# Association Between Diseases and Symptoms Diagnosed in Primary Care and the Subsequent Specific Risk of Multiple Sclerosis

Octave Guinebretiere, Thomas Nedelec, Laurène Gantzer, Beranger Lekens, Stanley Durrleman, Céline Louapre

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## To cite this version:

Octave Guinebretiere, Thomas Nedelec, Laurène Gantzer, Beranger Lekens, Stanley Durrleman, et al. "Association Between Diseases and Symptoms Diagnosed in Primary Care and the Subsequent Specific Risk of Multiple Sclerosis." Neurology, 2023, 101 (24), 10.1212/WNL.0000000000207981. hal-04330030

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Submitted on 8 Dec 2023

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1 Association Between Diseases and Symptoms Diagnosed in Primary Care

2 and the Subsequent Specific Risk of Multiple Sclerosis

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4 Octave Guinebretière, MSc¹; Thomas Nedelec, PhD¹; Laurène Gantzer, MSc²; Beranger

5 Lekens, MSc²; Stanley Durrleman, PhD¹; Céline Louapre, MD, PhD¹,³

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7 Affiliation

8 1. Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, Inria, Paris, France

9 2. Cegedim R&D, Boulogne-Billancourt, France

10 3. Department of Neurology, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Assistance

11 Publique-Hôpitaux de Paris, Paris, France

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13 Number of words (body of the manuscript): 4499

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15 Corresponding author

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17 Celine Louapre

18 Paris Brain Institute (ICM),

19 Hôpital Pitié-Salpêtrière,

20 47 bd de l'Hôpital,

21 75651 Paris Cedex 13

22 France

23 E-mail: celine.louapre@aphp.fr

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**Objective:**
Previous studies have reported a possible prodrome in multiple sclerosis (MS) defined by non-specific symptoms including mood disorder or genito-urinary symptoms and increased health care use detected several years before diagnosis.

This study aimed to evaluate agnostically the associations between diseases and symptoms diagnosed in primary care and the risk of multiple sclerosis (MS) relative to controls and two other autoimmune inflammatory diseases with similar population characteristics, namely lupus and Crohn's disease.

## Methods:

A case-control study was conducted using electronic health records from the Health Improvement Network database in the UK and France. We agnostically assessed the associations between 113 diseases and symptoms in the five years before and after diagnosis in patients with subsequent diagnosis of MS. Individuals with a diagnosis of MS were compared to individuals without MS, and individuals with two other auto-immune diseases, Crohn's disease and lupus.

## Results:

The study population consisted of patients with MS (n= 20,174), patients without MS (n=54,790), patients with Crohn's disease (n=30,477) or patients with lupus (n=7,337). Twelve ICD-10 codes were significantly positively associated with the risk of MS compared to controls without MS. After considering ICD-10 codes suggestive of neurological symptoms as the first diagnosis of MS, five ICD-10 codes remained significantly associated with MS: depression (UK OR 1.22 [95%CI 1.11-1.34]), sexual dysfunction (1.47 [1.11-1.95]), constipation (1.5 [1.27-1.78]), cystitis (1.21 [1.05-1.39]), and urinary tract infections of unspecified site (1.38 [1.18-1.61]). However, none of these conditions was selectively associated with MS in comparisons with both lupus and Crohn's disease. All five ICD-10 codes identified were still associated with MS during the five years after diagnosis.
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**Conclusion:**

We identified 5 health conditions associated with subsequent MS diagnosis, which may be considered not only prodromal but also early-stage symptoms. However, these health conditions overlap with prodrome of two other autoimmune diseases, hence lacking specificity to MS.

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**Introduction**

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A mismatch between clinical symptoms and visible brain lesions on magnetic resonance imaging (MRI), the so-called clinico-radiological paradox, has been known for decades in multiple sclerosis (MS).¹ While this phenomenon has been linked to the heterogeneity of MS clinical outcomes, it could also explain why certain subtle, non-specific symptoms were identified prior to the neurological diagnosis and described as MS prodrome. Moreover, recent studies suggest that patients with MS display increased serum neurofilament biomarkers before the onset of typical MS symptoms.²,³ Prodromal health conditions would not be sufficiently pronounced to warrant diagnosis, but they might indicate the start of the neuroinflammatory process, similar to preclinical pathophysiological mechanisms occurring before clinical onset in other neurological diseases.⁴,⁵ The recognition of a prodromal period would help to gain knowledge on the consequences of the appearance and accumulation of MS lesions but also on the temporality of MS pathophysiological processes. Although it is unlikely that the description of a prodrome in MS might lead to specific intervention in the general population, it could be important to identify such period in populations with a high risk of developing MS due to familial history or in the case of radiologically isolated syndrome (RIS). A recent study from the RISC consortium has found a 51% cumulative probability of a first clinical event at 10 years in patients with RIS.⁶ For those at highest risk of a first clinical event, identifying prodromal
health conditions within these 10 years might lead to potential earlier therapeutic intervention.

This assumption would be relevant only if MS prodrome would be rather specific to MS, and
not similar to other auto-immune conditions.

Previous studies have reported pre-diagnostic features, such as depression, fatigue, sleep
disorders or urinary infections, associated with MS and occurring up to 10 years before
diagnosis.⁷⁻⁹ However, most studies on MS prodrome have focused on either hypothesis-driven
searches for non-specific symptoms,⁸,⁹ or major disease categories.⁷ It is also important to
compare the early presentation of MS with other inflammatory diseases and to determine which
of the pre-diagnosis features are specific to MS. There is also a need for further analyses of
differences in the clinical presentation of MS prodrome by age,¹⁰ sex,⁹⁻¹¹ and year of diagnosis¹²
in order to improve our understanding of the prodrome onset.

We set up and analyzed two nested case-control studies based on data from two large primary
care databases in the UK and France, extracted from The Health Improvement Network (THIN)
database. We sought to confirm the previously reported associations ⁷⁻⁹ between pre-diagnosis
features and the subsequent diagnosis of MS, to assess whether combining these pre-diagnosis
features could provide a greater ability to discriminate between patients with subsequent MS
and patients without MS, and to compare presentations before and after diagnosis. We also
aimed to compare MS cohort with control cohorts of patients with other autoimmune diseases
— lupus and Crohn's disease — to determine whether the features identified were specific to
MS or common to several autoimmune diseases. Lupus and Crohn's disease were selected
because both have female predominance, affect young adults,¹³ and both present pre-clinical
non-specific signs and symptoms. In lupus, increased pre-diagnosis healthcare use has been
reported,¹⁴ notably childhood-onset lupus cases had higher frequency of pre-diagnosis
psychiatric conditions compared to matched controls.¹⁵ In Crohn's disease, an association
between pre-diagnosis depression and incident Crohn's disease was reported.¹⁶ Although these
diseases have distinct phenotypes and involve different target organs, there is an overlap of environmental risk factors for disease occurrence or exacerbation such as stress and smoking.<sup>17-19</sup> Hence, to determine which health conditions are specific to MS prodrome, we compared MS to both a systemic (lupus) and an organ-specific (Crohn's disease) auto-immune disease.

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## 131 Methods

### 132 *Study design and participants*

We used The Health Improvement Network (THIN) database,<sup>21</sup> a large standardized European database of fully anonymized and non-extrapolated electronic medical records collected from physicians by the company GERS SAS<sup>21</sup> and coded according to the International Classification of Diseases, 10th revision (ICD10). The THIN database complies with all current European data protection laws (General Data Protection Regulation) and adheres to the Observational Medical Outcomes Partnership model.<sup>21</sup> Details on data collection are specified in the method section of supplementary materials. We considered data recorded from Jan 1, 1996, to March 28, 2022 in the UK and from Jan 1, 1998, to March 28, 2022 in France.

In both countries, we defined a cohort of cases with incident MS and respectively three other control cohorts: i) individuals without incident MS; ii) patients with incident lupus; iii) patients with incident Crohn's disease. Patients with MS were required to have a record of the ICD-10 code G35, lupus the ICD-10 code M32, and Crohn's disease the ICD-10 code K50. The amount of co-occurrence between these diseases in our database did not warrant the exclusion of individuals with more than one auto-immune disease. We first compared the MS cohort to controls without MS in primary and sensitivity analyses and used all significant findings for further analyses in which we compared the MS cohort to lupus and Crohn's disease cohorts. In the primary analysis, index date was defined as the earliest date of at least one of the following conditions: i) G35 code; ii) other ICD-10 codes related to a demyelinating event (e.g myelitis
or optic neuritis, complete list in eTable 1). Age at MS onset was defined as age at the index date. As exact diagnosis date may be difficult to firmly determine in primary care setting, we also ran a sensitivity analysis, in which we shifted the index date further back, to the earliest ICD-10 code indicating neurological symptoms (e.g. paresthesia, dizziness) which could be interpreted retrospectively as MS clinical onset.¹² For this purpose, we used the ICD-10 codes listed in eTable 2.

For each country, we randomly selected three controls without MS for each MS case, matched in terms of age at index date, sex and year at index date. A symptom was considered to be present if either the corresponding ICD-10 code or the prescription of a symptom-specific drug was recorded (eTable 3 and eTable 4). Only individuals with available data at least two years before the index date in the case and control cohorts were included, as shown in the flowchart in eFigure 1, 2. For the sensitivity analysis, we applied the same shift in index date to each matched control. We also defined a cohort of patients with MS and individuals without MS with at least 5 years of data before diagnosis to ensure balanced available data between the two groups.

## Exposure extraction on the basis of ICD10 classification

We defined past exposure to the health conditions considered, based on the ICD-10 codes provided directly in both the French and UK databases. The validity of significant diagnoses in THIN is high.²²⁻²⁴ More specifically for MS, a previous study using one ICD-10 code G35 to define MS reported similar incidence and prevalence findings to a General Practice Research (GPRD) study.²⁵,²⁶ This previous study also had similar results to an internal validation study of MS identification in the GPRD which reported high accuracy.²⁶,²⁷ We used the first three characters of the code, defining disease category. In this exploratory approach, we assessed the
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association between MS and each of the health conditions defined by ICD-10 codes with a
relative frequency of more than 0.5% in both MS and control cohorts and in both countries.

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*Standard protocol approvals, registrations, and patients consent*

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Approval was sorted before carrying out this study (and for the use of datasets). The study was
a retrospective analysis of secondary anonymised patient data only. For the UK database, data
is only available to researchers carrying out approved medical research. Ethical approval was
granted by the NHS South-East Multicentre Research Ethics Committee in 2003 (ref:
03/01/073) for establishment of the THIN database, and it was updated in 2011. A further
update and approval was granted in 2020 by the NHS South Central, Oxford C Research Ethics
Committee (Ref: 20/SC/0011). For the French Database, several audits were conducted by
CNIL (Commission Nationale de l'Informatique et des Libertés, the French authority
responsible for the protection of personal data). Data are available from the GERS SAS for
researchers who meet the criteria for access to confidential data. Researchers willing to replicate
the results should address a request to the Cegedim company (info@the-health-improvement-
network.co.uk). The study was approved by the THIN Scientific Research Committee (SRC)
on 4th Feb 2022 (SRC reference 21-016). There was no need for written informed consent from
participants. No photographs, videos, or other information of recognizable persons is used in
this article. Authorization for disclosure was therefore not necessary.

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**Statistical analysis**

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We used logistic regression to analyse the association between each health condition
corresponding to a specific ICD10 code and the diagnosis of MS. We quantified the association
by calculating odds ratios (ORs) and 95% CIs for exposure to a particular health condition
within five years of the index date. P values were corrected for multiple comparisons with the

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Bonferroni method, with an alpha risk of 5%. Values of *p*<0·0004 in two-tailed tests were considered significant (*p*=0·05 with Bonferroni correction for 113 potential exposures). As the exclusion of some patients with MS and controls without MS (eFigure 1 and eFigure 2) led to a break in the matching, all analyses were adjusted for sex (dichotomous variable), age at diagnosis (continuous variable), year at diagnosis (continuous variable), and the duration of follow-up (continuous variable). For the comparison between MS and other autoimmune diseases, we performed a logistic regression analysis controlled for age at index date, sex, and duration of follow-up.

We studied post-diagnosis presentation, using a Cox regression model with MS as the exposure of interest, considering the given health condition as the outcome and the time to the event or the time to last visit or data extraction as the time variable. To compare pre and post-diagnosis presentation, we restricted the cohorts of patients with incident MS and no MS to patients with at least two years of data before and after the index date.

We stratified our analyses before and after MS diagnosis on sex, age at diagnosis, and year at diagnosis. To stratify on age at diagnosis, we split the data into three cohorts of equal size, using the 33rd and 66th percentiles for age at diagnosis as cutoff points. To stratify on year at diagnosis, we used the year 2010 and 2017 since new MS diagnostic criteria were defined in 2010²⁸ and 2017.²⁹ These criteria have been shown to facilitate earlier diagnosis and to increase sensitivity of MS diagnosis.³⁰,³¹

In investigations of temporal associations, we also used the significant findings from the comparison of the MS cohort to individuals without MS, with the exception of one condition, to chart the single-year prevalence of the prescription of symptom-specific drugs for each of the 15 years before and after MS diagnosis. We also investigated healthcare use, based on the mean number of GP visits per year. To handle patients who were not followed during the entire 30 years period, the prevalence was computed based on the exact number of patients at risk for
each specific year. We also included analyses on specific subsets of patients who were followed for at least x number of years (where x can be 15, 10, or 5) before and after diagnosis.

Finally, we conducted the analyses in each country, and we also pooled the data by combining individual patient records from the two countries, adding country as covariate to account for heterogeneity between countries (referred as pooled analyses). Indeed, data homogeneity is partly guaranteed by shared data collection process and OMOP data format between countries, but heterogeneity remains in the type of population and healthcare settings in each country.

Pooling individual patient records allowed to increase statistical power, and presenting results in separate countries allowed to examine the consistency of findings in different settings.

## 236 **Results**

### 237 *Demographic information*

In this analysis, from French and British health records, we included respectively 4,366 and 15,808 patients with MS, 12,531 and 42,226 individuals without a diagnosis of MS, 2,041 and 5,296 patients diagnosed with lupus, and 9,605 and 20,872 patients diagnosed with Crohn's disease. Age and sex distribution of MS cohort, and the three control cohorts of patients with other autoimmune diseases or individuals without MS are presented in **Table 1**.

Median age at MS diagnosis was 46 years (37–57 years) in the UK and 44 years (34–54 years) in France, with an age at first MS symptoms of 44 years (34–54 years) in the UK and 42 years (32–52 years) in France. For patients diagnosed after 2017, age at first MS symptoms decreased to 39 years (30–50 years) in the UK and 40 years (30–51 years) in France. More follow-up data were available from the UK sample, with 9 person-years of data available before the index date in the full analytical cohort versus only 6 person-years on average for the French sample.

Median number of visits per year was also higher in the UK than in France.

Female predominance was observed in MS, lupus, and Crohn's disease cohorts.
Lupus cohort contained slightly older patients and included more women than MS cohort, whereas Crohn's disease cohort contained younger patients, with fewer women than MS cohort.

Co-occurrence between MS and lupus and MS and Crohn's disease was respectively 6 (0.13%) and 15 (0.34%) in France and 89 (0.56%) and 28 (0.18%) in the UK, which did not warrant further consideration.

## Primary analysis

Overall, 113 health conditions were considered in the French and UK databases (eTable 5). We identified 12 health conditions as significantly positively associated with a diagnosis of MS when recorded in the five years before MS diagnosis, in both countries (eTable 6). Only one of these conditions was a neurologic disorder: epilepsy and recurrent seizures. Two psychiatric disorders, depression and sexual dysfunction (not caused by organic disorder or disease) were more frequently recorded in patients with MS than in controls without MS. The other associated health conditions were related to disorders of the vestibular system, functional intestinal disorders (principally constipation), limb pain, cystitis, disorders of the urinary system (principally urinary tract infection), skin paresthesia, dizziness and giddiness, headache, and malaise and fatigue. Skin paresthesia, dizziness and giddiness, and disorders of vestibular function may be interpreted as MS symptoms that were not recognized as such by the GP.

## Sensitivity analysis

Only major depressive disorder, sexual dysfunction, constipation, cystitis, and urinary tract infection of unspecified site remained significantly more frequent in patients with MS than in controls without MS in the sensitivity analysis (Figure 1, eTable 6). Overall, 91.2% of the patients diagnosed with functional intestinal disorders (ICD-10 code K59) in the UK and 92.4% of those diagnosed with such disorders in France had constipation (ICD-10 code K59.0).
Similarly, 98.8% of the patients diagnosed with disorders of the urinary system (ICD-10 code N39) in the UK and 97.9% of those diagnosed with such disorders in France had urinary tract of unspecified site infection (ICD-10 code N39.0). In the following, the ICD-10 codes K59 and N39 will be regarded respectively as constipation and urinary tract infection of unspecified site.

When restricting the analysis to patients with at least five years of history before the index date, all health conditions remained significantly positively associated in the UK and in the pooled analysis; however, sexual dysfunction, cystitis, and urinary tract infection (site not specified) were not significantly associated in the French cohort, most likely due to a lack of statistical power (eTable 7). Summary statistics for this cohort are presented (eTable 8). Characteristics of the cohorts are similar to those of the original cohorts with at least two years of retrospective data.

## Pre and post-diagnosis analysis

To facilitate the pre and post diagnosis comparison, we restricted our cohorts to patients with at least two years of data before and after diagnosis. Characteristics of the cohorts are similar to those of the original cohorts with at least two years of retrospective data (eTable 9). All health conditions considered to be associated with MS diagnosis in the pre-diagnosis analysis were also associated with MS diagnosis in the post-diagnosis analysis in both France and UK cohorts (Table 2 in pooled analysis, and eTable 10 and 11 for UK and France respectively). Moreover, in the UK and in the pooled analysis (Table 2 and eTable 10), ORs for all conditions were significantly higher in the post-diagnosis period compared to the pre-diagnosis period.

## Combination of pre-diagnosis health conditions

Combining observed pre-diagnosis features significantly increased the ability to discriminate MS cases and controls without MS for men (pooled OR 2.46, 2.05-2.95 for at least two
features), whereas no effect was observed for women or in subgroups stratified by age at onset (Table 3).

Comparison with other autoimmune diseases

Depression, sexual dysfunction, cystitis and urinary tract infection (site not specified) were found to be more frequent among people subsequently diagnosed with MS than in Crohn's disease patients, in the pooled analysis of data from France and the UK (Figure 2 in pooled analysis, and eFigure 3 for UK and France). However, no health condition was found to be significantly associated with MS in comparisons with lupus patients. Constipation was found to be significantly positively associated with Crohn's disease in comparison to MS.

Longitudinal analysis

We found that the difference in the prevalence of antidepressant use between MS and controls without MS was much more pronounced after than before MS diagnosis. Indeed, the period prevalence increased from 14% and 10% for MS patients and controls without MS, respectively, in the five years before diagnosis to 37% and 19%, respectively, in the five years after MS diagnosis, with the number of MS patients using antidepressants increasing by 20% during the year of MS diagnosis (Figure 3 for the pooled analysis, eFigure 4 and eFigure 5 for the UK and French cohort respectively). Increase in antidepressant prescriptions was less pronounced at the time of diagnosis for patients with lupus or Crohn's disease. For MS, lupus and Crohn's disease, there was a rise of number of GP visits after the diagnosis, with a peak with the first two years post-diagnosis of these auto-immune conditions. Concordant temporal trends of prescriptions and GP visits were observed in cohorts with data in the entire time periods (eFigure 6 and eFigure 7).
326 Stratification by age at diagnosis, sex, and year of diagnosis

327 The ORs for pre-diagnosis autonomic symptoms (functional intestinal disorders, cystitis, and
328 urinary tract infection of unspecified site) increased with increasing age at diagnosis, though
329 not reaching significance, whereas those for depression and sexual dysfunction did not vary
330 with age. Overall, ORs for pre-diagnosis presentations were higher in men than women,
331 especially for urinary tract infection (women: OR 1.29, 1.12–1.48; men: OR 2.16, 1.50–3.10).

