Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay

Benito-Lozano, Juan; Arias-Merino, Greta; Gómez-Martínez, Mario J.; Ancochea-Díaz, Alba; Aparicio-García, Aitor; Paz, Manuel Posada de la; Alonso-Ferreira, Verónica

doi:10.3390/ijerph19116456

Cited by 38 publications

(31 citation statements)

References 24 publications

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“…The present investigation suggests that a combination of a structured clinical assessment by an MDT and subsequent ES may reduce the diagnostic delay, and that ES was particularly beneficial for patients with ultra-rare genetic disorders. These findings are consistent with reports from other healthcare systems 19,[46][47][48][49][50] . In several patients from the present cohort, molecular diagnoses also resulted in a change of clinical management to a causal or even curative approach to therapy as described above.…”

Section: Discussionsupporting

confidence: 93%

Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Schmidt

Danyel

Grundmann

et al. 2023

Preprint

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Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency. ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders. To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization. The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

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Section: Discussionsupporting

confidence: 93%

Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Schmidt

Danyel

Grundmann

et al. 2023

Preprint

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“…Despite the limitations, the main strength of this study is that it is the first to quantify time to diagnosis of RDs in Spain, based on information sourced from a national registry open to any RD. Another point to be highlighted is that, in comparison with the only previous studies to furnish data on diagnostic delays in general for RDs in Spain [ 8 , 38 ], our study not only relied on information covering a greater number of diseases and persons affected, confirmed diagnoses of RD, and a heterogeneous population in socio-demographic terms, but the data were also gathered over a long period of time.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Benito-Lozano

López-Villalba

Arias-Merino

et al. 2022

Orphanet J Rare Dis

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Background According to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them. Methods Using data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960–2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression. Results Detailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2–7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07–1.45); in cases with symptom onset at age 30–44 years (OR 1.48; 95% CI 1.19–1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26–7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02–1.88). Conclusions This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

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“…The gold standard for the diagnosis of RTH-α is molecular studies targeting THRA defects or whole exome sequencing. 26,27 However, it is important to note that genetic analyses can be costly and unnecessary when dealing with many undiagnosed patients. Therefore, it is essential to consider clinical findings and laboratory characteristics before initiating any genetic analysis to evaluate patients.…”

Section: Discussionmentioning

confidence: 99%

Anaemia‐based screening for resistance to thyroid hormone alpha in children

Kağızmanlı,

Kırbıyık,

Abacı

et al. 2023

Clinical Endocrinology

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BackgroundThe hypothyroid phenotype associated with resistance to thyroid hormone alpha (RTH‐α) is associated with a diverse clinical picture. On the other hand, thyroid‐stimulating hormone (TSH) levels are normal. Free triiodothyronine (fT3) and free thyroxine (fT4) levels can also be normal; however, normo‐ or macrocytic anaemia is usually present in reported cases. Diagnosis is challenging and there is limited data regarding screening methods.ObjectiveThe study aimed to assess the efficiency of a screening strategy for RTH‐α.Subjects and MethodsOut of a total of 6540 children evaluated at the outpatient clinics of paediatric neurology over 2 years and who underwent complete blood count and thyroid function tests, 432 were found to have anaemia. Within this group, we identified 42 children without an underlying specific neurological aetiology who exhibited normo‐ or macrocytic anaemia, normal TSH levels, fT3 levels in the upper half of the normal range or high, and fT4 levels in the lower half of the normal range or low. We excluded one patient who had already been diagnosed with RTH‐α and nine patients could not be reached. Subsequently, clinical evaluation, biochemical assessment, and THRA sequencing analysis were conducted on 32 children. The findings were compared with those of the known RTH‐α patients in our unit.ResultsThe median age of the patients was 5.7 (5.1–7.4) years, and 22 of them were males (69%). The main reasons for assessment in paediatric neurology clinics were autism spectrum disorder (n = 12, 38%), epilepsy (n = 11, 34%), and delay in developmental stages (n = 8, 25%). Constipation was present in five of the cases (16%), while the closure of the anterior fontanelle and tooth eruption were delayed in two cases (6%) and one case (3%), respectively. The median length/height and weight standard deviation (SD) scores were 0.3 [(−0.8)–(1.1)] and −0.1 [(−0.8)–(0.3)], respectively. The median fT3, fT4, and TSH levels were 4.6 (4.2–5.0) pg/mL, 0.9 (0.8–1.0) ng/dL, and 2.2 (1.8–3.1) uIU/mL, respectively. Thirteen of the patients (41%) had high fT3 levels, while none of them had low fT4 levels. The normo‐ or macrocytic anaemia rate was 47% (normocytic/macrocytic, n = 8/7) at the time of reassessment. Serum creatine kinase (CK) was elevated in five patients (16%; one had anaemia). None of the subjects had a pathological variant in THRA. Known RTH‐α patients had significantly lower median height SD score, higher rates of delayed tooth eruption and closure of the anterior fontanelle, lower haemoglobin levels, and higher mean corpuscular volume (MCV) and CK levels as compared to those found without RTH‐α.ConclusionsThis approach found one known patient with RTH‐α but did not reveal any new cases. Notably, normo‐ or macrocytic anaemia did not persist in nearly half of the screened patients. A screening strategy that takes clinical findings and prominent laboratory features suggestive of RTH‐α into account could lower unnecessary genetic analysis of THRA in patients presenting with neurological problems.

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Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay

Cited by 38 publications

References 24 publications

Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Anaemia‐based screening for resistance to thyroid hormone alpha in children

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