cause-of-death statistics underestimate the burden of head and neck squamous cell carcinoma: a nationwide hospital study in France, 2008-2012

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: August 28, 2020

Manuscript Number: PONE-D-20-25023

“Underlying cause-of-death statistics underestimate the burden of head and neck squamous cell carcinoma: a nationwide hospital study in France, 2008 - 2012”

Dear Dr Brecht Devleesschauwer,

I deeply appreciate your kind consideration of me to review this manuscript. I reviewed it with great interest.

Authors have tried to highlight the underreporting of causes of death of head and neck squamous cell carcinoma (HNSCC) by comparing two national databases and identified some potential factors associated with that. The approach used in this study is interesting. The evidence of this study is of great importance to improve the coding of related deaths that would help to calculate the burden of disease estimates correctly.

The authors did not actually estimate the burden of death statistics of HNSCC but highlighted the under-reporting of death statistics. Therefore, I propose to revise the title of the manuscript such as “Factors associated with under-reporting of death statistics of HNSCC: A comparative study of two national databases in France from 2008 to 2012.”

The authors have performed a multivariate Poisson regression analysis to identify the factors associated with under-reporting of HNSCC death statistics. Overall analysis and the results are robust. However, this manuscript needs to improve the quality of writing throughout the manuscript and the structure of methods, results and discussion sections. Most of the sentences are too long and should split in short to make it clear and more comprehensible. Therefore, the authors should ask a native English speaker for its proofreading. Therefore, I proposed “major revisions” to improve the quality of writing of this manuscript. Please find my comments below this letter.

Sincerely,

Romana Haneef

Reviewer’s comments to authors

Formatting

Page numbers and line numbers are missing. The spacing between the references numbers is not appropriate. Please update the manuscript according to the guidelines of the journal.

Title:

The authors did not estimate the burden of death statistics of HNSCC but highlight the under-reporting of death statistics. Therefore, I propose to revise the title of the manuscript such as “Factors associated with under-reporting of death statistics of HNSCC: A comparative study of two national databases in France from 2008 to 2012.”

Abstract

Please add the following information:

• Objective: The authors can update and add another objective as follows: “Our objectives were to compare the reporting of death attributable to HNSCC from two national databases in France and to identify the underlying factors associated with under-reporting.”

• Methods: Authors used the word “The determinants of missing HNSCC…, it is better to replace it with under-reporting.

• Results: Please revise the sentence structures for the results section.

• Conclusions: Please revise the first sentence according to the updated title.

Introduction

• In the first paragraph, last sentence “to our knowledge […]”, authors used exposure to tobacco and alcohol account for larger population attributable fractions of HNSCC but did not take into account these factors in their analysis. It is unclear to me mention it here. I propose to remove it and rephrase it.

• Please replace the word “combining” with “linking” individual records […] at the beginning of the second paragraph.

• Please revise the text to improve the level of writing and avoid using words like instead, around, possibly.

Materials and methods

• Please add as a sub-heading the study design (part of the text from sub-section of the definition of HNSCC attributable deaths at hospital) and study population (inclusion and exclusion criteria from S2 table and cite S2 table under this section) just before the data sources.

• Please also add the definition of “unlikely cause of death” at the end of the sub-section of the definition of HNSCC attributable deaths at hospital).

• Please revise the text of the last paragraph of the sub-section of “characteristics of HNSCC attributable deaths at hospital” and mention the “end of life characteristics” as 1. palliative care and 2. place of death (under this characteristic, authors can report deaths recorded at different places). This description should correspond to the table, which is not numbered (I suppose, table 4).

• Please specify death at six age groups in the main text under the section of UCoD statistics for HNSCC.

• Please add the sub-section of study outcomes before the statistical analysis (the first paragraph of statistical analysis could be moved to the study outcome section).