332 Finally, pre-diagnosis depression and constipation decreased with more recent year of
333 diagnosis, though not reaching significance (Table 2).

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336 **Discussion**

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338 We used two large independent primary care databases to explore pre-diagnosis health
339 conditions associated with MS. To our knowledge, this is the first transnational data-driven
340 study of the pre and post-diagnosis presentations of MS.

341 Median age at first diagnosis was 39 and 40 in the UK and France in the sensitivity analysis
342 after 2017. This is slightly higher than the reported mean age at diagnosis of 37.6 years in a
343 previous study¹², but considerably lower than the reported 43 years and 47 years in other
344 previous studies.³²,³³ These previous studies were based on administrative claims data. In a
345 smaller clinical cohort linked to administrative data, mean age at symptom onset (as recalled
346 by the patient during a neurologist visit) was 36.5 years suggesting that the first clinical
347 manifestations of the disease might not have been recorded in our study and other previous
348 studies.³²

349 In the primary analysis, we identified a group of symptoms recorded by GPs during the five-
350 year period leading up to MS diagnosis. However, some of these symptoms suggested that the
351 patient had already experienced a relapse or onset of MS and, therefore, that the diagnosis of 352 MS recorded in the database was later than the actual onset of MS.¹² In the sensitivity analysis 353 using the earliest symptom suggestive of MS as the index date, five conditions were 354 significantly associated with a subsequent diagnosis of MS and were considered putative pre- 355 diagnosis features. Our findings confirmed the reported pre-diagnosis associations for 356 autonomic symptoms (intestinal function disorders, cystitis, and urinary tract infections) 8,9,32,34 357 and depression.⁷,⁸,³²,³⁴ Symptoms of sexual dysfunction have been recognized to occur at or 358 after the onset of MS symptoms or MS diagnosis; ³⁵⁻³⁷ however, to our knowledge, no other 359 study has ever reported a health condition related to sexual dysfunction as a pre-diagnosis 360 feature of MS. Sexual dysfunctions reported were coded as a psychological disorder not caused 361 by a disease. It remains unclear whether this health condition results from the patient's 362 experience of the prodrome — in which case, the psychological nature of the sexual dysfunction 363 would be confirmed — or whether it is caused by an ongoing disease, such as medullary MS 364 lesions, if the patient reports no motor or sensory symptoms. Other health conditions identified 365 in prodrome studies in the primary care context, such as anxiety, fatigue, anemia, and sleep 366 disorders,⁸,³⁴,³⁸ were not significantly associated with MS diagnosis in our sensitivity study. 367 This study is original as it investigates the possibility of an MS prodrome in two large countries, 368 and it may have eliminated several spurious correlations.

369 In our study, ORs for depression were higher in France compared to the UK, this difference 370 could be attributed to the difference in healthcare system or difference in the type of 371 remuneration (capitation based for the UK versus fee-for-service based for France).

372 A previous study reported a positive association between pre-diagnosis depression and the 373 incidence of inflammatory bowel disease, MS, and rheumatoid arthritis separately, which could 374 suggest similarities in the pre-diagnosis presentations (potentially due to shared risk factors or 375 etiology) of auto-immune diseases.³⁹ In our study, none of the observed associations was
376 selectively associated with MS in comparison with lupus, whereas urinary tract infection,
377 cystitis, sexual dysfunction, and major depressive disorder were found to be selectively
378 associated with MS in a comparison with Crohn's disease. However, these associations were
379 weak, suggesting that urinary tract infections, sexual dysfunction, and major depressive
380 disorder may not be specific to MS. The finding that depression is specifically associated with
381 MS in comparison to Crohn's disease contradicts a previous study which found no association.¹²
382 The other observed conditions were not tested in other studies. A previous review reported that
383 studies of the preclinical phase of lupus are complicated by the fact that lupus cannot be
384 diagnosed until sufficient clinical manifestations have occurred, potentially accounting for the
385 lack of difference between the prodromal features of MS and lupus.⁴⁰

386 Several previous studies have investigated whether pre-diagnosis presentations of MS vary with
387 age and sex.⁹⁻¹¹ One study reported higher rates of pre-diagnosis anemia in men than in women,
388 whereas sex had no effect on the rates of pre-diagnosis fatigue and pain.⁹ Our findings are
389 consistent with a previous study suggesting that males had more exacerbated pre-diagnosis
390 presentations, namely higher healthcare use and genito-urinary prescriptions (ATC level 1
391 classification).¹⁰ Another study observed that musculoskeletal diseases were more frequent for
392 women and reproductive system diseases more frequent for males.¹¹ However, these studies
393 used large disease categories (several groups of ICD-10 codes) or prescription categories (ATC
394 level 1) which did not allow us to properly compare with our findings. In our study, an effect
395 of sex was also observed when combining the observed pre-diagnosis features. Concerning the
396 effect of age, previous findings observed a stronger effect of MS on overall healthcare in the 5
397 years prior to the first demyelinating event for older vs. younger adults.¹⁰ In our work, we only
398 found that autonomic symptoms increased with age, though not reaching significance. Overall,
399 diversity in the presentation of pre-diagnosis conditions was observed for males and females,
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and across age groups which suggests that these variables should be used to investigate pre-clinical manifestations in MS.

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The associations were weaker for diagnoses established after 2010, but this difference was not statistically significant due to the small sample size. The updated diagnostic criteria have probably decreased time to diagnosis, as shown by the four-year decrease in the UK and the two-year decrease in France for age at MS diagnosis since 2010.

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It remains unclear whether the identified pre-clinical conditions are risk factors for MS, or nonspecific early MS symptoms. Moreover, due to the frequency of these symptoms in the general population and the non-specificity regarding prodrome form other auto-immune diseases, we should not expect that the identification of a prodrome will dramatically change clinical care, at least in the general population. We found that disclosure of MS diagnosis and evolution had a strong impact on all these associations. In large EHR databases, some time may elapse between disclosure of the diagnosis and the first record for a few patients. Given the large increase in antidepressant use at and after MS diagnosis, also reported in a previous study,³⁹ we cannot rule out the possibility that the observed association with depression can be explained by a few patients for whom the first record of MS appears several years after the first true diagnosis. Caution is therefore required in interpretation and it would probably be hasty to conclude that use of these observed prodromal associations would help to improve early diagnosis of MS.

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Our study has several strengths. It is a fully agnostic study of the MS prodrome, based on data from two large databases in two different countries. This should ensure that the results are highly generalizable. This study also includes a comparison with the period after MS diagnosis, and a stratification for age, sex, and year of diagnosis, in line with the recommendations of previous studies.⁴¹ However, like most studies based on primary care databases, it is also subject to several limitations. First, no data for potential confounding

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factors, such as education level, ethnicity, socioeconomic status, body-mass index, or genetic information, were available. Second, UK THIN database contains slightly fewer people aged under 25 years,²¹ possibly explaining that age at diagnosis is a bit higher than what we could expect from other epidemiological studies. Third, controls were also selected from primary care databases, therefore the control cohort did not include individuals who never consulted a general practitioner.

## Conclusion

We performed a modern large-scale data-driven survey of a potential prodrome of MS in the primary care setting. Our findings confirm that several pre-diagnostic features of MS can be observed in large-scale electronic health record data. We also show that the prodromal presentation depends on sex and that all pre-diagnosis health conditions associated with MS were recorded more frequently in the [0-5] years after MS diagnosis compared to the [0-5] years before MS diagnosis. Future studies are required to determine whether the detection of these health conditions can help to decrease age at diagnosis of MS, although our results suggest that they are probably not sufficiently specific to define an MS prodrome.
<table><thead><tr><th></th><th>Size, n</th><th>Sex (female)</th><th>Age at diagnosis</th><th>Age at first symptom of MS</th><th>Person-years of data available before diagnosis</th><th>Number of visits per year before diagnosis</th></tr></thead><tbody><tr><td colspan="7"><strong>UK</strong></td></tr><tr><td colspan="7"><strong>MS</strong></td></tr><tr><td>Whole cohort</td><td>15808</td><td>70.5%</td><td>46 (37 -57)</td><td>44 (34 - 54)</td><td>9 (5 -13)</td><td>6 (2 -7)</td></tr><tr><td>Year of MS diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;&lt;2010</td><td>10108</td><td>70.9%</td><td>48 (38 - 58)</td><td>46 (37 - 56)</td><td>7 (5 - 10)</td><td>6 (2 - 7)</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;[2010,2017]</td><td>4319</td><td>69.9%</td><td>44 (35-54)</td><td>41 (31 - 51)</td><td>13 (8 - 18)</td><td>6 (2 - 7)</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;&gt;2017</td><td>1381</td><td>69.1%</td><td>44 (34 - 55)</td><td>39 (30 - 50)</td><td>17 (9 - 23)</td><td>5 (2 - 7)</td></tr><tr><td>Lupus</td><td>5296</td><td>88.2%</td><td>48 (36 - 61)</td><td></td><td>9 (5 - 14)</td><td>8 (3 - 10)</td></tr><tr><td>Crohn's disease</td><td>20872</td><td>54.5%</td><td>42 (27 - 59)</td><td></td><td>7 (4 - 12)</td><td>6 (2 - 8)</td></tr><tr><td>No MS</td><td>42226</td><td>70.2%</td><td>46 (36 - 56)</td><td></td><td>7 (4 - 12)</td><td>5 (2 - 6)</td></tr><tr><td colspan="7"><strong>France</strong></td></tr><tr><td colspan="7"><strong>MS</strong></td></tr><tr><td>Whole cohort</td><td>4366</td><td>70.2%</td><td>44 (34 - 54)</td><td>42 (32 - 52)</td><td>6 (3 - 10)</td><td>4 (2 - 6)</td></tr><tr><td>Year of MS diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;&lt;2010</td><td>1890</td><td>69.8%</td><td>45 (35 - 55)</td><td>44 (34 - 55)</td><td>4 (3 - 6)</td><td>5 (2 - 7)</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;[2010,2017]</td><td>1708</td><td>70.4%</td><td>43 (34 - 52)</td><td>41 (32 - 50)</td><td>8 (4 - 11)</td><td>4 (2 - 5)</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;&gt;2017</td><td>768</td><td>71.0%</td><td>43 (32 - 54)</td><td>40 (30 - 51)</td><td>10 (5 - 15)</td><td>3 (1 - 5)</td></tr><tr><td>Lupus</td><td>2041</td><td>81.5%</td><td>47 (36 - 60)</td><td></td><td>7 (4 - 10)</td><td>5 (2 - 7)</td></tr><tr><td>Crohn's disease</td><td>9605</td><td>55.9%</td><td>40 (27 - 55)</td><td></td><td>7 (4 - 11)</td><td>4 (1 - 5)</td></tr><tr><td>No MS</td><td>12564</td><td>70.2%</td><td>43 (33 - 53)</td><td></td><td>4 (3 - 7)</td><td>3 (1 - 4)</td></tr></tbody></table>

Table 1. Characteristics of patients with MS, Crohn's disease, or lupus, and controls. The data are

shown as percentage or median (IQR).
<figure><img src="image_3.png" /><figcaption>**Figure 1.** ORs for significant associations in the sensitivity analysis for five years before the index date. Only significant associations both in the French and UK cohorts are shown, with red and blue dots, respectively. The size of the dot is proportional to the period prevalence. The period prevalence is defined as the number of diagnoses or symptoms observed over the period divided by the number of patients at risk during the period. Bars correspond to 95% CIs after correction for multiple comparison.</figcaption></figure>

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<table><caption>**Table 2. ORs for all health conditions individually associated with MS in the sensitivity analysis during the five years before and five years after the occurrence of the first symptoms.** Individuals with MS are compared with controls without MS. We used the whole sensitivity cohort, sex-based cohorts, age-at-onset cohorts, and year-at-diagnosis cohorts. Results are shown for the pooled data between France and UK cohorts. Results from the UK and French cohorts are shown in **eTable 10** and **11** respectively.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Whole cohort<br>(No. MS :<br>15454<br>No. no MS :<br>26253)</th><th colspan="3">Sex</th><th colspan="3">Age at onset</th><th colspan="3">Year of diagnosis</th></tr><tr><th>Women<br>(No. MS :<br>10966<br>No. no MS :<br>18821)</th><th>Men<br>(No. MS :<br>4488<br>No. no MS :<br>7442)</th><th>&lt;40<br>(No. MS :<br>5151<br>No. no MS :<br>7079)</th><th>[40,53]<br>(No. MS :<br>5152<br>No. D<br>no MS :<br>9620)</th><th>&gt;53<br>(No. MS :<br>5151<br>No. no MS :<br>9253)</th><th>&lt;2010<br>(No. MS :<br>10283<br>No. no MS :<br>18964)</th><th>[2010,2017]<br>(No. MS :<br>4417<br>No. no MS :<br>6419)</th><th>&gt;2017<br>(No. MS :<br>754<br>No. no MS :<br>732)</th></tr></thead><tbody><tr><td colspan="11"><strong>Before diagnosis</strong></td></tr><tr><td>F32 : Major depressive disorder, single episode</td><td>1.34 (1.24 - 1.45)*</td><td>1.31 (1.20 - 1.43)*</td><td>1.48 (1.26 - 1.74)*</td><td>1.34 (1.16 - 1.55)*</td><td>1.36 (1.20 - 1.53)*</td><td>1.32 (1.15 - 1.51)*</td><td>1.40 (1.27 - 1.53)*</td><td>1.26 (1.10 - 1.46)*</td><td>0.90 (0.63 - 1.29)</td></tr><tr><td>F52 : Sexual dysfunction</td><td>1.63 (1.31 - 2.03) *</td><td>1.60 (1.05 - 2.42)*</td><td>1.61 (1.24 - 2.09)*</td><td>1.85 (1.07 - 3.18)*</td><td>1.91 (1.35 - 2.70)*</td><td>1.42 (1.01 - 1.98)*</td><td>1.69 (1.29 - 2.22)*</td><td>1.59 (1.07 - 2.34)*</td><td>*</td></tr><tr><td>K59 : Constipation</td><td>1.89 (1.63 - 2.18)*</td><td>1.73 (1.47 - 2.04)*</td><td>2.55 (1.87 - 3.48)*</td><td>1.48 (1.12 - 1.96)*</td><td>1.99 (1.53 - 2.59)*</td><td>2.16 (1.73 - 2.70)*</td><td>2.05 (1.67 - 2.50)*</td><td>1.70 (1.35 - 2.14)*</td><td>1.17 (0.70 - 1.96)</td></tr><tr><td>N30 : Cystitis</td><td>1.39 (1.23 - 1.57)*</td><td>1.32 (1.16 - 1.49)*</td><td>2.78 (1.83 - 4.21)*</td><td>1.18 (0.95 - 1.47)</td><td>1.25 (1.02 - 1.54)*</td><td>1.72 (1.41 - 2.10)*</td><td>1.47 (1.26 - 1.71)*</td><td>1.20 (0.97 - 1.48)</td><td>1.24 (0.77 - 2.00)</td></tr><tr><td>N39 : Urinary tract infection, site not specified</td><td>1.38 (1.21 - 1.57)*</td><td>1.29 (1.12 - 1.48)*</td><td>2.16 (1.50 - 3.12)*</td><td>1.15 (0.89 - 1.47)</td><td>1.28 (1.02 - 1.61)*</td><td>1.65 (1.35 - 2.03)*</td><td>1.50 (1.29 - 2.22)*</td><td>1.09 (0.83 - 1.42)</td><td>1.32 (0.64 - 2.74)</td></tr><tr><td colspan="11"><strong>After diagnosis</strong></td></tr><tr><td>F32 : Major depressive disorder, single episode</td><td>1.96 (1.83 - 2.11)*</td><td>1.84 (1.69 - 1.99)**</td><td>2.42 (2.09 - 2.80)*</td><td>2.12 (1.88 - 2.39)*</td><td>1.98 (1.75 - 2.23)*</td><td>1.91 (1.67 - 2.20)*</td><td>1.97 (1.81 - 2.14)*</td><td>2.0 (1.73 - 2.32)*</td><td>1.68 (1.09 - 2.61)*</td></tr><tr><td>F52 : Sexual dysfunction</td><td>2.84 (2.43 - 3.31)*</td><td>1.96 (1.41 - 2.73)*</td><td>3.13 (2.62 - 3.73)*</td><td>4.64 (3.34 - 6.44)*</td><td>3.98 (3.06 - 5.18)*</td><td>1.43 (1.10 - 1.85)*</td><td>2.94 (2.46 - 3.52)*</td><td>2.56 (1.87 - 3.49)*</td><td>*</td></tr><tr><td>K59 : Constipation</td><td>3.36 (3.07 - 3.68)*</td><td>3.08 (2.77 - 3.42)*</td><td>4.29 (3.57 - 5.16)*</td><td>3.14 (2.62 - 3.76)*</td><td>4.14 (3.52 - 4.86)*</td><td>3.17 (2.75 - 3.65)*</td><td>3.57 (3.19 - 4.00)*</td><td>2.82 (2.40 - 3.32)*</td><td>2.65 (1.62 - 4.32)*</td></tr><tr><td>N30 : Cystitis</td><td>2.49 (2.29 - 2.72)*</td><td>2.2 (2.01 - 2.41)*</td><td>6.02 (4.58 - 7.93)*</td><td>2.14 (1.82 - 2.51)*</td><td>2.6 (2.24 - 3.02)*</td><td>2.84 (2.46 - 3.28)*</td><td>2.67 (2.40 - 2.96)*</td><td>2.07 (1.76 - 2.45)*</td><td>1.91 (1.23 - 2.96)*</td></tr><tr><td>N39 : Urinary tract infection, site not specified</td><td>2.69 (2.43 - 2.98)*</td><td>2.49 (2.23 - 2.78)*</td><td>3.92 (3.03 - 5.07)*</td><td>2.3 (1.90 - 2.79)*</td><td>2.76 (2.31 - 3.30)*</td><td>2.94 (2.50 - 3.44)*</td><td>2.77 (2.47 - 3.11)*</td><td>2.48 (1.98 - 3.11)*</td><td>3.23 (1.48 - 7.08)*</td></tr></tbody></table>

* cannot be calculated because too few presentations were recorded.

