# Care pathway heterogeneity in Amyotrophic Sclerosis:
## Effects of gender, age and onset

Marc Dibling, Juliette Ortholand, François Salachas, Adèle Hesters, Sophie

Tezenas Du Montcel

► To cite this version:

Marc Dibling, Juliette Ortholand, François Salachas, Adèle Hesters, Sophie Tezenas Du Montcel. Care pathway heterogeneity in Amyotrophic Sclerosis: Effects of gender, age and onset. ISCB 2025 - 45th Annual Conference of the International Society for Clinical Biostatistics, Jul 2025, Thessalonique, Grèce. hal-05285054

HAL Id: hal-05285054

https://hal.science/hal-05285054v1

Submitted on 26 Sep 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# POSTER SESSION B-02:
Electronic Health Records and Real-World Data
for Observational and Interventional Studies

P-B02-13

## Care pathway heterogeneity in Amyotrophic Lateral Sclerosis: Effects of gender, age and onset

Marc Dibling, Juliette Ortholand, Sophie Tezenas du Montcel

Aramis, Sorbonne Universite, Institut Du Cerveau - Paris Brain Institute - ICM, CNRS, INRIA, INSERM, AP-HP, Hopital De La Pitie Salpetriere, Paris, France

**Background:** Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by progressive motor neuron death resulting in loss of muscle function and accompanied with heterogeneous clinical manifestations. Care management is restricted to palliative strategies. However, benefit and timing assessment of ALS major clinical interventions remains challenging with different and unspecific time-to-events estimates reported in literature. Consequently, we proposed a care pathway investigation of strategies diversity and temporality, considering 3 patient characteristics reported to play a role in disease progression: age, gender, and onset site.

**Methods:** We developed an identification algorithm designed to specifically identify incident ALS patients in the French medico-administrative hospital database, based on age, hospital stays characteristics and diagnoses, and assessed its quality through comparison with literature. We compared patient profile-specific median time-to-clinical event and clinical interventions occurrence dynamics, through an Accelerated Failure Time model and a time-inhomogeneous multi-state model, defined by 15 transitions and 7 states, encompassing intervention history status. Twelve different patient profiles were defined according to sex, age group and the presence of symptoms indicative of the site of onset site, to model care pathway trajectories and estimate acceleration factors considering interactions.

**Results:** We identified 21,153 incident patients with ALS between 2013 and 2022 with a mean age of 67.7±13.1 years, male/female and spinal/bulbar ratios of 1.2 and 1.9, respectively. Non-invasive ventilation (NIV), gastrostomy, tracheostomy or death at hospital was recorded for 55.24% of the study population. We demonstrated that gender, age class and onset site influence care pathway strategies. Notably, older age and bulbar onset site and being a women prompt gastrostomy use and spinal onset site was associated with delayed NIV initiation while tracheostomy, mainly considered for younger patients (<64 years), is rarely indicated in ALS care management. Alongside investigation of time-to-event speed, we report extensively the patient profile-specific estimated median delay before clinical event start.

**Conclusion:** Care pathway strategy investigation is crucial in the context of rare diseases restricted to life-support care management to anticipate patient needs and foresee healthcare strategies. Health claims databases are powerful resources which, at the expense of rigorous data extraction methodology, offer a large sample size, growing temporal coverage and can be applied to such analyses. In conjunction with multi-state models, natural history data can provide a detailed analysis of care pathways which reveals disparities in ALS care management strategies depending on patient profiles and contributes to improved support strategy anticipation.
# Care pathway heterogeneity in amyotrophic lateral sclerosis: influence of gender, age class and onset site

<figure><img src="image_2.png" /></figure>

ARAMIS
LAB
BRAIN DATA SCIENCE

**Marc Dibling**¹, **Juliette Ortholand**¹, **Sophie Tezenas du Montcel**¹

(1) Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Inria, Inserm, AP-HP, Hôpital de la Pitié Salpêtrière, F-75013, Paris, France

<figure><img src="image_3.png" /></figure>

marc.dibling@icm-institute.org

## INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease characterized by progressive motor neuron death resulting in loss of muscle function and fatal paralysis.