• Please revise the text to improve the level of writing

Results

1. The authors can start the result section by reporting the “General characteristics of deaths attributable to HNSCC according to two national databases in France” as table 1 rather than table 2.

a. Please add the word “National”UCoD statistics in table 1 (currently table 2)

2. The second sub-section of results could be “Death attributable to HNSCC at hospital” as table 2.

a. Under this section, please also report the “unlikely death attributable to HNSCC” in the main text.

b. Authors can report the “relapse in the follow-up overall from 2008 to 2010 from S3table to the main text and in table 2 as well.

c. Citation of S2 table is not appropriate in this section.

d. Please remove the word “definition” from the legend of table 2 (currently table 1) and start with “Deaths attributable […]”.

e. In figure 1, please report the respective percentages of probable and possible causes of death attributable to HNSCC. Currently, it is unclear, for example in 2008, under in-hospital death, 70% corresponds to both causes of death (probable and possible)? Is this figure based on the data from S3 table?

3. The last paragraph of sub-section “Comparison of HNSCC […]”, please replace the word “multiple primary HNSCC” with “decedent”, which does not correspond to the table S4table.

a. Please update the title as follows: “Comparison of HNSCC […] with UCoD statistics”.

4. The last sub-section of the results is unclear with long sentences. I propose to revise it and split into short sentences to make it more comprehensible.

a. Under this sub-section, a table is reported and not numbered. I guess it should be table 4. Please add the table number and heading/legend of this table.

Discussion

• The authors should revise the overall text of the discussion section without repeating the same results, avoid long sentences, report strengths and limitations in a more clear text.

• This section could be started such as “The result of this study showed the underreporting of death attributable to HNSCC in national UCoD as compared to national hospital discharge database.”

• Avoid using words such as massive, unexpectedly, rather, indeed, altogether, etc.

• Authors mentioned again the same phrase as reported in the introduction section “To our knowledge […]”, it is nuclear. Please explain the reason to repeat this sentence.

Conclusions

Please update the conclusions section and do not report the results in this section.

Reviewer #2: Overall the paper is well written and the analyses presented is clear and strongly support the conclusions reached. Some minor comments to improve the paper are outlined below:

-The paper doesn't make it clear whether deaths with an associated cause of death recorded as HNSCC have been looked at. Analyses of Australian deaths data suggests that HNSCC deaths would increase by around one-third (33%) if associated causes of death are included. Can this be looked at in the French mortality data?. If not, or if no deaths are recorded with HNSCC as an associated cause, then suggest making this more explicit in the paper.

- The statistics reported in the paper to do include a variance measure (ie confidence intervals). Is it possible to include these, or if not, provide a reason why these have not been included or are deemed not to be needed for the analyses presented.

- Paper could benefit from a gramma check to fix minor grammatical errors eg in the abstract results - 'associated to' should be 'associated with'

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: Yes: Romana Haneef

Reviewer #2: Yes: Ms Michelle Gourley

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Attachment

Submitted filename: Major Revisions_PONE-D-20-25023.docx

Click here for additional data file.^{(22KB, docx)}

PLoS One. 2021 Feb 3;16(2):e0246252. doi: 10.1371/journal.pone.0246252.r002

Author response to Decision Letter 0

17 Nov 2020

Reviewer #1 Romana Haneef

Dear Dr Brecht Devleesschauwer,

I deeply appreciate your kind consideration of me to review this manuscript. I reviewed it with great interest.

Thank you for your positive appraisal of our study and the time taken to help improving the clarity of the manuscript. We have modified the title as suggested and the revised manuscript has been proofread.

Formatting

Page numbers and line numbers are missing. The spacing between the references numbers is not appropriate. Please update the manuscript according to the guidelines of the journal.

We are sorry for the inconvenience for the reviewing process. In the revised manuscript, we have added page numbers and line numbers per page. It seems double-spacing was already used throughout the manuscript, including for the references.

Title

We agree with the reviewer and the title has been changed accordingly into “Factors associated with under-reporting of head and neck squamous cell carcinoma in cause-of-death records: a comparative study of two national databases in France from 2008 to 2012”.

Abstract

Please add the following information:

We agree with the reviewer and objectives have been modified accordingly in the abstract.

• Methods: Authors used the word “The determinants of missing HNSCC…, it is better to replace it with under-reporting.

We agree with the reviewer that it is better to use the same terminology and “determinants of missing HNSCC” has been replaced by “factors associated with under-reporting of HNSCC” throughout the revised manuscript.