* for ORs associated with corrected p-values below 0.05 or initial p-value below 0.05/5. p-value are adjusted for multiple comparisons using the Bonferroni method.
<table><thead><tr><th rowspan="2"></th><th rowspan="2">Whole cohort<br>(No. MS : 20174<br>No. no MS :<br>54790)</th><th colspan="2">Sex</th><th colspan="2">Age at onset</th></tr><tr><th>Women<br>(No. MS : 14210<br>No. no MS :<br>38463)</th><th>Men<br>(No. MS : 5964<br>No. no MS :<br>16309)</th><th>&lt;40<br>(No. MS : 6724<br>No. no MS :<br>18263)</th><th>[40,53]<br>(No. MS : 6724<br>No. no MS : 18263)</th><th>&gt;53<br>(No. MS : 6726<br>No. no MS :<br>182635)</th></tr></thead><tbody><tr><td><strong>Before diagnosis</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>At least one feature</td><td>1.41 (1.35 -<br>1.47)**<br>(MS : 30.87<br>Control : 22.5)</td><td>1.32 (1.26 - 1.39)**<br>(MS : 33.72<br>Control : 25.82)</td><td>1.7 (1.57 - 1.85)**<br>(MS : 24.07<br>Control : 14.83)</td><td>1.3 (1.21 -<br>1.40)**<br>(MS : 28.41<br>Control : 21.37)</td><td>1.41 (1.31 -<br>1.51)**<br>(MS : 32.07<br>Control : 23.35)</td><td>1.48 (1.37 - 1.58)*<br>(MS : 32.1<br>Control : 23.12)</td></tr><tr><td>At least two features</td><td>1.47 (1.36 -<br>1.59)**<br>(MS : 7.16<br>Control : 4.52)</td><td>1.31 (1.20 - 1.43)*<br>(MS : 8.05<br>Control : 5.64)</td><td>2.46 (2.05 - 2.95)**<br>(MS : 5.02<br>Control : 1.95)</td><td>1.27 (1.10 - 1.47)*<br>(MS : 5.83<br>Control : 4.08)</td><td>1.46 (1.28 -<br>1.67)**<br>(MS : 7.14<br>Control : 4.52)</td><td>1.63 (1.44 - 1.84)<br>(MS : 8.49<br>Control : 5.05)</td></tr><tr><td>At least three features</td><td>1.63 (1.37 -<br>1.93)**<br>(MS : 1.46<br>Control : 0.8)</td><td>1.4 (1.16 - 1.68)**<br>(MS : 1.67<br>Control : 1.05)</td><td>4.07 (2.53 - 6.55)**<br>(MS : 0.95<br>Control : 0.22)</td><td>1.35 (0.94 -<br>1.94)<br>(MS : 0.93<br>Control : 0.59)</td><td>1.49 (1.11 -<br>2.0)*<br>(MS : 1.39<br>Control : 0.82)</td><td>1.94 (1.51 -<br>2.51)**<br>(MS : 2.06<br>Control : 0.99)</td></tr></tbody></table>

<caption>Table 3. ORs and prevalence in MS and non-MS cohorts (OR (95% CI) (MS :</caption>

frequency, Control : frequency)) for combinations of at least one, two, or three health problems individually associated with MS in the sensitivity analysis during the five years before the occurrence of the first symptoms. Individuals with MS are compared with controls without MS. We used the whole sensitivity cohort, sex-based cohorts, and age-at-onset cohorts. Results are shown for the pooled data between France and UK cohorts.

* for ORs associated with corrected p-values below 0.05 or initial p-value below 0.05/113. p-value are adjusted for multiple comparisons using the Bonferroni method.
<figure><img src="image_4.png" /><figcaption>**Figure 2.** ORs for significant associations in the sensitivity analysis for five years before the index date in comparison to other auto-immune diseases. Patients with MS are compared to patients with lupus and Crohn's disease in pooled data from the French and UK cohorts. OR > 1 indicates a higher association in MS cohort compared to Crohn's disease or lupus cohort. The size of the dot is proportional to the period prevalence. The period prevalence is defined as the number of diagnoses or symptoms observed over the period divided by the number of patients at risk during the period. Results from the French and UK cohorts individually are shown in eFigure 3.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Figure 3.** Period prevalence (%) of prescriptions associated with depression (A), urinary tract infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the physician per year (E) in the pooled UK and France cohort. For a given prescription, the period prevalence is defined as the number of prescriptions observed over the period divided by the number of patients at risk during the period. Results from the French and UK cohorts individually are shown in eFigure 4 and 5.</figcaption></figure>
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639 Erythematosus, Multiple Sclerosis and Type 1 Diabetes. *Front Immunol*. 2022;13:899372.

640 doi:10.3389/fimmu.2022.899372

641 41. Tremlett H, Munger KL, Makhani N. The Multiple Sclerosis Prodrome: Evidence to

642 Action. *Front Neurol*. 2022;12:761408. doi:10.3389/fneur.2021.761408

643

644

645

646

647

648 **Contributors** OG, TN, CL and SD conceived and designed the study. LG extracted the data.

649 LG and OG ensured data quality and OG, TN, CL and SD analysed the data. OG and TN

650 generated the figures. OG, LG, BL, CL and SD interpreted the results and contributed to the

651 writing of the final version of the manuscript. All authors agreed with the results and

652 conclusions and approved the final draft.
653
654 **Competing interest** CL has received consulting or travel fees from Biogen, Novartis, Roche,
655 Sanofi, Teva and Merck Serono, none related to the present work. LG and BL are full time
656 employees of Cegedim.

657
658 **Data sharing statement** The data used in the preparation of the article are available from the
659 Cegedim company upon reasonable request (info@the-health-improvement-network.co.uk).

660
661 **Acknowledgment** The research leading to these results has received funding from the joint
662 program in neurodegenerative diseases (JPND) ANR-21-JPW2-0002-01 (LeMeReND) and
663 the program "Investissements d'avenir" ANR-10-IAIHU-06. This work was funded in part by
664 the French government under management of Agence Nationale de la Recherche as part of the
665 "Investissements d'avenir" program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute).
666 Editorial support, in the form of medical writing and copyediting, was provided by Julie
667 Sappa of Alex Edelman and Associates.

668
669 **Ethics committee approval** Approval was sorted before carrying out this study (and for the
670 use of datasets). The study was a retrospective analysis of secondary anonymised patient data
671 only. For the UK database, data is only available to researchers carrying out approved medical
672 research. Ethical approval was granted by the NHS South-East Multicentre Research Ethics
673 Committee in 2003 (ref: 03/01/073) for establishment of the THIN database, and it was
674 updated in 2011. A further update and approval was granted in 2020 by the NHS South
675 Central, Oxford C Research Ethics Committee (Ref: 20/SC/0011). For the French Database,
676 several audits were conducted by CNIL (Commission Nationale de l'Informatique et des
677 Libertés, the French authority responsible for the protection of personal data). Data are
678 available from the GERS SAS for researchers who meet the criteria for access to confidential
679 data. Researchers willing to replicate the results should address a request to the Cegedim
680 company (info@the-health-improvement-network.co.uk). The study was approved by the
681 THIN Scientific Research Committee (SRC) on 4th Feb 2022 (SRC reference 21-016).

682 **Patient and Public involvement** We plan to disseminate the results of our research to the
683 public and relevant patient community through the current publication and its related press
684 release as well as presentations at scientific conferences.

685
686 The lead authors (CL, SD) affirm that this manuscript is an honest, accurate, and transparent
687 account of the study being reported; that no important aspects of the study have been omitted;
688 and that any discrepancies from the study as planned (and, if relevant, registered) have been
689 explained.

690
691
692
693
694
695
696
697
698
699
700
701
702
# Supplementary materials

703

704

## TABLE OF CONTENTS

706 - **Supplementary method.** Details on data collection in THIN database

707 - **eTable 1.** Health conditions suggestive of a demyelinating claim

708 - **eTable 2.** Health conditions suggestive of a MS relapse and positively associated with a future diagnosis of MS either in the French or British database

710 - **eFigure 4.** Patient selection flowchart for the French study

711 - **eFigure 5.** Patient selection flowchart for the UK study

712 - **eTable 3.** Proportion (%) of patients with at least one record of the conditions tested in the control populations in France and the UK at 5 years before the diagnosis

714 - **eTable 4.** Prescriptions linked to diagnoses in the French database

715 - **eTable 5.** ORs for all health conditions in over 0.5% of patients and controls individually associated with a future symptom specific of MS at 5 years before the index date

717 - **eTable 6.** ORs for all health conditions individually associated with a future diagnosis of MS for the five-year period leading up to the index date

719 - **eTable 7.** Pooled, UK, and French ORs for all health problems individually associated with MS in the sensitivity analysis during the five years before the occurrence of the first symptoms

721 - **eTable 8.** Characteristics of patients with MS and individuals without MS with at least five years of data before the index date in the two cohorts

723 - **eTable 9.** Characteristics of patients with MS and individuals without MS with at least two years of data before and after the index date in the two cohorts

725 - **eTable 10.** ORs in the UK cohort for all health conditions individually associated with MS in the sensitivity analysis during the five years before and five years after the occurrence of the first symptoms
728 - eTable 11. ORs in the French cohort for all health conditions individually associated with MS
729 in the sensitivity analysis during the five years before and five years after the occurrence of
730 the first symptoms

731 - eFigure 3. ORs for significant associations in the sensitivity analysis for five years before the
732 index date in comparison to other auto-immune diseases

733 - eFigure 6. Period prevalence (%) of prescriptions associated with depression (A), urinary tract
734 infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the
735 physician per year (E) in the UK cohort

736 - eFigure 5. Period prevalence (%) of prescriptions associated with depression (A), urinary tract
737 infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the
738 physician per year (E) in the French cohort.

739 - eFigure 6. Period prevalence (%) of prescriptions associated with depression (A), urinary tract
740 infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the
741 physician per year (E) in the pooled cohort, 15 years before diagnosis

742 - eFigure 7. Period prevalence (%) of prescriptions associated with depression (A), urinary tract
743 infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the
744 physician per year (E) in the pooled cohort, 5 years before diagnosis up to 10 years after
745 diagnosis
746 **Supplementary method:** Details on data collection in THIN database

747

748 French data were collected from a pool of 2500 general practitioners (GP),1 and were

749 representative of the French population in terms of age, sex, and area of residence.2 UK data

750 were collected from 400 general practices covering about 6% of the UK population, selected

751 for the THIN quality data-recording scheme with Vision practice management software.3

752 Several studies have already reported that the electronically coded diagnoses in this database

753 are representative of the UK general practice population in terms of demographics and type of

754 consultation.4 For each patient, diagnosis corresponding to each visit, prescriptions made by

755 the GP, and all other diagnoses associated with these prescriptions were available. Data for

756 education level and social status were not provided, to preserve anonymity.

757 1. Iordache L, Strazzulla A, Lekens B, Bergmann J, Diamantis S. Évaluation du suivi des

758 recommandations de prise en charge des infections urinaires en médecine de ville en France.

759 Médecine et Maladies Infectieuses. 2018;48(4):S101-S102.

760 doi:10.1016/j.medmal.2018.04.253

761 2. Kopp A, Mangin O, Gantzer L, et al. Pneumococcal vaccination coverage in France by

762 general practitioners in adults with a high risk of pneumococcal disease. Hum Vaccin

763 Immunother. January 2, 2021:162-169.

764 3. Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of

765 Parkinson's disease in primary care: a case-control study. The Lancet Neurology.

766 2015;14(1):57-64. doi:10.1016/S1474-4422(14)70287-X

767 4. Blak B, Thompson M, Dattani H, Bourke A. Generalisability of The Health

768 Improvement Network (THIN) database:demographics, chronic disease prevalence and

769 mortality rates. Journal of Innovation in Health Informatics. 2011;19(4):251-255.

770 doi:10.14236/jhi.v19i4.820
771

772
773

eTable 1. Health conditions suggestive of a demyelinating claim

Encephalitis, myelitis, encephalomyelitis (G04, G05)

Sequelae of inflammatory diseases of central nervous system (G09)

Demyelinating diseases of the CNS (G36, G37)

Retrobulbar neuritis and other disorders of the optic nerve and the visual pathways (H46, H47, H48)

774

775
776 eTable 2. Health conditions suggestive of a MS relapse and positively associated with a future diagnosis of

777 MS either in the French or British database.

Paresthesia of skin (R20)

Tetany (R29)

Dizziness and giddiness (R42)

Abnormal and involuntary movement (R25)

Carpal tunnel syndrome (G56)

Disorders of vestibular function (H81)

Visual disturbances (H53)

Contracture of muscle (M62)