Clinical manifestations are heterogeneous and care management is restricted to palliative strategies Non-Invasive Ventilation (NIV), Tracheostomy and Gastrostomy (Hardiman et al., Nature, 2017).

<figure><img src="image_4.png" /><figcaption>Spinal onset
(70%)</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>Bulbar onset
(30%)</figcaption></figure>

<caption>Facial and pharyngeal
muscles</caption>

However, benefit and timing assessment of ALS major clinical interventions remains challenging with guidelines for initiation and unspecific estimations rather than time-to-clinical event estimates (Takahiko et al., Muscle Nerve, 2018, Kleopa et al., J Neurol Sci, 1999, Bond et al., Brain Sci, 2019).

**Objective:**
Investigate care pathway strategies considering age, gender and onset site to identify sources of heterogeneity, provide clearer event timelines and improved disease anticipation.

## METHODS

**Data:** We leveraged natural history data from the French medico-administrative hospital registry (PMSI).

**Patient identification:** We developed an incident ALS patient identification process which relied exclusively on age, registered diagnoses, stays characteristics and assessed its quality through comparison of patient characteristics with literature.

Patient identification process:

<figure><img src="image_6.png" /></figure>

**Statistical analysis:** We defined 12 different patient profiles according to gender (Men, Women), age class ( [18;64] , [64;74] , [74;103] ) and symptoms indicative of onset site ( Spinal , Bulbar ) to model profile-specific care pathway trajectories via a time-inhomogeneous multi-state model with 7 states encompassing clinical history.

Such a model provides a generalized framework to simultaneously describe and compare the care trajectories while considering intermediate events occurring during disease progression.

Alongside analysis of median time before transition, we compared speed of entry into states depending on patient profile through acceleration factors (AF), which quantify the transition-specific survival curve shift.

AF > 1 implies a reduced expectation of event time (acceleration) whereas AF < 1 indicate a delayed event initiation.

## RESULTS

We identified 21,153 incident ALS patients (65.6% with spinal onset and 34.4% with bulbar onset) with a mean age at inclusion of 67.7 ± 13.1. Median in-hospital survival, from the first "Motor Neuron Diseases" coded hospitalization stay, was 2.44 [2.35; 2.53] years.

Multi-state model and significantly REDUCED or INCREASED time-to-clinical event:

<figure><img src="image_7.png" /></figure>

**Key findings:**

We reported wide variations in median time-to-event depending on patient profile. → Considering the gender, age and onset is crucial to anticipate care pathway.

Bulbar onset was associated with rapid NIV or gastrostomy initiation from 2 up to 24 times faster than the reference group.

→ Symptoms are treated rapidly among bulbar onset patients.

Regardless of onset, at fixed age, Women initiated gastrostomy faster than Men and increased age ( [64;74] , [74;103] ) is associated with rapid initiation.

→ Sex and age influence metabolism, body fat percentage and consequently disease progression. Weight and appetite loss are common in ALS and may explain prompt gastrostomy need along with concerns about maintaining adequate nutrition orally.

Tracheostomy is a rare event mainly considered for younger patients ( [18;64] ).

→ Tracheostomy is an invasive procedure characterized by multiple risks and complications indicated in emergencies or after unsuccessful NIV initiation.

Increased age class is mostly associated with shorter survival.

→ Older patients with multiple comorbidities may experience a quicker decline in functional status and nutritional health.

## CONCLUSION

**Care pathway investigation** is pivotal to anticipate patient needs and foresee healthcare strategies, especially in the context of rare diseases, often restricted to life-support care management.

**Health claims databases** are powerful resources which, at the expense of rigorous data extraction methodology, offer natural history data from a large sample size, a growing temporal coverage and accommodate for complex models, such as multi-state models, designed to capture and analyse intricate processes.

**Our investigation** demonstrated that gender, age and onset partially explained the clinical event timeline and should therefore be considered to describe disease progression and anticipate care trajectory.

<figure><img src="image_8.png" /></figure>

Paris Brain Institute

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

SORBONNE
UNIVERSITÉ

ASSISTANCE
PUBLIQUE

<figure><img src="image_12.png" /></figure>

HÔPITAUX
DE PARIS

<figure><img src="image_13.png" /></figure>

Inserm