• Results: Please revise the sentence structures for the results section.

The revised manuscript has been proofread.

• Conclusions: Please revise the first sentence according to the updated title.

This has been done in the revised manuscript.

Introduction

We agree with the reviewer and we removed this from the Introduction in the revised manuscript. The ideas are now taken up in the Discussion.

• Please replace the word “combining” with “linking” individual records […] at the beginning of the second paragraph.

This has been corrected in the revised manuscript.

• Please revise the text to improve the level of writing and avoid using words like instead, around, possibly.

We have rewritten the second paragraph to improve clarity in the revised manuscript that has been proofread.

Materials and methods

Following the reviewer’s suggestion, we have added a Study design section at the beginning of Material and Methods in the revised manuscript. In addition, inclusion and exclusion criteria (S2 Table), which are specific to the retrospective analysis of the national hospital discharge database have been transferred from the Results to the corresponding section in the Material and Methods (Identification of HNSCC-attributable deaths at hospital).

• Please also add the definition of “unlikely cause of death” at the end of the sub-section of the definition of HNSCC attributable deaths at hospital).

This has been added in the revised manuscript.

This has been modified in the revised manuscript and “place of death” is now described in the Material and Methods, consistent with the terminology used in Table 3. All Tables were numbered in the submitted manuscript and there was no Table 4.

• Please specify death at six age groups in the main text under the section of UCoD statistics for HNSCC.

We have specified age groups in the revised manuscript.

• Please add the sub-section of study outcomes before the statistical analysis (the first paragraph of statistical analysis could be moved to the study outcome section)

This has been done in the revised manuscript.

• Please revise the text to improve the level of writing

The revised manuscript has been proofread.

Results

We would prefer to keep the initial order of presentation of the results (main text and Tables 1 and 2) in the revised manuscript. It seems more appropriate first to describe the HNSCC-attributable in-hospital deaths (Table 1) and then to compare these in-hospital deaths with those extracted from the national UCoD statistics (Table 2).

a. Please add the word “National” UCoD statistics in table 1 (currently table 2)

This has been added in the revised manuscript.

2. The second sub-section of results could be “Death attributable to HNSCC at hospital” as table 2.

Please see above about reordering of the presentation of results.

a. Under this section, please also report the “unlikely death attributable to HNSCC” in the main text.

This has been added in the revised manuscript.

b. Authors can report the “relapse in the follow-up overall from 2008 to 2010 from S3table to the main text and in table 2 as well.

This has been added in the revised manuscript.

c. Citation of S2 table is not appropriate in this section.

This has been removed in the revised manuscript.

d. Please remove the word “definition” from the legend of table 2 (currently table 1) and start with “Deaths attributable […]”.

This has been done in the revised manuscript

We agree with the reviewer that Figure 1, which presents annual detection rates of HNSCC-attributable in-hospital deaths identified in the national UCoD statistics could also be used to document the proportion of probable and possible in-hospital HNSCC deaths (presented in S3 Table). In line with the reviewer’s suggestion, we have clarified this in the revised manuscript. Figure 1 was removed from the first sub-section of the results (about probable/possible cause of death) to the second sub-section (about detection rates of HNSCC-attributable in-hospital deaths identified in the national UCoD statistics). Citation of Figure 1 in the first sub-section of results (about probable/possible cause of death) has been replaced by citation of S3 Table.

3. The last paragraph of sub-section “Comparison of HNSCC […]”, please replace the word “multiple primary HNSCC” with “decedent”, which does not correspond to the table S4table.

This has been corrected in the revised manuscript.

a. Please update the title as follows: “Comparison of HNSCC […] with UCoD statistics”.

This has been corrected in the revised manuscript.

4. The last sub-section of the results is unclear with long sentences. I propose to revise it and split into short sentences to make it more comprehensible.

This sub-section has been shortened to improve clarity in the revised manuscript.

a. Under this sub-section, a table is reported and not numbered. I guess it should be table 4. Please add the table number and heading/legend of this table.

This was actually the second part (elasticities) of Table 3. The two parts (relative risks and elasticities) of Table 3 have been reconciled when reformatting the revised manuscript.