778

779
<figure><img src="image_6.png" /><figcaption>eFigure 7. Patient selection flowchart for the French study. Note: the index date for controls is taken as the last contact date recorded during the year of contact selected randomly</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>eFigure 8. Patient selection flowchart for the UK study. Note: the index date for controls is taken as the last contact date recorded during the year of contact selected randomly</figcaption></figure>
<table><caption>eTable 3. Proportion (%) of patients with at least one record of the conditions tested in the control populations in France and the UK at 5 years before the diagnosis. The 113 ICD10 codes that were recorded with a relative frequency of more than 0.5 % in both countries were considered.</caption><thead><tr><th></th><th>FR<br>Controls (UK)<br>n=42266</th><th>UK<br>Controls (FR)<br>n=12564</th></tr></thead><tbody><tr><td>B00 : Herpesviral [herpes simplex] infections</td><td>3.36</td><td>2.02</td></tr><tr><td>B02 : Zoster</td><td>1.73</td><td>0.84</td></tr><tr><td>B07 : Viral warts</td><td>3.11</td><td>0.73</td></tr><tr><td>B34 : Viral infection of unspecified site</td><td>2.12</td><td>2.08</td></tr><tr><td>B35 : Dermatophytosis</td><td>5.5</td><td>2.39</td></tr><tr><td>B37 : Candidiasis</td><td>5.54</td><td>2.63</td></tr><tr><td>D50 : Iron deficiency anemia</td><td>1.89</td><td>1.09</td></tr><tr><td>D64 : Other anemias</td><td>0.73</td><td>0.97</td></tr><tr><td>E03 : Other hypothyroidism</td><td>4.51</td><td>2.39</td></tr><tr><td>E11 : Type 2 diabetes mellitus</td><td>3.77</td><td>2.45</td></tr><tr><td>E14 : Other diabetes</td><td>1.71</td><td>0.76</td></tr><tr><td>E66 : Overweight and obesity</td><td>1.48</td><td>1.88</td></tr><tr><td>E78 : Disorders of lipoprotein metabolism and other lipidemias</td><td>9.02</td><td>6.51</td></tr><tr><td>F10 : Alcohol related disorders</td><td>1.19</td><td>0.59</td></tr><tr><td>F32 : Major depressive disorder, single episode</td><td>19.65</td><td>10.75</td></tr><tr><td>F40 : Phobic anxiety disorders</td><td>0.88</td><td>1.19</td></tr><tr><td>F41 : Other anxiety disorders</td><td>8.43</td><td>10.27</td></tr><tr><td>F43 : Reaction to severe stress</td><td>1.49</td><td>3.3</td></tr><tr><td>F52 : Sexual dysfunction</td><td>1.54</td><td>1.96</td></tr><tr><td>G40 : Epilepsy and recurrent seizures</td><td>0.86</td><td>0.57</td></tr><tr><td>G43 : Migraine</td><td>4.7</td><td>4.9</td></tr><tr><td>G47 : Sleep disorders</td><td>1.92</td><td>6.47</td></tr><tr><td>G56 : Carpal tunnel syndrome</td><td>1.45</td><td>1.13</td></tr><tr><td>H00 : Hordeolum and chalazion</td><td>1.59</td><td>0.85</td></tr><tr><td>H10 : Conjunctivitis</td><td>6.02</td><td>4.21</td></tr><tr><td>H60 : Otitis externa</td><td>4.53</td><td>1.89</td></tr><tr><td>H61 : Other disorders of external ear</td><td>3.11</td><td>0.93</td></tr><tr><td>H66 : Suppurative and unspecified otitis media</td><td>2.2</td><td>5.1</td></tr><tr><td>H81 : Disorders of vestibular function</td><td>1.32</td><td>1.47</td></tr><tr><td>H92 : Otalgia and effusion of ear</td><td>2.51</td><td>3.01</td></tr><tr><td>H93 : Other disorders of ear</td><td>1.03</td><td>1.05</td></tr><tr><td>I10 : Essential (primary) hypertension</td><td>13.7</td><td>10.51</td></tr><tr><td>I20 : Angina pectoris</td><td>1.14</td><td>0.58</td></tr><tr><td>I80 : Phlebitis and thrombophlebitis</td><td>1.09</td><td>0.71</td></tr><tr><td>I83 : Varicose veins of lower extremities</td><td>1.97</td><td>1.14</td></tr><tr><td>I84 : Hemorrhoids</td><td>6.62</td><td>3.37</td></tr><tr><td>J00 : Acute nasopharyngitis [common cold]</td><td>2.71</td><td>24.56</td></tr><tr><td>J01 : Acute sinusitis</td><td>5.7</td><td>9.52</td></tr></tbody></table>
<table>
  <tr>
    <td>J02: Acute pharyngitis</td>
    <td>6.52</td>
    <td>17.18</td>
  </tr>
  <tr>
    <td>J04: Acute laryngitis and tracheitis</td>
    <td>1.8</td>
    <td>11.36</td>
  </tr>
  <tr>
    <td>J11: Influenza due to unidentified influenza virus</td>
    <td>2.97</td>
    <td>11.58</td>
  </tr>
  <tr>
    <td>J20: Acute bronchitis</td>
    <td>2.54</td>
    <td>9.62</td>
  </tr>
  <tr>
    <td>J30: Vasomotor and allergic rhinitis</td>
    <td>5.0</td>
    <td>2.71</td>
  </tr>
  <tr>
    <td>J31: Chronic rhinitis, nasopharyngitis and pharyngitis</td>
    <td>1.17</td>
    <td>2.16</td>
  </tr>
  <tr>
    <td>J32: Chronic sinusitis</td>
    <td>0.69</td>
    <td>0.82</td>
  </tr>
  <tr>
    <td>J34: Other and unspecified disorders of nose and nasal sinuses</td>
    <td>1.17</td>
    <td>2.11</td>
  </tr>
  <tr>
    <td>J40: Bronchitis</td>
    <td>0.6</td>
    <td>3.53</td>
  </tr>
  <tr>
    <td>J45: Asthma</td>
    <td>7.99</td>
    <td>5.07</td>
  </tr>
  <tr>
    <td>K04: Diseases of pulp and periapical tissues</td>
    <td>1.06</td>
    <td>1.03</td>
  </tr>
  <tr>
    <td>K12: Stomatitis and related lesions</td>
    <td>0.98</td>
    <td>0.9</td>
  </tr>
  <tr>
    <td>K21: Gastro-esophageal reflux disease</td>
    <td>2.76</td>
    <td>4.86</td>
  </tr>
  <tr>
    <td>K29: Gastritis and duodenitis</td>
    <td>1.66</td>
    <td>3.42</td>
  </tr>
  <tr>
    <td>K30: Functional dyspepsia</td>
    <td>3.72</td>
    <td>1.1</td>
  </tr>
  <tr>
    <td>K44: Diaphragmatic hernia</td>
    <td>1.24</td>
    <td>5.91</td>
  </tr>
  <tr>
    <td>K58: Irritable bowel syndrome</td>
    <td>3.42</td>
    <td>4.25</td>
  </tr>
  <tr>
    <td>K59: Functional intestinal disorders</td>
    <td>4.37</td>
    <td>5.22</td>
  </tr>
  <tr>
    <td>K62: Other diseases of anus and rectum</td>
    <td>2.44</td>
    <td>0.9</td>
  </tr>
  <tr>
    <td>K80: Cholelithiasis</td>
    <td>0.89</td>
    <td>0.85</td>
  </tr>
  <tr>
    <td>L02: Cutaneous abscess, furuncle and carbuncle</td>
    <td>2.21</td>
    <td>1.55</td>
  </tr>
  <tr>
    <td>L03: Cellulitis and acute lymphangitis</td>
    <td>3.43</td>
    <td>0.89</td>
  </tr>
  <tr>
    <td>L21: Seborrheic dermatitis</td>
    <td>1.44</td>
    <td>0.6</td>
  </tr>
  <tr>
    <td>L29: Pruritus</td>
    <td>2.43</td>
    <td>3.17</td>
  </tr>
  <tr>
    <td>L30: Other and unspecified dermatitis</td>
    <td>4.74</td>
    <td>4.8</td>
  </tr>
  <tr>
    <td>L40: Psoriasis</td>
    <td>2.07</td>
    <td>1.13</td>
  </tr>
  <tr>
    <td>L50: Urticaria</td>
    <td>1.69</td>
    <td>1.0</td>
  </tr>
  <tr>
    <td>L65: Other nonscarring hair loss</td>
    <td>0.98</td>
    <td>1.05</td>
  </tr>
  <tr>
    <td>L70: Acne</td>
    <td>3.51</td>
    <td>1.6</td>
  </tr>
  <tr>
    <td>L98: Other disorders of skin and subcutaneous tissue</td>
    <td>4.61</td>
    <td>0.94</td>
  </tr>
  <tr>
    <td>M10: Gout</td>
    <td>1.11</td>
    <td>0.53</td>
  </tr>
  <tr>
    <td>M13: Other arthritis</td>
    <td>1.16</td>
    <td>0.89</td>
  </tr>
  <tr>
    <td>M19: Other and unspecified osteoarthritis</td>
    <td>3.09</td>
    <td>3.77</td>
  </tr>
  <tr>
    <td>M25: Pain in joint</td>
    <td>8.05</td>
    <td>8.63</td>
  </tr>
  <tr>
    <td>M47: Spondylosis</td>
    <td>1.3</td>
    <td>1.82</td>
  </tr>
  <tr>
    <td>M51: Thoracic, thoracolumbar, and lumbosacral intervertebral disc disorders</td>
    <td>0.84</td>
    <td>0.93</td>
  </tr>
  <tr>
    <td>M53: Cervicobrachial syndrome</td>
    <td>0.73</td>
    <td>2.82</td>
  </tr>
  <tr>
    <td>M54: Dorsalgia</td>
    <td>15.5</td>
    <td>24.57</td>
  </tr>
  <tr>
    <td>M62: Contracture of muscle</td>
    <td>0.63</td>
    <td>2.09</td>
  </tr>
  <tr>
    <td>M75: Shoulder lesions</td>
    <td>2.53</td>
    <td>5.6</td>
  </tr>
  <tr>
    <td>M77: Other enthesopathies</td>
    <td>3.31</td>
    <td>6.11</td>
  </tr>
  <tr>
    <td>M79: Pain in limb, foot / Myalgia</td>
    <td>14.24</td>
    <td>8.77</td>
  </tr>
  <tr>
    <td>M81: Osteoporosis without current pathological fracture</td>
    <td>0.96</td>
    <td>0.98</td>
  </tr>
</table>
<table>
  <tr>
    <td>N30 : Cystitis</td>
    <td>6.99</td>
    <td>6.81</td>
  </tr>
  <tr>
    <td>N39 : Urinary tract infection, site not specified</td>
    <td>5.36</td>
    <td>2.77</td>
  </tr>
  <tr>
    <td>N64 : Other disorders of breast</td>
    <td>2.72</td>
    <td>0.9</td>
  </tr>
  <tr>
    <td>N76 : Other inflammation of vagina and vulva</td>
    <td>1.25</td>
    <td>1.17</td>
  </tr>
  <tr>
    <td>N91 : Absent, scanty and rare menstruation</td>
    <td>2.23</td>
    <td>1.44</td>
  </tr>
  <tr>
    <td>N92 : Excessive, frequent and irregular menstruation</td>
    <td>7.58</td>
    <td>1.72</td>
  </tr>
  <tr>
    <td>N94 : Pain and other conditions associated with female genital organs and menstrual cycle</td>
    <td>2.33</td>
    <td>1.52</td>
  </tr>
  <tr>
    <td>N95 : Menopausal and other perimenopausal disorders</td>
    <td>4.91</td>
    <td>3.13</td>
  </tr>
  <tr>
    <td>R05 : Cough</td>
    <td>0.83</td>
    <td>16.59</td>
  </tr>
  <tr>
    <td>R06 : Abnormalities of breathing</td>
    <td>1.36</td>
    <td>1.93</td>
  </tr>
  <tr>
    <td>R07 : Pain in throat and chest</td>
    <td>2.0</td>
    <td>3.92</td>
  </tr>
  <tr>
    <td>R10 : Abdominal and pelvic pain</td>
    <td>4.93</td>
    <td>12.45</td>
  </tr>
  <tr>
    <td>R20 : Paresthesia of skin</td>
    <td>0.86</td>
    <td>0.82</td>
  </tr>
  <tr>
    <td>R21 : Rash and other nonspecific skin eruption</td>
    <td>2.35</td>
    <td>1.13</td>
  </tr>
  <tr>
    <td>R25 : Abnormal involuntary movements</td>
    <td>1.25</td>
    <td>1.33</td>
  </tr>
  <tr>
    <td>R42 : Dizziness and giddiness</td>
    <td>3.95</td>
    <td>3.31</td>
  </tr>
  <tr>
    <td>R51 : Headache</td>
    <td>2.0</td>
    <td>7.23</td>
  </tr>
  <tr>
    <td>R52 : Pain, unspecified</td>
    <td>0.99</td>
    <td>4.52</td>
  </tr>
  <tr>
    <td>R53 : Malaise and fatigue</td>
    <td>1.64</td>
    <td>12.53</td>
  </tr>
  <tr>
    <td>R55 : Syncope and collapse</td>
    <td>0.94</td>
    <td>0.85</td>
  </tr>
  <tr>
    <td>R59 : Enlarged lymph nodes</td>
    <td>0.65</td>
    <td>1.54</td>
  </tr>
  <tr>
    <td>R60 : Edema, not elsewhere classified</td>
    <td>0.92</td>
    <td>1.32</td>
  </tr>
  <tr>
    <td>R63 : Abnormal weight loss or gain</td>
    <td>0.68</td>
    <td>1.32</td>
  </tr>
  <tr>
    <td>S83 : Dislocation and sprain of joints and ligaments of knee</td>
    <td>0.78</td>
    <td>0.87</td>
  </tr>
  <tr>
    <td>S93 : Dislocation and sprain of joints and ligaments at ankle; foot and toe level</td>
    <td>1.32</td>
    <td>2.39</td>
  </tr>
  <tr>
    <td>T14 : Injury of unspecified body region</td>
    <td>3.55</td>
    <td>8.27</td>
  </tr>
  <tr>
    <td>T78 : Adverse effects, not elsewhere classified</td>
    <td>1.56</td>
    <td>8.34</td>
  </tr>
  <tr>
    <td>Z01 : Encounter for other special examination without complaint, suspected or reported diagnosis</td>
    <td>0.6</td>
    <td>1.63</td>
  </tr>
  <tr>
    <td>Z02 : Encounter for administrative examination</td>
    <td>3.61</td>
    <td>11.89</td>
  </tr>
  <tr>
    <td>Z13 : Encounter for screening for other diseases and disorders</td>
    <td>0.75</td>
    <td>2.09</td>
  </tr>
  <tr>
    <td>Z30 : Encounter for contraceptive management</td>
    <td>14.1</td>
    <td>8.36</td>
  </tr>
  <tr>
    <td>Z76 : Persons encountering health services in other circumstances</td>
    <td>1.5</td>
    <td>10.29</td>
  </tr>
</table>
<table><caption>eTable 4. Prescriptions linked to diagnoses in the French database. Prescriptions are deemed as linked when they were given to more than 80 different people, and given in more than one out of three times for a particular diagnosis/symptom</caption><thead><tr><th>ATC codes</th><th>ICD-10 codes</th></tr></thead><tbody><tr><td>Ispaghula (psylla seeds) (A06AC01)</td><td>Other functional intestinal disorders (K59)</td></tr><tr><td>Macrogol (A06AD15)</td><td>Other functional intestinal disorders (K59)</td></tr><tr><td>Macrogol, combinations (A06AD65)</td><td>Other functional intestinal disorders (K59)</td></tr><tr><td>Enema combinations (A06AG20)</td><td>Other functional intestinal disorders (K59)</td></tr><tr><td>Carbon dioxide producing drugs (A06AX02)</td><td>Other functional intestinal disorders (K59)</td></tr><tr><td>Amphotericin B (A07AA07)</td><td>Candidiasis (B37)</td></tr><tr><td>Insulin glargine (A10AE04)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Metformin (A10BA02)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Gliclazide (A10BB09)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Glimepiride (A10BB12)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Metformin and sitagliptin (A10BD07)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Sitagliptin (A10BH01)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Repaglinide (A10BX02)</td><td>Type 2 diabetes mellitus (E11)</td></tr><tr><td>Vitamins, other combinations (A11JC)</td><td>Other nonscarring hair loss (L65)</td></tr><tr><td>Tranexamic acid (B02AA02)</td><td>Excessive, frequent and irregular menstruation (N92)</td></tr><tr><td>Hydrochlorothiazide (C03AA03)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Indapamide (C03BA11)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Spironolactone (C03DA01)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Other agents for treatment of hemorrhoids and anal fissures for topical use in ATC (C05AX)</td><td>Hemorrhoids (I84)</td></tr><tr><td>Other preparations, combinations (C05AX03)</td><td>Hemorrhoids (I84)</td></tr><tr><td>Rutoside, combinations (C05CA51)</td><td>Other disorders of veins (I87)</td></tr><tr><td>Atenolol (C07AB03)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Acebutolol (C07AB04)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Bisoprolol (C07AB07)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Celiprolol (C07AB08)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Nebivolol (C07AB12)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Amlodipine (C08CA01)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Nicardipine (C08CA04)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Lercanidipine (C08CA13)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Perindopril (C09AA04)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Ramipril (C09AA05)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Perindopril and diuretics (C09BA04)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Losartan (C09CA01)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Valsartan (C09CA03)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Irbesartan (C09CA04)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Candesartan (C09CA06)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Telmisartan (C09CA07)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Olmesartan medoxomil (C09CA08)</td><td>Essential (primary) hypertension (I10)</td></tr><tr><td>Losartan and diuretics (C09DA01)</td><td>Essential (primary) hypertension (I10)</td></tr></tbody></table>
Valsartan and diuretics (C09DA03)
Irbesartan and diuretics (C09DA04)
Valsartan and amlodipine (C09DB01)
Simvastatin (C10AA01)
Pravastatin (C10AA03)
Fluvastatin (C10AA04)
Atorvastatin (C10AA05)
Rosuvastatin (C10AA07)
Fenofibrate (C10AB05)
Ezetimibe (C10AX09)
Amorolfine (D01AE16)
Terbinafine (D01BA02)
Calcipotriol, combinations (D05AX52)
Aciclovir (D06BB03)
Metronidazole (D06BX01)
Benzoyl peroxide (D10AE01)
Erythromycin (D10AF02)
Wart and anti-corn preparations (D11AF)
Other gynecologicals in ATC (G02CX)
Levonorgestrel and ethinylestradiol (G03AA07)
Desogestrel and ethinylestradiol (G03AA09)
Gestodene and ethinylestradiol (G03AA10)
Drospirenone and ethinylestradiol (G03AA12)
Levonorgestrel and ethinylestradiol (G03AB03)
Levonorgestrel (G03AC03)
Desogestrel (G03AC09)
Estradiol (G03CA03)
Cyproterone and estrogen (G03HB01)
Tadalafil (G04BE08)
Tamsulosin (G04CA02)
Levothyroxine sodium (H03AA01)
Pivmecillinam (J01CA08)
Phenoxymethylpenicillin (J01CE02)
Norfloxacin (J01MA06)
Moxifloxacin (J01MA14)
Nitrofurantoin (J01XE01)
Fosfomycin (J01XX01)
Aciclovir (J05AB01)
Oseltamivir (J05AH02)
Pneumococcus, purified polysaccharides antigen (J07AL01)
Tetanus toxoid (J07AM01)
Typhoid, purified polysaccharide antigen (J07AP03)
Hepatitis B, purified antigen (J07BC01)

Essential (primary) hypertension (I10)
Essential (primary) hypertension (I10)
Essential (primary) hypertension (I10)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Disorders of lipoprotein metabolism and other lipidemias (E78)
Dermatophytosis (B35)
Dermatophytosis (B35)
Psoriasis (L40)
Herpesviral [herpes simplex] infections (B00)
Rosacea (L71)
Acne (L70)
Acne (L70)
Viral warts (B07)
Menopausal and other perimenopausal disorders (N95)
Encounter for contraceptive management (Z30)
Encounter for contraceptive management (Z30)
Encounter for contraceptive management (Z30)
Encounter for contraceptive management (Z30)
Encounter for contraceptive management (Z30)
Encounter for contraceptive management (Z30)
Encounter for contraceptive management (Z30)
Menopausal and other perimenopausal disorders (N95)
Encounter for contraceptive management (Z30)
Sexual dysfunction not caused by organic disorder or disease (F52)
Benign prostatic hyperplasia (N40)
Other hypothyroidism (E03)
Cystitis (N30)
Acute pharyngitis (J02)
Cystitis (N30)
Acute sinusitis (J01)
Cystitis (N30)
Cystitis (N30)
Herpesviral [herpes simplex] infections (B00)
Influenza due to unidentified influenza virus (J11)
Need for immunization against other single infectious diseases (Z26)
Need for immunization against other single infectious diseases (Z26)
Need for immunization against other single infectious diseases (Z26)
Need for immunization against other single infectious diseases (Z26)
<table>
  <tr>
    <td>Hepatitis A, inactivated, whole virus (J07BC02)</td>
    <td>Need for immunization against other single infectious diseases (Z26)</td>
  </tr>
  <tr>
    <td>Measles, combinations with mumps and rubella, live attenuated (J07BD52)</td>
    <td>Need for immunization against other single infectious diseases (Z26)</td>
  </tr>
  <tr>
    <td>Papillomavirus (human types 6, 11, 16, 18) (J07BM01)</td>
    <td>Need for immunization against other single infectious diseases (Z26)</td>
  </tr>
  <tr>
    <td>Diphtheria-poliomyelitis-tetanus (J07CA01)</td>
    <td>Need for immunization against other single infectious diseases (Z26)</td>
  </tr>
  <tr>
    <td>Diphtheria-pertussis-poliomyelitis-tetanus (J07CA02)</td>
    <td>Need for immunization against other single infectious diseases (Z26)</td>
  </tr>
  <tr>
    <td>Meloxicam (M01AC06)</td>
    <td>Dorsalgia (M54)</td>
  </tr>
  <tr>
    <td>Methocarbamol (M03BA03)</td>
    <td>Dorsalgia (M54)</td>
  </tr>
  <tr>
    <td>Colchicine (M04AC01)</td>
    <td>Gout (M10)</td>
  </tr>
  <tr>
    <td>Risedronic acid (M05BA07)</td>
    <td>Osteoporosis without current pathological fracture (M81)</td>
  </tr>
  <tr>
    <td>Sumatriptan (N02CC01)</td>
    <td>Migraine (G43)</td>
  </tr>
  <tr>
    <td>Naratriptan (N02CC02)</td>
    <td>Migraine (G43)</td>
  </tr>
  <tr>
    <td>Zolmitriptan (N02CC03)</td>
    <td>Migraine (G43)</td>
  </tr>
  <tr>
    <td>Almotriptan (N02CC05)</td>
    <td>Migraine (G43)</td>
  </tr>
  <tr>
    <td>Eletriptan (N02CC06)</td>
    <td>Migraine (G43)</td>
  </tr>
  <tr>
    <td>Frovatriptan (N02CC07)</td>
    <td>Migraine (G43)</td>
  </tr>
  <tr>
    <td>Loprazolam (N05CD11)</td>
    <td>Sleep disorders (G47)</td>
  </tr>
  <tr>
    <td>Fluoxetine (N06AB03)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Citalopram (N06AB04)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Paroxetine (N06AB05)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Sertraline (N06AB06)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Escitalopram (N06AB10)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Mianserin (N06AX03)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Mirtazapine (N06AX11)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Venlafaxine (N06AX16)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Duloxetine (N06AX21)</td>
    <td>Major depressive disorder, single episode (F32)</td>
  </tr>
  <tr>
    <td>Varenicline (N07BA03)</td>
    <td>Nicotine dependence (F17)</td>
  </tr>
  <tr>
    <td>Betahistine (N07CA01)</td>
    <td>Dizziness and giddiness (R42)</td>
  </tr>
  <tr>
    <td>Proguanil, combinations (P01BB51)</td>
    <td>Persons encountering health services for other counseling and medical advice, not elsewhere classified (Z71)</td>
  </tr>
  <tr>
    <td>Ivermectin (P02CF01)</td>
    <td>Scabies (B86)</td>
  </tr>
  <tr>
    <td>Benzyl benzoate (P03AX01)</td>
    <td>Scabies (B86)</td>
  </tr>
  <tr>
    <td>Dexamethasone, combinations (R01AD53)</td>
    <td>Acute nasopharyngitis [common cold] (J00)</td>
  </tr>
  <tr>
    <td>Other nasal preparation combinations in ATC (R01AX30)</td>
    <td>Acute nasopharyngitis [common cold] (J00)</td>
  </tr>
  <tr>
    <td>Pseudoephedrine (R01BA02)</td>
    <td>Acute nasopharyngitis [common cold] (J00)</td>
  </tr>
  <tr>
    <td>Fusafungine (R02AB03)</td>
    <td>Acute nasopharyngitis [common cold] (J00)</td>
  </tr>
  <tr>
    <td>Terbutaline (R03AC03)</td>
    <td>Asthma (J45)</td>
  </tr>
  <tr>
    <td>Formoterol (R03AC13)</td>
    <td>Asthma (J45)</td>
  </tr>
  <tr>
    <td>Salmeterol and fluticasone (R03AK06)</td>
    <td>Asthma (J45)</td>
  </tr>
  <tr>
    <td>Montelukast (R03DC03)</td>
    <td>Asthma (J45)</td>
  </tr>
  <tr>
    <td>OTHER COLD PREPARATIONS in ATC (R05X)</td>
    <td>Acute nasopharyngitis [common cold] (J00)</td>
  </tr>
  <tr>
    <td>Tobramycin (S01AA12)</td>
    <td>Conjunctivitis (H10)</td>
  </tr>
  <tr>
    <td>Fusidic acid (S01AA13)</td>
    <td>Conjunctivitis (H10)</td>
  </tr>
  <tr>
    <td>Azithromycin (S01AA26)</td>
    <td>Conjunctivitis (H10)</td>
  </tr>
  <tr>
    <td>Sodium borate (S01AX07)</td>
    <td>Conjunctivitis (H10)</td>
  </tr>
</table>
eTable 5. ORs for all health conditions in over 0.5% of patients and controls individually associated with a future symptom specific of MS at 5 years before the index date. In the primary analysis, we used the first recorded demyelinating event as the index date, while in the sensitivity analysis, we used the first symptom suggestive of MS as the index date. * cannot be calculated because too few presentations were recorded (health conditions defined by ICD-10 codes with a relative frequency of less than 0.5). ORs and p-value are adjusted for multiple comparisons using the Bonferroni method. P-values greater to 1 are clipped to 1.

<table><thead><tr><th rowspan="2"></th><th colspan="4">Primary analysis</th><th colspan="4">Sensitivity analysis</th></tr><tr><th>OR (Adjusted 95% CI)</th><th>FR</th><th>Adjusted p value</th><th>OR (Adjusted 95% CI)</th><th>UK</th><th>Adjusted p value</th><th>OR (Adjusted 95% CI)</th><th>FR</th><th>Adjusted p value</th><th>OR (Adjusted 95% CI)</th><th>UK</th><th>Adjusted p value</th></tr></thead><tbody><tr><td>B00 : Herpesviral [herpes simplex] infections</td><td>1.36 (0.89 - 2.08)</td><td>1</td><td></td><td>1.02 (0.84 - 1.24)</td><td>1</td><td></td><td>1.06 (0.66 - 1.73)</td><td>1</td><td></td><td>1.0 (0.80 - 1.24)</td><td>1</td><td></td></tr><tr><td>B02 : Zoster</td><td>2.59 (1.49 - 4.51)</td><td>&lt;0.0001</td><td></td><td>0.93 (0.70 - 1.23)</td><td>1</td><td></td><td>1.32 (0.66 - 2.64)</td><td>1</td><td></td><td>0.85 (0.62 - 1.16)</td><td>1</td><td></td></tr><tr><td>B07 : Viral warts</td><td>1.51 (0.76 - 2.98)</td><td>1</td><td></td><td>0.74 (0.59 - 0.93)</td><td>0.0001</td><td></td><td>1.13 (0.52 - 2.46)</td><td>1</td><td></td><td>0.82 (0.65 - 1.03)</td><td>0.159</td><td></td></tr><tr><td>B34 : Viral infection of unspecified site</td><td>1.4 (0.92 - 2.13)</td><td>0.38</td><td></td><td>1.0 (0.77 - 1.28)</td><td>1</td><td></td><td>1.4 (0.89 - 2.20)</td><td>0.731</td><td></td><td>0.96 (0.73 - 1.25)</td><td>1</td><td></td></tr><tr><td>B35 : Dermatophytosis</td><td>1.5 (1.03 - 2.20)</td><td>0.009</td><td></td><td>0.89 (0.76 - 1.05)</td><td>1</td><td></td><td>1.29 (0.84 - 1.98)</td><td>1</td><td></td><td>0.88 (0.74 - 1.05)</td><td>1</td><td></td></tr><tr><td>B37 : Candidiasis</td><td>1.58 (1.10 - 2.27)</td><td>0.0003</td><td></td><td>0.88 (0.74 - 1.03)</td><td>0.397</td><td></td><td>1.35 (0.89 - 2.04)</td><td>0.958</td><td></td><td>0.82 (0.69 - 0.98)</td><td>0.006</td><td></td></tr><tr><td>D50 : Iron deficiency anemia</td><td>1.82 (1.07 - 3.10)</td><td>0.004</td><td></td><td>0.8 (0.60 - 1.06)</td><td>0.537</td><td></td><td>1.71 (0.97 - 3.03)</td><td>0.059</td><td></td><td>0.73 (0.53 - 1.00)</td><td>0.03</td><td></td></tr><tr><td>D64 : Other anemias</td><td>1.3 (0.70 - 2.42)</td><td>1</td><td></td><td>1.04 (0.69 - 1.59)</td><td>1</td><td></td><td>1.02 (0.49 - 2.11)</td><td>1</td><td></td><td>1.0 (0.63 - 1.58)</td><td>1</td><td></td></tr><tr><td>E03 : Other hypothyroidism</td><td>1.35 (0.90 - 2.00)</td><td>0.771</td><td></td><td>1.0 (0.84 - 1.19)</td><td>1</td><td></td><td>1.28 (0.82 - 1.99)</td><td>1</td><td></td><td>1.01 (0.84 - 1.21)</td><td>1</td><td></td></tr><tr><td>E11 : Type 2 diabetes mellitus</td><td>1.56 (1.07 - 2.28)</td><td>0.001</td><td></td><td>0.76 (0.62 - 0.93)</td><td>&lt;0.0001</td><td></td><td>1.27 (0.82 - 1.96)</td><td>1</td><td></td><td>0.78 (0.62 - 0.97)</td><td>0.003</td><td></td></tr><tr><td>E14 : Other diabetes</td><td>0.9 (0.41 - 1.98)</td><td>1</td><td></td><td>0.85 (0.63 - 1.14)</td><td>1</td><td></td><td>0.76 (0.31 - 1.87)</td><td>1</td><td></td><td>0.89 (0.65 - 1.22)</td><td>1</td><td></td></tr><tr><td>E66 : Overweight and obesity</td><td>1.25 (0.79 - 1.99)</td><td>1</td><td></td><td>0.73 (0.53 - 1.03)</td><td>0.076</td><td></td><td>1.26 (0.78 - 2.04)</td><td>1</td><td></td><td>0.66 (0.46 - 0.96)</td><td>0.005</td><td></td></tr><tr><td>E78 : Disorders of lipoprotein metabolism and other lipidemias</td><td>1.27 (0.99 - 1.64)</td><td>0.053</td><td></td><td>0.85 (0.75 - 0.97)</td><td>0.0003</td><td></td><td>1.07 (0.81 - 1.42)</td><td>1</td><td></td><td>0.8 (0.69 - 0.92)</td><td>&lt;0.0001</td><td></td></tr><tr><td>F10 : Alcohol related disorders</td><td>1.38 (0.63 - 3.05)</td><td>1</td><td></td><td>0.55 (0.36 - 0.84)</td><td>&lt;0.0001</td><td></td><td>*</td><td>*</td><td></td><td>0.51 (0.32 - 0.81)</td><td>&lt;0.0001</td><td></td></tr><tr><td>F32 : Major depressive disorder, single episode</td><td>1.84 (1.52 - 2.21)</td><td>&lt;0.0001</td><td></td><td>1.24 (1.14 - 1.36)</td><td>&lt;0.0001</td><td></td><td>1.62 (1.32 - 1.98)</td><td>&lt;0.0001</td><td></td><td>1.22 (1.11 - 1.34)</td><td>&lt;0.0001</td><td></td></tr><tr><td>F40 : Phobic anxiety disorders</td><td>1.84 (1.09 - 3.09)</td><td>0.001</td><td></td><td>0.87 (0.58 - 1.31)</td><td>1</td><td></td><td>1.56 (0.92 - 2.66)</td><td>0.233</td><td></td><td>0.73 (0.45 - 1.16)</td><td>1</td><td></td></tr><tr><td>F41 : Other anxiety disorders</td><td>1.57 (1.29 - 1.91)</td><td>&lt;0.0001</td><td></td><td>0.85 (0.74 - 0.98)</td><td>0.001</td><td></td><td>1.4 (1.13 - 1.73)</td><td>&lt;0.0001</td><td></td><td>0.78 (0.67 - 0.91)</td><td>&lt;0.0001</td><td></td></tr><tr><td>F43 : Reaction to severe stress</td><td>1.69 (1.23 - 2.32)</td><td>&lt;0.0001</td><td></td><td>0.83 (0.60 - 1.15)</td><td>1</td><td></td><td>1.47 (1.05 - 2.07)</td><td>0.003</td><td></td><td>1.07 (0.89 - 1.28)</td><td>1</td><td></td></tr><tr><td>F52 : Sexual dysfunction</td><td>1.92 (1.29 - 2.86)</td><td>&lt;0.0001</td><td></td><td>1.54 (1.19 - 1.99)</td><td>&lt;0.0001</td><td></td><td>1.69 (1.10 - 2.62)</td><td>0.0008</td><td></td><td>1.47 (1.11 - 1.95)</td><td>&lt;0.0001</td><td></td></tr><tr><td>G40 : Epilepsy and recurrent seizures</td><td>2.54 (1.30 - 4.97)</td><td>&lt;0.0001</td><td></td><td>1.43 (1.00 - 2.04)</td><td>0.021</td><td></td><td>*</td><td>*</td><td></td><td>1.46 (1.00 - 2.12)</td><td>0.022</td><td></td></tr><tr><td>G43 : Migraine</td><td>1.55 (1.18 - 2.03)</td><td>&lt;0.0001</td><td></td><td>1.12 (0.95 - 1.32)</td><td>1</td><td></td><td>1.21 (0.89 - 1.65)</td><td>1</td><td></td><td>1.07 (0.89 - 1.28)</td><td>1</td><td></td></tr><tr><td>G47 : Sleep disorders</td><td>1.64 (1.30 - 2.08)</td><td>&lt;0.0001</td><td></td><td>1.07 (0.82 - 1.39)</td><td>1</td><td></td><td>1.36 (1.04 - 1.78)</td><td>0.002</td><td></td><td>1.01 (0.76 - 1.34)</td><td>1</td><td></td></tr><tr><td>G56 : Carpal tunnel syndrome</td><td>4.22</td><td>&lt;0.0001</td><td></td><td>1.67</td><td>0.304</td><td></td><td>*</td><td>*</td><td></td><td>*</td><td>*</td><td></td></tr><tr><td>H00 : Hordeolum and chalazion</td><td>2.53 (1.47 - 4.36)</td><td>&lt;0.0001</td><td></td><td>0.92 (0.68 - 1.23)</td><td>1</td><td></td><td>2.08 (1.12 - 3.83)</td><td>0.001</td><td></td><td>0.91 (0.66 - 1.26)</td><td>1</td><td></td></tr><tr><td>H10 : Conjunctivitis</td><td>1.42 (1.05 - 1.91)</td><td>0.002</td><td></td><td>0.85 (0.73 - 1.00)</td><td>0.026</td><td></td><td>1.28 (0.93 - 1.77)</td><td>0.514</td><td></td><td>0.82 (0.70 - 0.98)</td><td>0.003</td><td></td></tr><tr><td>H60 : Otitis externa</td><td>1.45 (0.94 - 2.24)</td><td>0.184</td><td></td><td>0.85 (0.71 - 1.02)</td><td>0.146</td><td></td><td>1.49 (0.93 - 2.37)</td><td>0.195</td><td></td><td>0.76 (0.62 - 0.93)</td><td>&lt;0.0001</td><td></td></tr><tr><td>H61 : Other disorders of external ear</td><td>1.58 (0.87 - 2.85)</td><td>0.576</td><td></td><td>1.0 (0.81 - 1.23)</td><td>1</td><td></td><td>1.28 (0.66 - 2.50)</td><td>1</td><td></td><td>0.94 (0.75 - 1.17)</td><td>1</td><td></td></tr><tr><td>H66 : Suppurative and unspecified otitis media</td><td>1.45 (1.11 - 1.91)</td><td>&lt;0.0001</td><td></td><td>0.87 (0.68 - 1.13)</td><td>1</td><td></td><td>1.32 (0.98 - 1.76)</td><td>0.054</td><td></td><td>0.93 (0.71 - 1.22)</td><td>1</td><td></td></tr><tr><td>H81 : Disorders of vestibular function</td><td>2.22 (1.44 - 3.43)</td><td>&lt;0.0001</td><td></td><td>1.49 (1.13 - 1.97)</td><td>&lt;0.0001</td><td></td><td>*</td><td>*</td><td></td><td>*</td><td>*</td><td></td></tr><tr><td>H92 : Otalgia and effusion of ear</td><td>1.59 (1.13 - 2.23)</td><td>&lt;0.0001</td><td></td><td>0.9 (0.71 - 1.14)</td><td>1</td><td></td><td>1.5 (1.03 - 2.18)</td><td>0.007</td><td></td><td>0.8 (0.62 - 1.04)</td><td>0.24</td><td></td></tr><tr><td>H93 : Other disorders of ear, not elsewhere classified</td><td>1.38 (0.77 - 2.46)</td><td>1</td><td></td><td>1.02 (0.71 - 1.45)</td><td>1</td><td></td><td>0.87 (0.42 - 1.82)</td><td>1</td><td></td><td>0.78 (0.51 - 1.20)</td><td>1</td><td></td></tr><tr><td>I10 : Essential (primary) hypertension</td><td>1.28 (1.05 - 1.57)</td><td>0.0006</td><td></td><td>0.79 (0.70 - 0.88)</td><td>&lt;0.0001</td><td></td><td>1.09 (0.87 - 1.37)</td><td>23.439</td><td></td><td>0.78 (0.69 - 0.88)</td><td>&lt;0.0001</td><td></td></tr><tr><td>I20 : Angina pectoris</td><td>1.15 (0.49 - 2.70)</td><td>1</td><td></td><td>0.86 (0.60 - 1.24)</td><td>1</td><td></td><td>0.98 (0.38 - 2.52)</td><td>1</td><td></td><td>0.78 (0.53 - 1.16)</td><td>1</td><td></td></tr><tr><td>I80 : Phlebitis and thrombophlebitis</td><td>1.65 (0.84 - 3.24)</td><td>0.817</td><td></td><td>0.93 (0.65 - 1.33)</td><td>1</td><td></td><td>1.31 (0.57 - 3.01)</td><td>1</td><td></td><td>0.92 (0.62 - 1.35)</td><td>1</td><td></td></tr></tbody></table>
<table>
  <tbody>
    <tr>
      <td>I83 : Varicose veins of lower extremities</td>
      <td>1.47 (0.84 - 2.55)</td>
      <td>1</td>
      <td>0.67 (0.50 - 0.91)</td>
      <td>&lt;0.0001</td>
      <td>1.32 (0.72 - 2.41)</td>
      <td>1</td>
      <td>0.68 (0.49 - 0.93)</td>
      <td>0.0006</td>
    </tr>
    <tr>
      <td>I84 : Hemorrhoids</td>
      <td>1.46 (1.05 - 2.04)</td>
      <td>0.002</td>
      <td>0.82 (0.70 - 0.96)</td>
      <td>0.0002</td>
      <td>1.28 (0.89 - 1.83)</td>
      <td>1</td>
      <td>0.81 (0.68 - 0.95)</td>
      <td>0.0001</td>
    </tr>
    <tr>
      <td>J00 : Acute nasopharyngitis [common cold]</td>
      <td>1.4 (1.20 - 1.62)</td>
      <td>&lt;0.0001</td>
      <td>1.02 (0.82 - 1.27)</td>
      <td>1</td>
      <td>1.3 (1.12 - 1.52)</td>
      <td>&lt;0.0001</td>
      <td>0.97 (0.77 - 1.23)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>J01 : Acute sinusitis</td>
      <td>1.82)</td>
      <td>&lt;0.0001</td>
      <td>0.91 (0.78 - 1.07)</td>
      <td>1</td>
      <td>1.39 (1.11 - 1.72)</td>
      <td>&lt;0.0001</td>
      <td>0.91 (0.77 - 1.08)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>J02 : Acute pharyngitis</td>
      <td>1.35 (1.14 - 1.59)</td>
      <td>&lt;0.0001</td>
      <td>0.83 (0.71 - 0.96)</td>
      <td>0.0004</td>
      <td>1.32 (1.11 - 1.57)</td>
      <td>&lt;0.0001</td>
      <td>0.81 (0.69 - 0.96)</td>
      <td>0.0004</td>
    </tr>
    <tr>
      <td>J04 : Acute laryngitis and tracheitis</td>
      <td>1.36 (1.12 - 1.65)</td>
      <td>&lt;0.0001</td>
      <td>0.94 (0.71 - 1.24)</td>
      <td>1</td>
      <td>1.3 (1.05 - 1.59)</td>
      <td>0.0003</td>
      <td>0.93 (0.69 - 1.25)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>J11 : Influenza due to unidentified influenza virus</td>
      <td>1.31 (1.08 - 1.60)</td>
      <td>&lt;0.0001</td>
      <td>0.87 (0.70 - 1.09)</td>
      <td>1</td>
      <td>1.25 (1.02 - 1.54)</td>
      <td>0.005</td>
      <td>0.86 (0.68 - 1.09)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>J20 : Acute bronchitis</td>
      <td>1.46 (1.19 - 1.80)</td>
      <td>&lt;0.0001</td>
      <td>0.84 (0.65 - 1.07)</td>
      <td>1</td>
      <td>1.41 (1.14 - 1.75)</td>
      <td>&lt;0.0001</td>
      <td>0.74 (0.56 - 0.97)</td>
      <td>0.003</td>
    </tr>
    <tr>
      <td>J30 : Vasomotor and allergic rhinitis</td>
      <td>1.42 (0.98 - 2.06)</td>
      <td>0.048</td>
      <td>0.7 (0.58 - 0.85)</td>
      <td>&lt;0.0001</td>
      <td>1.39 (0.93 - 2.08)</td>
      <td>0.288</td>
      <td>0.72 (0.59 - 0.88)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>J31 : Chronic rhinitis, nasopharyngitis and pharyngitis</td>
      <td>1.44 (0.96 - 2.18)</td>
      <td>0.123</td>
      <td>0.94 (0.67 - 1.33)</td>
      <td>1</td>
      <td>1.3 (0.85 - 2.00)</td>
      <td>1</td>
      <td>0.75 (0.51 - 1.11)</td>
      <td>0.97</td>
    </tr>
    <tr>
      <td>J32 : Chronic sinusitis</td>
      <td>1.45 (0.75 - 2.82)</td>
      <td>1</td>
      <td>0.77 (0.47 - 1.24)</td>
      <td>1</td>
      <td>1.25 (0.62 - 2.53)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>J34 : Other and unspecified disorders of nose and nasal sinuses</td>
      <td>1.11 (0.71 - 1.73)</td>
      <td>1</td>
      <td>0.81 (0.57 - 1.17)</td>
      <td>1</td>
      <td>1.08 (0.66 - 1.75)</td>
      <td>1</td>
      <td>0.81 (0.55 - 1.18)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>J40 : Bronchitis, not specified as acute or chronic</td>
      <td>1.51 (1.10 - 2.07)</td>
      <td>0.0001</td>
      <td>1.18 (0.75 - 1.85)</td>
      <td>1</td>
      <td>1.37 (0.96 - 1.96)</td>
      <td>0.126</td>
      <td>1.18 (0.75 - 1.85)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>J45 : Asthma</td>
      <td>1.38 (1.05 - 1.83)</td>
      <td>0.001</td>
      <td>0.81 (0.70 - 0.93)</td>
      <td>&lt;0.0001</td>
      <td>1.28 (0.95 - 1.73)</td>
      <td>0.266</td>
      <td>0.83 (0.72 - 0.97)</td>
      <td>0.0007</td>
    </tr>
    <tr>
      <td>K04 : Diseases of pulp and periapical tissues</td>
      <td>1.6 (0.91 - 2.80)</td>
      <td>0.275</td>
      <td>0.88 (0.61 - 1.28)</td>
      <td>1</td>
      <td>1.47 (0.79 - 2.76)</td>
      <td>1</td>
      <td>0.8 (0.54 - 1.20)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>K12 : Stomatitis and related lesions</td>
      <td>1.11 (0.56 - 2.18)</td>
      <td>1</td>
      <td>0.77 (0.51 - 1.14)</td>
      <td>1</td>
      <td>1.03 (0.50 - 2.12)</td>
      <td>1</td>
      <td>0.76 (0.50 - 1.17)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>K21 : Gastro-esophageal reflux disease</td>
      <td>1.26 (0.94 - 1.68)</td>
      <td>0.48</td>
      <td>0.74 (0.58 - 0.94)</td>
      <td>0.0005</td>
      <td>1.1 (0.80 - 1.52)</td>
      <td>1</td>
      <td>0.7 (0.53 - 0.92)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>K29 : Gastritis and duodenitis</td>
      <td>1.23 (0.68 - 2.23)</td>
      <td>&lt;0.0001</td>
      <td>0.75 (0.55 - 1.02)</td>
      <td>0.081</td>
      <td>1.26 (0.88 - 1.79)</td>
      <td>1</td>
      <td>0.67 (0.47 - 0.95)</td>
      <td>0.003</td>
    </tr>
    <tr>
      <td>K30 : Functional dyspepsia</td>
      <td>1.42 (1.10 - 1.83)</td>
      <td>1</td>
      <td>0.77 (0.63 - 0.95)</td>
      <td>0.0005</td>
      <td>0.9 (0.44 - 1.82)</td>
      <td>1</td>
      <td>0.72 (0.58 - 0.91)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>K44 : Diaphragmatic hernia</td>
      <td>1.43 (1.06 - 1.93)</td>
      <td>&lt;0.0001</td>
      <td>0.67 (0.46 - 0.98)</td>
      <td>0.011</td>
      <td>1.31 (1.00 - 1.72)</td>
      <td>0.027</td>
      <td>0.67 (0.45 - 1.01)</td>
      <td>0.042</td>
    </tr>
    <tr>
      <td>K58 : Irritable bowel syndrome</td>
      <td>1.9 (1.47 - 2.44)</td>
      <td>&lt;0.0001</td>
      <td>0.82 (0.66 - 1.01)</td>
      <td>0.068</td>
      <td>1.42 (1.04 - 1.94)</td>
      <td>0.003</td>
      <td>0.82 (0.65 - 1.03)</td>
      <td>0.189</td>
    </tr>
    <tr>
      <td>K59 : Functional intestinal disorders</td>
      <td>1.4 (0.75 - 2.61)</td>
      <td>1</td>
      <td>1.58 (1.35 - 1.84)</td>
      <td>&lt;0.0001</td>
      <td>1.66 (1.27 - 2.17)</td>
      <td>&lt;0.0001</td>
      <td>1.5 (1.27 - 1.78)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>K62 : Other diseases of anus and rectum</td>
      <td>1.35 (0.69 - 2.63)</td>
      <td>1</td>
      <td>0.86 (0.68 - 1.10)</td>
      <td>1</td>
      <td>1.11 (0.53 - 2.33)</td>
      <td>1</td>
      <td>0.77 (0.58 - 1.01)</td>
      <td>0.05</td>
    </tr>
    <tr>
      <td>K80 : Cholelithiasis</td>
      <td>1.5 (0.93 - 2.40)</td>
      <td>0.201</td>
      <td>0.81 (0.54 - 1.22)</td>
      <td>1</td>
      <td>1.33 (0.67 - 2.66)</td>
      <td>1</td>
      <td>0.74 (0.47 - 1.19)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L02 : Cutaneous abscess, furuncle and carbuncle</td>
      <td>1.78 (0.99 - 3.20)</td>
      <td>0.036</td>
      <td>0.84 (0.65 - 1.09)</td>
      <td>1</td>
      <td>1.37 (0.80 - 2.34)</td>
      <td>1</td>
      <td>0.82 (0.62 - 1.09)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L03 : Cellulitis and acute lymphangitis</td>
      <td>1.67 (0.81 - 3.45)</td>
      <td>1</td>
      <td>1.01 (0.83 - 1.23)</td>
      <td>1</td>
      <td>1.57 (0.82 - 3.03)</td>
      <td>1</td>
      <td>0.92 (0.74 - 1.15)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L21 : Seborrheic dermatitis</td>
      <td>1.3 (0.91 - 1.85)</td>
      <td>0.865</td>
      <td>0.86 (0.63 - 1.19)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
      <td>0.88 (0.63 - 1.24)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L29 : Pruritus</td>
      <td>1.43 (1.08 - 1.89)</td>
      <td>0.0002</td>
      <td>1.0 (0.84 - 1.18)</td>
      <td>1</td>
      <td>1.16 (0.79 - 1.71)</td>
      <td>1</td>
      <td>0.85 (0.65 - 1.11)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L30 : Other and unspecified dermatitis</td>
      <td>1.97 (1.18 - 3.27)</td>
      <td>&lt;0.0001</td>
      <td>0.92 (0.71 - 1.20)</td>
      <td>1</td>
      <td>1.37 (1.01 - 1.87)</td>
      <td>0.016</td>
      <td>1.0 (0.84 - 1.20)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L40 : Psoriasis</td>
      <td>1.83 (1.05 - 3.18)</td>
      <td>0.006</td>
      <td>0.83 (0.61 - 1.12)</td>
      <td>1</td>
      <td>1.44 (0.80 - 2.61)</td>
      <td>1</td>
      <td>0.91 (0.69 - 1.20)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>L50 : Urticaria</td>
      <td>1.84 (1.07 - 3.16)</td>
      <td>0.003</td>
      <td>0.68 (0.45 - 1.04)</td>
      <td>0.089</td>
      <td>1.84 (1.02 - 3.30)</td>
      <td>0.014</td>
      <td>0.71 (0.51 - 1.00)</td>
      <td>0.031</td>
    </tr>
    <tr>
      <td>L65 : Other nonscarring hair loss</td>
      <td>1.86 (1.20 - 2.89)</td>
      <td>&lt;0.0001</td>
      <td>0.79 (0.64 - 0.98)</td>
      <td>0.006</td>
      <td>1.92 (1.06 - 3.49)</td>
      <td>0.006</td>
      <td>0.72 (0.46 - 1.12)</td>
      <td>0.871</td>
    </tr>
    <tr>
      <td>L70 : Acne</td>
      <td>1.38 (0.74 - 2.57)</td>
      <td>1</td>
      <td>0.75 (0.62 - 0.91)</td>
      <td>&lt;0.0001</td>
      <td>1.72 (1.08 - 2.75)</td>
      <td>0.002</td>
      <td>0.77 (0.61 - 0.96)</td>
      <td>0.001</td>
    </tr>
    <tr>
      <td>L98 : Other disorders of skin and subcutaneous tissue, not elsewhere classified</td>
      <td>1.11 (0.45 - 2.73)</td>
      <td>1</td>
      <td>0.53 (0.34 - 0.81)</td>
      <td>&lt;0.0001</td>
      <td>1.45 (0.73 - 2.90)</td>
      <td>1</td>
      <td>0.7 (0.57 - 0.86)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>M10 : Gout</td>
      <td>1.26 (0.65 - 2.43)</td>
      <td>1</td>
      <td>0.75 (0.52 - 1.10)</td>
      <td>0.768</td>
      <td>*</td>
      <td>*</td>
      <td>0.53 (0.33 - 0.85)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>M13 : Other arthritis</td>
      <td>1.2 (0.86 - 1.67)</td>
      <td>1</td>
      <td>0.73 (0.58 - 0.92)</td>
      <td>&lt;0.0001</td>
      <td>1.11 (0.52 - 2.33)</td>
      <td>1</td>
      <td>0.69 (0.45 - 1.04)</td>
      <td>0.106</td>
    </tr>
    <tr>
      <td>M19 : Other and unspecified osteoarthritis</td>
      <td>1.48 (0.82 - 2.69)</td>
      <td>1</td>
      <td>0.97 (0.85 - 1.11)</td>
      <td>1</td>
      <td>1.02 (0.70 - 1.48)</td>
      <td>1</td>
      <td>0.68 (0.52 - 0.87)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>M25 : Pain in joint</td>
      <td>1.5 (1.21 - 1.86)</td>
      <td>&lt;0.0001</td>
      <td>1.2 (0.89 - 1.62)</td>
      <td>1</td>
      <td>1.39 (1.10 - 1.75)</td>
      <td>&lt;0.0001</td>
      <td>0.91 (0.79 - 1.05)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>M47 : Spondylosis</td>
      <td>1.51 (0.97 - 2.34)</td>
      <td>0.067</td>
      <td>1.13 (0.77 - 1.66)</td>
      <td>1</td>
      <td>1.24 (0.76 - 2.00)</td>
      <td>1</td>
      <td>1.09 (0.78 - 1.52)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>M51 : Thoracic, thoracolumbar, and lumbosacral intervertebral disc disorders</td>
      <td>1.48 (0.82 - 2.69)</td>
      <td>1</td>
      <td>1.13 (0.77 - 1.66)</td>
      <td>1</td>
      <td>1.23 (0.60 - 2.52)</td>
      <td>1</td>
      <td>1.0 (0.65 - 1.53)</td>
      <td>1</td>
    </tr>
  </tbody>
</table>
<table>
  <tbody>
    <tr>
      <td>M53 : Cervicobrachial syndrome</td>
      <td>1.85 (1.32 - 2.57)</td>
      <td>&lt;0.0001</td>
      <td>1.15 (0.77 - 1.73)</td>
      <td>1</td>
      <td>1.47 (1.01 - 2.16)</td>
      <td>0.019</td>
      <td>1.01 (0.65 - 1.57)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>M54 : Dorsalgia</td>
      <td>1.56 (1.35 - 1.80)</td>
      <td>&lt;0.0001</td>
      <td>1.0 (0.90 - 1.10)</td>
      <td>1</td>
      <td>1.38 (1.18 - 1.61)</td>
      <td>&lt;0.0001</td>
      <td>0.9 (0.81 - 1.01)</td>
      <td>0.057</td>
    </tr>
    <tr>
      <td>M62 : Contracture of muscle</td>
      <td>2.09 (1.44 - 3.02)</td>
      <td>&lt;0.0001</td>
      <td>0.98 (0.62 - 1.55)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>M75 : Shoulder lesions</td>
      <td>1.28 (0.98 - 1.68)</td>
      <td>0.065</td>
      <td>0.89 (0.70 - 1.12)</td>
      <td>1</td>
      <td>1.11 (0.82 - 1.51)</td>
      <td>1</td>
      <td>0.78 (0.60 - 1.03)</td>
      <td>0.106</td>
    </tr>
    <tr>
      <td>M77 : Other enthesopathies</td>
      <td>1.38 (1.07 - 1.77)</td>
      <td>0.0003</td>
      <td>0.77 (0.62 - 0.96)</td>
      <td>0.0009</td>
      <td>1.11 (0.84 - 1.48)</td>
      <td>1</td>
      <td>0.74 (0.58 - 0.94)</td>
      <td>0.0003</td>
    </tr>
    <tr>
      <td>M79 : Pain in limb, foot / Myalgia</td>
      <td>1.72 (1.40 - 2.11)</td>
      <td>&lt;0.0001</td>
      <td>1.1 (1.00 - 1.22)</td>
      <td>0.057</td>
      <td>1.46 (1.16 - 1.83)</td>
      <td>&lt;0.0001</td>
      <td>0.96 (0.86 - 1.07)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>M81 : Osteoporosis without current pathological fracture</td>
      <td>1.35 (0.73 - 2.48)</td>
      <td>1</td>
      <td>1.07 (0.74 - 1.53)</td>
      <td>1</td>
      <td>1.21 (0.61 - 2.39)</td>
      <td>1</td>
      <td>1.0 (0.67 - 1.49)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>N30 : Cystitis</td>
      <td>1.68 (1.34 - 2.12)</td>
      <td>&lt;0.0001</td>
      <td>1.22 (1.07 - 1.39)</td>
      <td>&lt;0.0001</td>
      <td>1.5 (1.16 - 1.94)</td>
      <td>&lt;0.0001</td>
      <td>1.21 (1.05 - 1.39)</td>
      <td>0.0001</td>
    </tr>
    <tr>
      <td>N39 : Urinary tract infection, site not specified</td>
      <td>1.79 (1.27 - 2.51)</td>
      <td>&lt;0.0001</td>
      <td>1.47 (1.27 - 1.70)</td>
      <td>&lt;0.0001</td>
      <td>1.68 (1.14 - 2.46)</td>
      <td>&lt;0.0001</td>
      <td>1.38 (1.18 - 1.61)</td>
      <td>&lt;0.0001</td>
    </tr>
    <tr>
      <td>N64 : Other disorders of breast</td>
      <td>2.15 (1.24 - 3.74)</td>
      <td>&lt;0.0001</td>
      <td>0.88 (0.70 - 1.11)</td>
      <td>1</td>
      <td>1.48 (0.78 - 2.79)</td>
      <td>1</td>
      <td>0.77 (0.60 - 1.00)</td>
      <td>0.033</td>
    </tr>
    <tr>
      <td>N76 : Other inflammation of vagina and vulva</td>
      <td>1.57 (0.92 - 2.69)</td>
      <td>0.233</td>
      <td>0.86 (0.61 - 1.21)</td>
      <td>1</td>
      <td>1.38 (0.75 - 2.53)</td>
      <td>1</td>
      <td>0.83 (0.58 - 1.19)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>N91 : Absent, scanty and rare menstruation</td>
      <td>1.62 (0.99 - 2.63)</td>
      <td>0.03</td>
      <td>0.85 (0.65 - 1.10)</td>
      <td>1</td>
      <td>1.22 (0.70 - 2.13)</td>
      <td>1</td>
      <td>0.87 (0.66 - 1.15)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>N92 : Excessive, frequent and irregular menstruation</td>
      <td>1.7 (1.10 - 2.62)</td>
      <td>0.0005</td>
      <td>0.85 (0.73 - 0.98)</td>
      <td>0.002</td>
      <td>1.45 (0.91 - 2.33)</td>
      <td>0.447</td>
      <td>0.86 (0.73 - 1.00)</td>
      <td>0.018</td>
    </tr>
    <tr>
      <td>N94 : Pain and other conditions associated with female genital organs and menstrual cycle</td>
      <td>1.54 (0.96 - 2.48)</td>
      <td>0.084</td>
      <td>0.99 (0.78 - 1.27)</td>
      <td>1</td>
      <td>1.56 (0.95 - 2.56)</td>
      <td>0.113</td>
      <td>0.99 (0.77 - 1.27)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>N95 : Menopausal and other perimenopausal disorders</td>
      <td>1.18 (0.82 - 1.70)</td>
      <td>1</td>
      <td>0.92 (0.77 - 1.09)</td>
      <td>1</td>
      <td>1.0 (0.66 - 1.51)</td>
      <td>1</td>
      <td>0.88 (0.73 - 1.07)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R05 : Cough</td>
      <td>1.24 (1.04 - 1.47)</td>
      <td>0.0005</td>
      <td>1.04 (0.71 - 1.55)</td>
      <td>1</td>
      <td>1.2 (1.01 - 1.44)</td>
      <td>0.014</td>
      <td>0.96 (0.62 - 1.47)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R06 : Abnormalities of breathing</td>
      <td>1.39 (0.90 - 2.15)</td>
      <td>0.61</td>
      <td>0.79 (0.56 - 1.11)</td>
      <td>1</td>
      <td>1.33 (0.82 - 2.17)</td>
      <td>1</td>
      <td>0.7 (0.48 - 1.02)</td>
      <td>0.061</td>
    </tr>
    <tr>
      <td>R07 : Pain in throat and chest</td>
      <td>1.32 (0.97 - 1.81)</td>
      <td>0.115</td>
      <td>0.82 (0.63 - 1.08)</td>
      <td>1</td>
      <td>1.2 (0.84 - 1.70)</td>
      <td>1</td>
      <td>0.71 (0.52 - 0.96)</td>
      <td>0.003</td>
    </tr>
    <tr>
      <td>R10 : Abdominal and pelvic pain</td>
      <td>1.28 (1.06 - 1.55)</td>
      <td>0.0001</td>
      <td>0.88 (0.74 - 1.05)</td>
      <td>1</td>
      <td>1.18 (0.97 - 1.45)</td>
      <td>0.285</td>
      <td>0.84 (0.70 - 1.01)</td>
      <td>0.077</td>
    </tr>
    <tr>
      <td>R20 : Paresthesia of skin</td>
      <td>14.81 (9.74 - 22.52)</td>
      <td>&lt;0.0001</td>
      <td>9.45 (7.42 - 12.04)</td>
      <td>&lt;0.0001</td>
      <td>*</td>
      <td>*</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>R21 : Rash and other nonspecific skin eruption</td>
      <td>1.4 (0.80 - 2.45)</td>
      <td>1</td>
      <td>1.04 (0.82 - 1.31)</td>
      <td>1</td>
      <td>1.02 (0.51 - 2.05)</td>
      <td>1</td>
      <td>0.93 (0.72 - 1.20)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R25 : Abnormal involuntary movements</td>
      <td>1.47 (0.89 - 2.45)</td>
      <td>0.654</td>
      <td>2.32 (1.80 - 2.99)</td>
      <td>&lt;0.0001</td>
      <td>1.21 (0.66 - 2.19)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>R42 : Dizziness and giddiness</td>
      <td>3.41)</td>
      <td>&lt;0.0001</td>
      <td>2.08 (1.78 - 2.41)</td>
      <td>&lt;0.0001</td>
      <td>*</td>
      <td>*</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>R51 : Headache</td>
      <td>1.48 (1.18 - 1.87)</td>
      <td>&lt;0.0001</td>
      <td>1.28 (1.01 - 1.62)</td>
      <td>0.019</td>
      <td>1.17 (0.90 - 1.51)</td>
      <td>1</td>
      <td>1.14 (0.88 - 1.48)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R52 : Pain, unspecified</td>
      <td>1.66 (1.26 - 2.18)</td>
      <td>&lt;0.0001</td>
      <td>0.96 (0.67 - 1.39)</td>
      <td>1</td>
      <td>1.32 (0.96 - 1.82)</td>
      <td>0.172</td>
      <td>0.83 (0.55 - 1.25)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R53 : Malaise and fatigue</td>
      <td>1.76 (1.47 - 2.10)</td>
      <td>&lt;0.0001</td>
      <td>1.45 (1.13 - 1.87)</td>
      <td>&lt;0.0001</td>
      <td>1.55 (1.28 - 1.88)</td>
      <td>&lt;0.0001</td>
      <td>1.21 (0.92 - 1.59)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R55 : Syncope and collapse</td>
      <td>1.76 (1.12 - 2.78)</td>
      <td>0.0007</td>
      <td>1.07 (0.74 - 1.55)</td>
      <td>1</td>
      <td>1.33 (0.70 - 2.54)</td>
      <td>1</td>
      <td>0.93 (0.62 - 1.41)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R59 : Enlarged lymph nodes</td>
      <td>1.47 (0.88 - 2.47)</td>
      <td>0.0004</td>
      <td>0.86 (0.54 - 1.39)</td>
      <td>1</td>
      <td>1.68 (1.04 - 2.69)</td>
      <td>0.006</td>
      <td>0.79 (0.51 - 1.22)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R60 : Edema, not elsewhere classified</td>
      <td>1.28 (1.02 - 1.61)</td>
      <td>0.005</td>
      <td>0.99 (0.68 - 1.44)</td>
      <td>1</td>
      <td>1.36 (0.75 - 2.44)</td>
      <td>1</td>
      <td>0.81 (0.49 - 1.33)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>R63 : Abnormal weight loss or gain</td>
      <td>1.7 (1.04 - 2.78)</td>
      <td>0.007</td>
      <td>1.03 (0.67 - 1.59)</td>
      <td>1</td>
      <td>1.55 (0.88 - 2.70)</td>
      <td>0.502</td>
      <td></td>
      <td></td>
    </tr>
    <tr>
      <td>S83 : Dislocation and sprain of joints and ligaments of knee</td>
      <td>1.51 (0.81 - 2.80)</td>
      <td>1</td>
      <td>0.7 (0.44 - 1.12)</td>
      <td>0.717</td>
      <td>1.27 (0.63 - 2.54)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>S93 : Dislocation and sprain of joints and ligaments at ankle, foot and toe level</td>
      <td>1.69 (1.17 - 2.45)</td>
      <td>&lt;0.0001</td>
      <td>1.06 (0.78 - 1.45)</td>
      <td>1</td>
      <td>1.41 (0.94 - 2.10)</td>
      <td>0.204</td>
      <td>0.97 (0.69 - 1.36)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>T14 : Injury of unspecified body region</td>
      <td>1.66 (1.34 - 2.05)</td>
      <td>&lt;0.0001</td>
      <td>0.93 (0.76 - 1.14)</td>
      <td>1</td>
      <td>1.34 (1.06 - 1.69)</td>
      <td>0.0003</td>
      <td>0.87 (0.70 - 1.08)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>T78 : Adverse effects, not elsewhere classified</td>
      <td>1.28 (1.02 - 1.61)</td>
      <td>0.005</td>
      <td>0.92 (0.68 - 1.25)</td>
      <td>1</td>
      <td>1.24 (0.97 - 1.57)</td>
      <td>0.149</td>
      <td>0.92 (0.67 - 1.28)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>Z01 : Encounter for other special examination without complaint, suspected or reported diagnosis</td>
      <td>1.16 (0.71 - 1.91)</td>
      <td>1</td>
      <td>1.11 (0.70 - 1.74)</td>
      <td>1</td>
      <td>0.75 (0.39 - 1.44)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>Z02 : Encounter for administrative examination</td>
      <td>1.37 (1.13 - 1.65)</td>
      <td>&lt;0.0001</td>
      <td>1.24 (1.04 - 1.48)</td>
      <td>0.0009</td>
      <td>1.2 (0.98 - 1.48)</td>
      <td>0.106</td>
      <td>1.03 (0.84 - 1.27)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>Z13 : Encounter for screening for other diseases and disorders</td>
      <td>1.04 (0.66 - 1.65)</td>
      <td>1</td>
      <td>0.65 (0.41 - 1.05)</td>
      <td>0.128</td>
      <td>1.04 (0.64 - 1.70)</td>
      <td>1</td>
      <td>*</td>
      <td>*</td>
    </tr>
    <tr>
      <td>Z30 : Encounter for contraceptive management</td>
      <td>1.35 (1.08 - 1.68)</td>
      <td>&lt;0.0001</td>
      <td>0.98 (0.89 - 1.09)</td>
      <td>1</td>
      <td>1.4 (1.11 - 1.76)</td>
      <td>&lt;0.0001</td>
      <td>1.06 (0.96 - 1.18)</td>
      <td>1</td>
    </tr>
    <tr>
      <td>Z76 : Persons encountering health services</td>
      <td>1.22 (0.99 - 1.50)</td>
      <td>0.065</td>
      <td>0.81 (0.59 - 1.11)</td>
      <td>1</td>
      <td>1.12 (0.89 - 1.40)</td>
      <td>1</td>
      <td>0.84 (0.59 - 1.20)</td>
      <td>1</td>
    </tr>
  </tbody>
</table>
eTable 6. ORs for all health conditions individually associated with a future diagnosis of MS for the five-year period leading up to the index date. In the primary analysis, we used the first recorded G35 code or demyelinating event as the index date, whereas, in the sensitivity analysis, we used the first recorded G35, or demyelinating event or first symptom suggestive of MS as the index date. \* cannot be calculated because the health condition is used to define the index date in the sensitivity analysis. \*\* cannot be calculated because too few presentations were recorded (health conditions defined by ICD-10 codes with a relative frequency of less than 0.5%). ORs and p-value are adjusted for multiple comparisons using the Bonferroni method. P-values greater to 1 are clipped to 1.