Discussion

• The authors should revise the overall text of the discussion section without repeating the same results, avoid long sentences, report strengths and limitations in a more clear text.

We somewhat disagree on the first point of the reviewer as it seems better to elaborate the discussion starting from the main results. In addition, while we agree that Introduction/M&M/Results should be as concise as possible (see agreements with the previous comments of the reviewer), we do much appreciate having no words count limit in Plos One to put results into perspective. The revised manuscript has been proofread.

• This section could be started such as “The result of this study showed the underreporting of death attributable to HNSCC in national UCoD as compared to national hospital discharge database.”

This has been done in the revised manuscript and the first paragraph of the Discussion has been rewritten.

• Avoid using words such as massive, unexpectedly, rather, indeed, altogether, etc.

The revised manuscript has been proofread.

• Authors mentioned again the same phrase as reported in the introduction section “To our knowledge […]”, it is nuclear. Please explain the reason to repeat this sentence.

This has been removed in the revised manuscript.

Conclusions

Please update the conclusions section and do not report the results in this section.

This has been done in the revised manuscript.

Reviewer #2: Ms Michelle Gourley

Overall the paper is well written and the analyses presented is clear and strongly support the conclusions reached.

Thank you very much for your positive appraisal of our study.

Some minor comments to improve the paper are outlined below:

- The paper doesn't make it clear whether deaths with an associated cause of death recorded as HNSCC have been looked at. Analyses of Australian deaths data suggests that HNSCC deaths would increase by around one-third (33%) if associated causes of death are included. Can this be looked at in the French mortality data? If not, or if no deaths are recorded with HNSCC as an associated cause, then suggest making this more explicit in the paper.

National UCoD statistics only provide summary data for any selected UCoD (by year, gender, age group, region of residence). For this reason, we had no access to individual MCoD (multiple causes of death) nor to the number of HNSCC that may be coded as an associated cause of death. Following the reviewer’s comment, we have explicitly clarified that we had no access to MCoD data in the revised manuscript and discussed this point among the limitations of our study.

- The statistics reported in the paper do not include a variance measure (ie confidence intervals). Is it possible to include these, or if not, provide a reason why these have not been included or are deemed not to be needed for the analyses presented.

We did not calculate confidence intervals for summary statistics presented in Table 1 and 2 (counts), Figure 1 (counts), and Figures 2 to 5 (ASMR) because the summary statistics are related to observations at the national level and it was not relevant to account for sampling error. Otherwise, 95% confidence intervals were presented for all coefficients estimated in the multivariate Poisson regression (Table 3).

- Paper could benefit from a gramma check to fix minor grammatical errors eg in the abstract results 'associated to' should be 'associated with'

This has been corrected in the revised manuscript that has been also proofread.

Attachment

Submitted filename: PONE-D-20-25023_Responses to Reviewers.docx

Click here for additional data file.^{(36.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0246252.r003

Decision Letter 1

Brecht Devleesschauwer

15 Dec 2020

PONE-D-20-25023R1

Factors associated with under-reporting of head and neck squamous cell carcinoma in cause-of-death records: a comparative study of two national databases in France from 2008 to 2012

PLOS ONE

Dear Dr. Schwarzinger,

Please submit your revised manuscript by Jan 29 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Brecht Devleesschauwer

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The reviewers appreciated your efforts to address their comments, but raised some remaining smaller editorial issues. These can be addressed in a final, minor revision round.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Reviewer’s comments to authors

Abstract

• Results: Please add the word “national” before UCoD records [..] in the first phrase.

Materials and methods

• May be revise the title of the sub-section as “characteristics of HNSCC attributable deaths in national hospital discharge database (PMSI)”.

• Please add one sentence to introduce PMSI database in this section and explicit the abbreviation (programme de médicalisation des systèmes d’information).

• It is better to use “national hospital discharge database (PMSI)” than only PMSI. In France, it is well known but in general using this abbreviation may be confusing. Therefore, I suggest adding, “national hospital discharge database and mention in bracket the PMSI”. Please update it throughout the manuscript.

Results

• Please revise the title of the section as suggested above in the method section as “Deaths attributable to HNSCC in national hospital discharge database (PMSI)”.