<table><thead><tr><th rowspan="3"></th><th colspan="6">Primary analysis</th><th colspan="6">Sensitivity analysis</th></tr><tr><th colspan="3">FR</th><th colspan="3">UK</th><th colspan="3">FR</th><th colspan="3">UK</th></tr><tr><th>No. (%)<br>[MS:controls]</th><th>OR<br>(Adjusted<br>95% CI)</th><th>Adjusted p<br>value</th><th>No. (%)<br>[MS:controls]</th><th>OR<br>(Adjusted<br>95% CI)</th><th>Adjusted p<br>value</th><th>No. (%)<br>[MS:controls]</th><th>OR<br>(Adjusted<br>95% CI)</th><th>Adjusted p<br>value</th><th>No. (%)<br>[MS:controls]</th><th>OR<br>(Adjusted<br>95% CI)</th><th>Adjusted p<br>value</th></tr></thead><tbody><tr><td>F32: Major depressive disorder, single episode</td><td>789 (18.1):<br>1350 (10.8)</td><td>1.84<br>(1.52 - 2.21)</td><td>&lt;0.0001</td><td>3801 (24.0):<br>8297 (19.6)</td><td>1.24<br>(1.14 - 1.36)</td><td>&lt;0.0001</td><td>630 (14.4):<br>1139 (9.1)</td><td>1.62<br>(1.32 - 1.98)</td><td>&lt;0.0001</td><td>3295 (20.8):<br>7030 (16.6)</td><td>1.22<br>(1.11 - 1.34)</td><td>&lt;0.0001</td></tr><tr><td>F52: Sexual dysfunction</td><td>154 (3.6):<br>246 (2.0)</td><td>1.92<br>(1.29 - 2.86)</td><td>&lt;0.0001</td><td>388 (2.5):<br>650 (1.5)</td><td>1.54<br>(1.19 - 1.99)</td><td>&lt;0.0001</td><td>123 (2.8):<br>209 (1.7)</td><td>1.69<br>(1.10 - 2.62)</td><td>0.0008</td><td>305 (1.9):<br>515 (1.2)</td><td>1.47<br>(1.11 - 1.95)</td><td>&lt;0.0001</td></tr><tr><td>G40: Epilepsy and recurrent seizures</td><td>61 (1.4):<br>71 (0.6)</td><td>2.54<br>(1.30 - 4.97)</td><td>&lt;0.0001</td><td>188 (1.2):<br>363 (0.9)</td><td>1.43<br>(1.00 - 2.04)</td><td>0.021</td><td>**</td><td>**</td><td>**</td><td>167 (1.1):<br>308 (0.7)</td><td>1.46 (1.00 -<br>2.12)</td><td>0.022</td></tr><tr><td>H81: Disorders of vestibular function</td><td>144 (3.3):<br>184 (1.5)</td><td>2.22<br>(1.44 - 3.43)</td><td>&lt;0.0001</td><td>330 (2.1):<br>557 (1.5)</td><td>1.49<br>(1.13 - 1.97)</td><td>&lt;0.0001</td><td>**</td><td>**</td><td>**</td><td>**</td><td>**</td><td>**</td></tr><tr><td>K59: Functional intestinal disorders</td><td>406 (9.3):<br>655 (5.2)</td><td>1.9<br>(1.47 - 2.44)</td><td>&lt;0.0001</td><td>1171 (7.4):<br>1845 (4.4)</td><td>1.58<br>(1.35 - 1.84)</td><td>&lt;0.0001</td><td>340 (7.8):<br>591 (4.7)</td><td>1.66<br>(1.27 - 2.17)</td><td>&lt;0.0001</td><td>904 (5.7):<br>1427 (3.4)</td><td>1.5<br>(1.27 - 1.78)</td><td>&lt;0.0001</td></tr><tr><td>N30: Cystitis</td><td>478 (11.0):<br>855 (6.8)</td><td>1.68<br>(1.34 - 2.12)</td><td>&lt;0.0001</td><td>1422 (9.0):<br>2951 (7.0)</td><td>1.22<br>(1.07 - 1.39)</td><td>&lt;0.0001</td><td>367 (8.4):<br>687 (5.5)</td><td>1.5<br>(1.16 - 1.94)</td><td>&lt;0.0001</td><td>1176 (7.4):<br>2385 (5.6)</td><td>1.21<br>(1.05 - 1.39)</td><td>0.0001</td></tr><tr><td>N39: Urinary tract infection, site not specified</td><td>217 (5.0):<br>348 (2.8)</td><td>1.79<br>(1.27 - 2.51)</td><td>&lt;0.0001</td><td>1218 (7.7):<br>2263 (5.4)</td><td>1.47<br>(1.27 - 1.70)</td><td>&lt;0.0001</td><td>165 (3.8):<br>268 (2.1)</td><td>1.68<br>(1.14 - 2.46)</td><td>&lt;0.0001</td><td>997 (6.3):<br>1904 (4.5)</td><td>1.38<br>(1.18 - 1.61)</td><td>&lt;0.0001</td></tr><tr><td>R20: Paresthesia of skin</td><td>512 (11.7):<br>103 (0.8)</td><td>14.81<br>(9.74 - 22.52)</td><td>&lt;0.0001</td><td>1220 (7.7):<br>363 (0.9)</td><td>9.45<br>(7.42 - 12.04)</td><td>&lt;0.0001</td><td>**</td><td>**</td><td>**</td><td>**</td><td>**</td><td>**</td></tr><tr><td>R42: Dizziness and giddiness</td><td>372 (8.5):<br>415 (3.3)</td><td>2.57<br>(1.93 - 3.41)</td><td>&lt;0.0001</td><td>1300 (8.2):<br>1667 (4.0)</td><td>2.08<br>(1.78 - 2.41)</td><td>&lt;0.0001</td><td>**</td><td>**</td><td>**</td><td>**</td><td>**</td><td>**</td></tr><tr><td>R51: Headache</td><td>464 (10.6):<br>908 (7.2)</td><td>1.48<br>(1.18 - 1.87)</td><td>&lt;0.0001</td><td>403 (2.6):<br>844 (2.0)</td><td>1.28<br>(1.00 - 1.62)</td><td>0.019</td><td>333 (7.6):<br>776 (6.2)</td><td>1.17<br>(0.90 - 1.51)</td><td>1</td><td>324 (2.0):<br>730 (1.7)</td><td>1.14<br>(0.88 - 1.48)</td><td>1</td></tr><tr><td>R53: Malaise and fatigue</td><td>891 (20.4):<br>1574 (12.5)</td><td>1.76<br>(1.47 - 2.10)</td><td>&lt;0.0001</td><td>376 (2.4):<br>692 (1.6)</td><td>1.45<br>(1.13 - 1.87)</td><td>&lt;0.0001</td><td>703 (16.1):<br>1301 (10.4)</td><td>1.55<br>(1.28 - 1.88)</td><td>&lt;0.0001</td><td>294 (1.9):<br>633 (1.5)</td><td>1.21<br>(0.92 - 1.59)</td><td>1</td></tr></tbody></table>
<caption>eTable 7. Pooled, UK, and French ORs for all health problems individually associated with MS in the</caption>

sensitivity analysis during the five years before the occurrence of the first symptoms. We used the whole

sensitivity cohort and excluded patients with less than 5 years of history before the index date in the database.

* for ORs associated with corrected p-values below 0.05 or initial p-values below 0.05/113. ORs and p-value are

adjusted for multiple comparisons using the Bonferroni method.

<table><thead><tr><th rowspan="3"></th><th colspan="2">Pooled cohort<br>(No. MS: 14932<br>No. no MS: 25193)</th><th colspan="2">UK cohort<br>(No. MS: 12412<br>No. no MS: 21736)</th><th colspan="2">French cohort<br>(No. MS: 2520<br>No. no MS: 3457)</th></tr><tr><th>No. (%)</th><th>OR</th><th>No. (%)</th><th>OR</th><th>No. (%)</th><th>OR</th></tr><tr><th>[MS: no MS]</th><th>(adjusted 95% CI)</th><th>[MS: no MS]</th><th>(adjusted 95% CI)</th><th>[MS: no MS]</th><th>(adjusted 95% CI)</th></tr></thead><tbody><tr><td>F32: Major depressive disorder, single episode</td><td>2956 (19.80):<br>3902 (15.49)</td><td>1.30 (1.20 - 1.40)*</td><td>2574 (20.74):<br>3554 (16.35)</td><td>1.29 (1.14 - 1.45)*</td><td>382 (15.16):<br>349 (10.10)</td><td>1.57 (1.17 - 2.11)*</td></tr><tr><td>F52: Sexual dysfunction</td><td>310 (2.08):<br>343 (1.36)</td><td>1.50 (1.20 - 1.87)*</td><td>241 (1.94):<br>285 (1.31)</td><td>1.43 (1.03 - 1.99)*</td><td>70 (2.78):<br>59 (1.71)</td><td>1.67 (0.86 - 3.22)</td></tr><tr><td>K59: Constipation</td><td>918 (6.15):<br>948 (3.76)</td><td>1.59 (1.39 - 1.82)*</td><td>712 (5.74):<br>767 (3.53)</td><td>1.55 (1.23 - 1.94)*</td><td>206 (8.17):<br>180 (5.21)</td><td>1.62 (1.10 - 2.40)*</td></tr><tr><td>N30: Cystitis</td><td>1135 (7.60):<br>1517 (6.02)</td><td>1.23 (1.10 - 1.38)*</td><td>923 (7.44):<br>1298 (5.97)</td><td>1.20 (1.01 - 1.43)*</td><td>212 (8.41):<br>218 (6.31)</td><td>1.34 (0.92 - 1.94)</td></tr><tr><td>N39: Urinary tract infection, site not specified</td><td>876 (5.87):<br>1091 (4.33)</td><td>1.36 (1.19 - 1.55)*</td><td>779 (6.28):<br>991 (4.56)</td><td>1.38 (1.14 - 1.66)*</td><td>97 (3.85):<br>99 (2.86)</td><td>1.32 (0.77 - 2.26)</td></tr></tbody></table>
<table><caption>eTable 8. Characteristics of patients with MS and individuals without MS with at least five years of data before the index date in the two cohorts. The data are shown as percentages or medians (IQR).</caption><thead><tr><th></th><th>Size, n</th><th>Sex (female)</th><th>Age at first symptom of MS</th><th>Person-years of data available before diagnosis</th><th>Number of visits per year before diagnosis</th></tr></thead><tbody><tr><td><strong>Pooled</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>MS</td><td>14932</td><td>70.7%</td><td>44 (34 - 55)</td><td>8.4 (5.8 - 12.3)</td><td>4.6 (1.3 - 5.5)</td></tr><tr><td>No MS</td><td>25193</td><td>70.2%</td><td>46 (37 - 56)</td><td>8.5 (5.9 - 12.4)</td><td>3.8 (1.1 - 5.0)</td></tr><tr><td><strong>UK</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>MS</td><td>12412</td><td>70.7%</td><td>45 (35 - 55)</td><td>8.6 (6.0 - 12.6)</td><td>4.6 (1.3 - 5.6)</td></tr><tr><td>No MS</td><td>21736</td><td>70.2%</td><td>46 (36 - 56)</td><td>8.7 (6.1 - 12.7)</td><td>4.0 (1.2 - 5.2)</td></tr><tr><td><strong>France</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>MS</td><td>2520</td><td>70.7%</td><td>41 (32 - 51)</td><td>7.2 (5.1 - 10.2)</td><td>4.3 (1.3 - 5.0)</td></tr><tr><td>No MS</td><td>3457</td><td>70.5%</td><td>42 (33 - 53)</td><td>7.3 (5.3 - 10.3)</td><td>2.9 (0.7 - 3.9)</td></tr></tbody></table>
<table><caption>eTable 9. Characteristics of patients with MS and individuals without MS with at least two years of data before and after the index date in the two cohorts. The data are shown as percentages or medians (IQR).</caption><thead><tr><th rowspan="3"></th><th colspan="10">Sex</th><th colspan="5">Age at onset</th><th colspan="4">Year of diagnosis</th></tr><tr><th colspan="2">Whole cohort</th><th colspan="2">Women</th><th colspan="2">Men</th><th colspan="2">&lt;40</th><th colspan="2">[40,53]</th><th colspan="2">&gt;53</th><th colspan="2">&lt;2010</th><th colspan="2">[2010,2017]</th><th colspan="2">&gt;2017</th></tr><tr><th>MS</th><th>No MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th><th>MS</th><th>no MS</th></tr></thead><tbody><tr><td colspan="19"><strong>Pooled</strong></td></tr><tr><td>Size, n</td><td>15454</td><td>26253</td><td>10966</td><td>18821</td><td>4488</td><td>7442</td><td>5151</td><td>7079</td><td>5152</td><td>9620</td><td>5151</td><td>9253</td><td>10283</td><td>18964</td><td>4417</td><td>6419</td><td>754</td><td>732</td></tr><tr><td>Sex (female)</td><td>71.3%</td><td>72.0%</td><td>100%</td><td>100%</td><td>0%</td><td>0%</td><td>73.9%</td><td>74.6%</td><td>71.8%</td><td>73.2%</td><td>68.6%</td><td>69.1%</td><td>71.8%</td><td>72.3%</td><td>69.9%</td><td>70.9%</td><td>73.1%</td><td>74.4%</td></tr><tr><td>Age at index date</td><td>44 (35 - 54)</td><td>45 (37 - 54)</td><td>44 (34 - 54)</td><td>45 (36 - 54)</td><td>46 (36 - 55)</td><td>46 (37 - 56)</td><td>31 (26 - 35)</td><td>31 (26 - 35)</td><td>44 (41 - 48)</td><td>44 (41 - 48)</td><td>59 (54 - 66)</td><td>60 (56 - 67)</td><td>46 (36 - 56)</td><td>46 (37 - 56)</td><td>41 (32 - 51)</td><td>43 (37 - 55)</td><td>40 (31 - 51)</td><td>41 (33 - 52)</td></tr><tr><td>Person-years of data available before diagnosis</td><td>6.3 (3.5 - 10.2)</td><td>6.3 (3.6 - 9.9)</td><td>6.3 (3.5 - 10.2)</td><td>6.3 (3.6 - 9.9)</td><td>6.3 (3.4 - 10.1)</td><td>6.3 (3.6 - 9.8)</td><td>5.8 (3.2 - 9.8)</td><td>5.3 (3.1 - 8.8)</td><td>6.3 (3.6 - 10.0)</td><td>6.2 (3.6 - 9.7)</td><td>6.7 (3.6 - 10.5)</td><td>6.9 (4.0 - 10.7)</td><td>5.7 (3.3 - 8.6)</td><td>5.9 (3.5 - 8.8)</td><td>8.4 (3.9 - 13.8)</td><td>8.2 (4.2 - 13.7)</td><td>9.9 (4.5 - 16.6)</td><td>8.1 (3.7 - 16.9)</td></tr><tr><td>Number of visits per year before diagnosis</td><td>5.3 (1.5 - 6.3)</td><td>4.1 (1.3 - 5.4)</td><td>5.5 (1.6 - 6.5)</td><td>4.4 (1.4 - 5.8)</td><td>4.7 (1.1 - 5.3)</td><td>3.5 (1.0 - 4.5)</td><td>4.6 (1.4 - 5.5)</td><td>3.7 (1.2 - 4.8)</td><td>5.1 (1.3 - 5.8)</td><td>3.7 (1.2 - 4.8)</td><td>6.2 (1.7 - 7.8)</td><td>4.9 (1.5 - 6.5)</td><td>5.3 (1.3 - 6.4)</td><td>4.0 (1.2 - 5.3)</td><td>5.2 (1.7 - 6.0)</td><td>4.3 (1.5 - 5.7)</td><td>5.2 (1.7 - 5.5)</td><td>4.9 (1.9 - 6.0)</td></tr><tr><td colspan="19"><strong>UK</strong></td></tr><tr><td>Size, n</td><td>12565</td><td>22751</td><td>8964</td><td>16396</td><td>3601</td><td>6365</td><td>4076</td><td>5993</td><td>4279</td><td>8318</td><td>4299</td><td>8189</td><td>8848</td><td>17087</td><td>3207</td><td>5106</td><td>510</td><td>544</td></tr><tr><td>Sex (female)</td><td>71.3%</td><td>72.0%</td><td>100%</td><td>100%</td><td>0%</td><td>0%</td><td>73.9%</td><td>74.6%</td><td>71.8%</td><td>73.2%</td><td>68.6%</td><td>69.1%</td><td>71.8%</td><td>72.3%</td><td>69.9%</td><td>70.9%</td><td>73.1%</td><td>74.4%</td></tr><tr><td>Age at index date</td><td>45 (35 - 55)</td><td>46 (37 - 55)</td><td>44 (35 - 54)</td><td>46 (36 - 55)</td><td>46 (36 - 56)</td><td>47 (38 - 56)</td><td>31 (26 - 35)</td><td>31 (26 - 35)</td><td>44 (41 - 48)</td><td>44 (41 - 48)</td><td>59 (55 - 66)</td><td>60 (56 - 67)</td><td>46 (37 - 56)</td><td>49 (40 - 58)</td><td>41 (32 - 51)</td><td>43 (34 - 52)</td><td>40 (30 - 51)</td><td>41 (33 - 52)</td></tr><tr><td>Person-years of data available before diagnosis</td><td>6.8 (3.9 - 10.8)</td><td>6.6 (3.8 - 10.4)</td><td>6.8 (3.9 - 10.9)</td><td>6.6 (3.8 - 10.4)</td><td>6.8 (3.9 - 10.6)</td><td>6.6 (3.8 - 10.3)</td><td>6.3 (3.5 - 10.6)</td><td>5.6 (3.2 - 9.2)</td><td>6.8 (4.1 - 10.5)</td><td>6.5 (3.8 - 10.2)</td><td>7.3 (4.2 - 11.0)</td><td>7.2 (4.3 - 11.1)</td><td>6.1 (3.8 - 9.1)</td><td>6.1 (3.6 - 9.2)</td><td>9.9 (4.8 - 15.5)</td><td>9.2 (4.6 - 14.7)</td><td>12.3 (5.7 - 18.6)</td><td>10.2 (4.4 - 17.8)</td></tr><tr><td>Number of visits per year before diagnosis</td><td>5.3 (1.4 - 6.3)</td><td>4.2 (1.2 - 5.5)</td><td>5.5 (1.6 - 6.6)</td><td>4.4 (1.4 - 5.8)</td><td>4.8 (1.1 - 5.3)</td><td>3.4 (0.9 - 4.4)</td><td>4.6 (1.4 - 5.5)</td><td>3.8 (1.2 - 4.9)</td><td>5.0 (1.2 - 5.8)</td><td>3.7 (1.1 - 4.8)</td><td>6.2 (1.7 - 7.9)</td><td>4.9 (1.4 - 6.6)</td><td>5.2 (1.3 - 6.3)</td><td>4.0 (1.1 - 5.3)</td><td>5.5 (1.7 - 6.4)</td><td>4.5 (1.6 - 6.0)</td><td>5.6 (1.7 - 6.0)</td><td>5.2 (1.9 - 6.3)</td></tr><tr><td colspan="19"><strong>FR</strong></td></tr><tr><td>Size, n</td><td>2889</td><td>3502</td><td>2002</td><td>2425</td><td>887</td><td>1077</td><td>1075</td><td>1086</td><td>873</td><td>1302</td><td>852</td><td>1064</td><td>1435</td><td>1877</td><td>1210</td><td>1313</td><td>244</td><td>189</td></tr><tr><td>Sex (female)</td><td>69.3%</td><td>69.2%</td><td>100%</td><td>100%</td><td>0%</td><td>0%</td><td>71.1%</td><td>70.9%</td><td>72.1%</td><td>71.9%</td><td>63.2%</td><td>63.8%</td><td>69.4%</td><td>68.4%</td><td>68.8%</td><td>69.8%</td><td>71.7%</td><td>73.5%</td></tr><tr><td>Age at index date</td><td>42 (33 - 52)</td><td>44 (34 - 54)</td><td>42 (33 - 51)</td><td>44 (35 - 53)</td><td>44 (34 - 55)</td><td>45 (35 - 55)</td><td>30 (24 - 32)</td><td>31 (24 - 36)</td><td>44 (41 - 48)</td><td>45 (41 - 49)</td><td>58 (54 - 66)</td><td>59 (55 - 67)</td><td>43 (34 - 55)</td><td>45 (35 - 5)</td><td>41 (32 - 50)</td><td>41 (33 - 50)</td><td>41 (31 - 51)</td><td>43 (51 - 52)</td></tr><tr><td>Person-years of data available before diagnosis</td><td>5.6 (3.3 - 9.2)</td><td>4.9 (3.2 - 7.6)</td><td>5.6 (3.3 - 8.9)</td><td>4.9 (3.2 - 7.6)</td><td>5.7 (3.1 - 9.6)</td><td>4.9 (3.2 - 7.6)</td><td>5.3 (3.4 - 8.7)</td><td>4.4 (3.0 - 6.8)</td><td>6.2 (3.6 - 9.7)</td><td>5.0 (3.3 - 7.7)</td><td>5.8 (3.6 - 9.2)</td><td>4.9 (3.1 - 7.6)</td><td>4.0 (2.7 - 6.0)</td><td>3.2 (2.3 - 5.1)</td><td>5.5 (2.8 - 9.4)</td><td>5.4 (3.4 - 8.8)</td><td>6.7 (3.3 - 11.9)</td><td>4.5 (2.6 - 8.8)</td></tr><tr><td>Number of visits per year before diagnosis</td><td>4.9 (2.1 - 6.4)</td><td>3.8 (1.5 - 5.0)</td><td>5.0 (2.2 - 6.5)</td><td>4.0 (1.6 - 5.2)</td><td>4.7 (1.8 - 5.9)</td><td>3.5 (1.5 - 4.6)</td><td>4.0 (2.0 - 5.1)</td><td>3.1 (1.4 - 4.0)</td><td>4.8 (1.9 - 6.3)</td><td>3.8 (1.5 - 4.7)</td><td>5.9 (1.9 - 7.6)</td><td>4.9 (1.9 - 6.2)</td><td>6.1 (1.9 - 7.0)</td><td>4.1 (1.5 - 5.3)</td><td>4.3 (1.5 - 5.2)</td><td>3.5 (1.3 - 4.6)</td><td>4.5 (1.6 - 4.7)</td><td>3.9 (1.8 - 4.6)</td></tr></tbody></table>
836 eTable 10. ORs in the UK cohort for all health conditions individually associated with MS in the sensitivity analysis during the five years before and five years after the occurrence of the first symptoms. Individuals 837 with MS are compared with controls without MS. We used the whole sensitivity cohort, sex-based cohorts, age- 838 at-onset cohorts, and year-at-diagnosis cohorts. * cannot be calculated because too few presentations were 839 recorded. * for ORs associated with corrected p-values below 0.05 or initial p-value below 0.05/5. p-value are 840 adjusted for multiple comparisons using the Bonferroni method. 841