• Update the title of table 1 as well.

Discussion

This section needs some revisions and please check with an English native speaker for the proofreading of this section. Some suggestion to update the followings items:

• Please update the sentence as “This study showed significant under-reporting […]”

• First paragraph, last sentence: « […] national UCoD records was less than half of the

the PMSI database. »

• Second paragraph, last sentence, could split in two sentences as follows:

« This situation seems particularly critical for HNSCC-attributable deaths, since exposure to tobacco and alcohol are major risk factors for HNSCC. Moreover, multiple other causes of death that are declared in death certificates, may be responsible for that. »

• Third paragraph, in second sentence, please remove the word “consistently”.

• On page 27

o line 2-3, please remove the word “taken together” and start the sentence with “These findings […].

o Line 6, please remove “U.S.”.

o Line 8-9, update the sentence as follows: “HNSCC-attributable deaths in PMSI database were considered as the rule than exception […].

o Line 13, please remove the word “generally”.

o Iine 16-17, please remove the work “again” and “in general”.

Conclusions

• Please remove the word “in particular”.

Reviewer #2: The authors have adequately addressed my previous comments.

One additional comment to consider is to add to the discussion that some of the head and neck SCC deaths may be hidden/included in the group of ICD 10 codes C76-C80 Malignant neoplasms of ill-defined, secondary and unspecified site. This could be the case where the certifying doctor has not provided specific details about the site and type of cancer on the medical certificate of cause of death.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Romana Haneef

Reviewer #2: Yes: Ms Michelle Gourley

PLoS One. 2021 Feb 3;16(2):e0246252. doi: 10.1371/journal.pone.0246252.r004

Author response to Decision Letter 1

15 Jan 2021

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #2 who is a native English speaker found that both manuscript and R1 were “presented in an intelligible fashion and written in standard English”. Following the first comments of reviewer #1, the revised version of the manuscript (R1) has been entirely proofread by a native English speaker. We thank reviewer #1 for her continued scrutiny and all her comments were taken into account, although we do not believe that re-asking that R2 is proofread by a native English speaker is worth the extra time and money at this stage.

Reviewer #1: Reviewer’s comments to authors

Abstract

• Results: Please add the word “national” before UCoD records [..] in the first phrase.

This has been added in the R2 version of the manuscript.

Materials and methods

• May be revise the title of the sub-section as “characteristics of HNSCC attributable deaths in national hospital discharge database (PMSI)”.

This has been modified in the R2 version of the manuscript into “characteristics of HNSCC attributable deaths in the national hospital discharge database” as subtitles should be better kept short and reference to “PMSI” is provided at all occurrences in the text (see below).

• Please add one sentence to introduce PMSI database in this section and explicit the abbreviation (programme de médicalisation des systèmes d’information).

This was already done in the R1 version of the manuscript (lines 3-4 page 4).

We agree with the reviewer. This has been modified in the R2 version of the manuscript except in subtitles and Table/Figure titles where the mention of “(PMSI)” has been removed (see above).

Results

• Please revise the title of the section as suggested above in the method section as “Deaths attributable to HNSCC in national hospital discharge database (PMSI)”.

This has been modified in the R2 version of the manuscript (see above).

• Update the title of table 1 as well.

This has been modified in the R2 version of the manuscript (see above).

Discussion

This section needs some revisions and please check with an English native speaker for the proofreading of this section. Some suggestion to update the followings items:

Please see above our overall comment.

• Please update the sentence as “This study showed significant under-reporting […]”

This has been modified in the R2 version of the manuscript.

• First paragraph, last sentence: « […] national UCoD records was less than half of the PMSI database. »

This has been modified in the R2 version of the manuscript.

• Second paragraph, last sentence, could split in two sentences as follows: « This situation seems particularly critical for HNSCC-attributable deaths, since exposure to tobacco and alcohol are major risk factors for HNSCC. Moreover, multiple other causes of death that are declared in death certificates, may be responsible for that. »

We agree with the reviewer. This has been clarified in the R2 version of the manuscript.

• Third paragraph, in second sentence, please remove the word “consistently”.