842

<table><thead><tr><th rowspan="2"></th><th rowspan="2">Whole cohort (MS : 12565 Control : 22751)</th><th colspan="2">Sex</th><th colspan="2">Age at onset</th><th colspan="2">Year of diagnosis</th></tr><tr><th>Women (MS : 8964 Control : 16396)</th><th>Men (No. MS : 3601 No. Control 6365)</th><th>&lt;40 (No. MS : 4076 No. Control 5993)</th><th>[40,53] (No. MS : 4279 No. Control : 8318)</th><th>&gt;53 (No. MS : 4299 No. Control : 8189)</th><th>&lt;2010 (No. MS : 8848 No. Control : 17087)</th><th>[2010,2017] (No. MS : 3207 No. Control : 5106)</th><th>&gt;2017 (No. MS : 510 No. Control : 544)</th></tr></thead><tbody><tr><td colspan="10"><strong>Before diagnosis</strong></td></tr><tr><td>F32 : Major depressive disorder, single episode</td><td>1.36 (1.22 - 1.52)*</td><td>1.34 (1.18 - 1.51)*</td><td>1.49 (1.18 - 1.88)*</td><td>1.34 (1.09 - 1.64)*</td><td>1.39 (1.17 - 1.65)*</td><td>1.33 (1.10 - 1.61)*</td><td>1.39 (1.22 - 1.58)*</td><td>1.31 (1.07 - 1.62)*</td><td>1.02 (0.60 - 1.72)</td></tr><tr><td>F52 : Sexual dysfunction</td><td>1.65 (1.18 - 2.31)*</td><td>1.08 (0.45 - 2.60)</td><td>1.75 (1.21 - 2.54)*</td><td>1.58 (0.65 - 3.84)</td><td>1.95 (1.12 - 3.39)*</td><td>1.53 (0.94 - 2.49)</td><td>1.67 (1.10 - 2.52)*</td><td>1.61 (0.88 - 2.94)</td><td>.*</td></tr><tr><td>K59 : Constipation</td><td>1.87 (1.50 - 2.35)*</td><td>1.69 (1.31 - 2.18)*</td><td>2.70 (1.65 - 4.43)*</td><td>1.35 (0.85 - 2.13)</td><td>1.86 (1.23 - 2.80)*</td><td>2.30 (1.65 - 3.21)*</td><td>2.11 (1.53 - 2.91)*</td><td>1.66 (1.18 - 2.35)*</td><td>1.15 (0.53 - 2.49)</td></tr><tr><td>N30 : Cystitis</td><td>1.36 (1.14 - 1.63)*</td><td>1.30 (1.08 - 1.57)</td><td>2.49 (1.33 - 4.69)*</td><td>1.14 (0.82 - 1.59)</td><td>1.19 (0.87 - 1.62)</td><td>1.73 (1.30 - 2.31)*</td><td>1.44 (1.15 - 1.79)*</td><td>1.22 (0.88 - 1.68)</td><td>1.09 (0.51 - 2.34)</td></tr><tr><td>N39 : Urinary tract infection, site not specified</td><td>1.41 (1.18 - 1.69)*</td><td>1.31 (1.08 - 1.60)</td><td>2.27 (1.36 - 3.80)*</td><td>1.16 (0.81 - 1.64)</td><td>1.32 (0.96 - 1.81)</td><td>1.70 (1.28 - 2.26)*</td><td>1.51 (1.23 - 1.86)*</td><td>1.10 (0.74 - 1.64)</td><td>1.53 (0.46 - 5.05)</td></tr><tr><td colspan="10"><strong>After diagnosis</strong></td></tr><tr><td>F32 : Major depressive disorder, single episode</td><td>2.0 (1.85 - 2.16)*</td><td>1.84 (1.69 - 2.02)*</td><td>2.54 (2.17 - 2.98)*</td><td>2.17 (1.91 - 2.47)*</td><td>2.05 (1.79 - 2.34)*</td><td>1.91 (1.65 - 2.22)*</td><td>1.96 (1.79 - 2.14)*</td><td>2.11 (1.79 - 2.48)*</td><td>2.11 (1.21 - 3.68)*</td></tr><tr><td>F52 : Sexual dysfunction</td><td>3.03 (2.56 - 3.59)*</td><td>1.62 (1.04 - 2.53)*</td><td>3.35 (2.78 - 4.03)*</td><td>5.57 (3.85 - 8.05)*</td><td>4.3 (3.20 - 5.78)*</td><td>1.45 (1.09 - 1.92)*</td><td>3.17 (2.61 - 3.86)*</td><td>2.74 (1.93 - 3.89)*</td><td>.*</td></tr><tr><td>K59 : Constipation</td><td>3.56 (3.22 - 3.92)*</td><td>3.2 (2.86 - 3.59)*</td><td>4.83 (3.95 - 5.90)*</td><td>3.27 (2.70 - 3.98)*</td><td>4.57 (3.83 - 5.45)*</td><td>3.34 (2.87 - 3.88)*</td><td>3.77 (3.34 - 4.25)*</td><td>3.07 (2.57 - 3.67)*</td><td>2.54 (1.47 - 4.39)*</td></tr><tr><td>N30 : Cystitis</td><td>2.66 (2.42 - 2.92)*</td><td>2.36 (2.13 - 2.61)*</td><td>5.9 (4.43 - 7.86)*</td><td>2.33 (1.95 - 2.79)*</td><td>2.88 (2.45 - 3.38)*</td><td>2.86 (2.46 - 3.34)*</td><td>2.76 (2.46 - 3.09)*</td><td>2.34 (1.95 - 2.81)*</td><td>2.21 (1.34 - 3.64)*</td></tr><tr><td>N39 : Urinary tract infection, site not specified</td><td>2.81 (2.53 - 3.13)*</td><td>2.57 (2.29 - 2.89)*</td><td>4.33 (3.30 - 5.70)*</td><td>2.35 (1.92 - 2.88)*</td><td>3.0 (2.48 - 3.63)*</td><td>3.02 (2.55 - 3.57)*</td><td>2.86 (2.54 - 3.22)*</td><td>2.74 (2.11 - 3.56)*</td><td>2.53 (1.08 - 5.91)*</td></tr></tbody></table>

843
<table><caption>eTable 11. ORs in the French cohort for all health conditions individually associated with MS in the sensitivity analysis during the five years before and five years after the occurrence of the first symptoms. Individuals with MS are compared with controls without MS. We used the whole sensitivity cohort, sex-based cohorts, age-at-onset cohorts, and year-at-diagnosis cohorts. * cannot be calculated because too few presentations were recorded. * for ORs associated with corrected p-values below 0.05 or initial p-value below 0.05/5. p-value are adjusted for multiple comparisons using the Bonferroni method.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Whole cohort<br>(MS: 2889<br>Control: 3502)</th><th colspan="2">Sex</th><th colspan="2">Age at onset</th><th colspan="2">Year of diagnosis</th></tr><tr><th>Women<br>(MS: 2002<br>Control: 2425)</th><th>Men<br>(No. MS: 887<br>No. Control: 1077)</th><th>&lt;40<br>(No. MS: 1075<br>No. Control: 1086)</th><th>[40,53]<br>(No. MS: 873<br>No. Control: 1302)</th><th>&gt;53<br>(No. MS: 852<br>No. Control: 1064)</th><th>&lt;2010<br>(No. MS: 1435<br>No. Control: 1877)</th><th>[2010,2017]<br>(No. MS: 1210<br>No. Control: 1313)</th><th>&gt;2017<br>(No. MS: 244<br>No. Control: 189)</th></tr></thead><tbody><tr><td colspan="10"><strong>Before diagnosis</strong></td></tr><tr><td>F32: Major depressive disorder, single episode</td><td>1.31 (1.07 - 1.62)*</td><td>1.26 (0.99 - 1.60)</td><td>1.50 (0.97 - 2.32)</td><td>1.86 (1.20 - 2.86)*</td><td>1.23 (0.90 - 1.70)</td><td>1.23 (0.84 - 1.78)</td><td>1.46 (1.11 - 1.93)*</td><td>1.31 (0.93 - 1.86)</td><td>0.86 (0.35 - 2.10)</td></tr><tr><td>F52: Sexual dysfunction</td><td>1.26 (0.82 - 1.92)</td><td>1.43 (0.83 - 2.46)</td><td>1.01 (0.50 - 2.02)</td><td>1.89 (0.74 - 4.85)</td><td>1.41 (0.75 - 2.64)</td><td>0.85 (0.38 - 1.88)</td><td>1.36 (0.80 - 2.43)</td><td>1.39 (0.65 - 2.97)</td><td>*</td></tr><tr><td>K59: Constipation</td><td>1.48 (1.12 - 1.94)*</td><td>1.39 (1.01 - 1.91)*</td><td>1.78 (1.01 - 3.14)*</td><td>1.32 (0.82 - 2.13)</td><td>1.84 (1.12 - 3.00)*</td><td>1.36 (0.84 - 2.19)</td><td>1.44 (1.00 - 2.06)*</td><td>1.76 (1.08 - 2.89)*</td><td>1.39 (0.46 - 4.25)</td></tr><tr><td>N30: Cystitis</td><td>1.24 (0.96 - 1.61)*</td><td>1.12 (0.85 - 1.48)</td><td>3.21 (1.35 - 7.62)<br>*</td><td>1.12 (0.71 - 1.76)</td><td>1.24 (0.80 - 1.92)</td><td>1.42 (0.89 - 2.26)</td><td>1.44 (1.00 - 2.06)*</td><td>1.05 (0.68 - 1.60)</td><td>1.39 (0.57 - 3.39)</td></tr><tr><td>N39: Urinary tract infection, site not specified</td><td>1.38 (0.92 - 2.07)</td><td>1.33 (0.86 - 2.06)</td><td>1.78 (0.62 - 5.14)</td><td>1.41 (0.68 - 2.92)</td><td>1.17 (0.59 - 2.35)</td><td>1.58 (0.79 - 3.15)</td><td>1.36 (0.94 - 1.95)</td><td>1.09 (0.59 - 2.00)</td><td>0.80 (0.23 - 2.81)</td></tr><tr><td colspan="10"><strong>After diagnosis</strong></td></tr><tr><td>F32: Major depressive disorder, single episode</td><td>1.85 (1.52 - 2.24)*</td><td>1.82 (1.46 - 2.27)*</td><td>1.93 (1.27 - 2.92)*</td><td>2.02 (1.43 - 2.85)*</td><td>1.64 (1.21 - 2.23)*</td><td>1.98 (1.32 - 2.98)*</td><td>1.96 (1.52 - 2.52)*</td><td>1.85 (1.32 - 2.60)*</td><td>1.06 (0.51 - 2.24)</td></tr><tr><td>F52: Sexual dysfunction</td><td>1.99 (1.37 - 2.87)*</td><td>1.78 (1.08 - 2.94)*</td><td>2.26 (1.30 - 3.93)*</td><td>2.06 (1.00 - 4.27)*</td><td>2.54 (1.41 - 4.58)*</td><td>1.33 (0.69 - 2.56)</td><td>1.75 (1.12 - 2.75)*</td><td>2.12 (1.07 - 4.22)*</td><td>*</td></tr><tr><td>K59: Constipation</td><td>2.35 (1.83 - 3.00)*</td><td>2.37 (1.77 - 3.17)*</td><td>2.26 (1.43 - 3.57)*</td><td>2.62 (1.61 - 4.29)*</td><td>2.15 (1.43 - 3.23)*</td><td>2.2 (1.46 - 3.33)*</td><td>2.24 (1.61 - 3.11)*</td><td>2.27 (1.52 - 3.38)*</td><td>3.57 (1.14 - 11.18)*</td></tr><tr><td>N30: Cystitis</td><td>1.69 (1.36 - 2.11)*</td><td>1.46 (1.16 - 1.83)*</td><td>*</td><td>1.35 (0.94 - 1.92)</td><td>1.44 (0.99 - 2.10)</td><td>2.76 (1.79 - 4.26)*</td><td>1.92 (1.44 - 2.55)*</td><td>1.43 (0.99 - 2.08)</td><td>1.31 (0.50 - 3.48)</td></tr><tr><td>N39: Urinary tract infection, site not specified</td><td>2.24 (1.66 - 3.01)*</td><td>2.24 (1.63 - 3.10)*</td><td>2.15 (0.99 - 4.68)</td><td>2.31 (1.30 - 4.07))*</td><td>1.77 (1.08 - 2.92)*</td><td>2.73 (1.65 - 4.53)*</td><td>2.36 (1.57 - 3.55)*</td><td>1.83 (1.17 - 2.88)*</td><td>*</td></tr></tbody></table>
<figure><img src="image_8.png" /><figcaption>eFigure 3. ORs for significant associations in the sensitivity analysis for five years before the index date in comparison to other auto-immune diseases. Patients with MS are compared to patients with lupus and Crohn's disease both in the French and UK cohorts. The size of the dot is proportional to the period prevalence. OR > 1 indicates a higher association in MS cohort compared to Crohn or lupus cohort. The period prevalence is defined as the number of diagnoses or symptoms observed over the period divided by the number of patients at risk during the period.</figcaption></figure>

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<figure><img src="image_9.png" /><figcaption>eFigure 9. Period prevalence (%) of prescriptions associated with depression (A), urinary tract infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the physician per year (E) in the UK cohort. For a given prescription, the period prevalence is defined as the number of prescriptions observed over the period divided by the number of patients at risk during the period.</figcaption></figure>
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ion (A), urinary tract infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the physician per year (E) in the French cohort. For a given prescription, the period prevalence is defined as the number of prescriptions observed over the period divided by the number of patients at risk during the period.

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<figure><img src="image_15.png" /><figcaption>eFigure 6. Period prevalence (%) of prescriptions associated with depression (A), urinary tract infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the physician per year (E) in the pooled cohort, 15 years before diagnosis. Data are from the pooled cohort with individuals having data for the entire 15 years before diagnosis time-window. For a given prescription, the period prevalence is defined as the number of prescriptions observed over the period divided by the number of patients at risk during the period. No. MS : 2726 (women: 1976), No. no MS : 2082 (W: 1488), No. Crohn's disease : 4849 (W: 2660), No. Lupus : 1040 (W: 903)</figcaption></figure>

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<figure><img src="image_16.png" /></figure>

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eFigure 7. Period prevalence (%) of prescriptions associated with depression (A), urinary tract infections (B), bacterial infections (C), and constipation (D), and mean number of visits to the physician per year (E) in the pooled cohort, 5 years before diagnosis up to 10 years after diagnosis. Data are from the pooled cohort with individuals having data for the entire 5 years before diagnosis to 10 years after diagnosis time-window. For a given prescription, the period prevalence is defined as the number of prescriptions observed over the period divided by the number of patients at risk during the period. No. MS : 3531 (women: 2581), No. no MS : 2060 (W: 1579), No. Crohn's disease : 4934 (W: 2814), No. Lupus : 1380 (W:1246)

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