Predictive Clinical and Biological Criteria for Gene Panel Positivity in Suspected Inherited Autoinflammatory Diseases: Insights from a Case–Control Study
Abstract
:1. Introduction
2. Methods
2.1. Selection of Cases and Controls
2.2. Clinical and Biological Characteristics
2.3. Study Design
2.4. Statistical Analysis
2.5. Patients
3. Results
3.1. Positive Panel Results
3.2. Clinical and Biological Characteristics
3.3. Diagnostic and Predictive Values
3.4. Panel Subgroup Analyses
3.5. Exploratory Analyses
4. Discussion
4.1. Clinical and Biological Criteria as Positive Panel Predictors?
4.2. Limitations
5. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Abbreviations | Meaning |
CI | Confidence Interval |
CRP | C-Reactive Protein |
FMF | Familial Mediterranean Fever |
HLH | Hemophagocytic LymphoHistiocytosis |
HS | Hidradenitis Suppurativa |
IBD | Inflammatory Bowl Diseases |
ISSAIDS | International Society of Systemic Auto-Inflammatory Diseases |
MDS | Myelo-Dysplasic Syndrome |
NGS | Next-Generation Sequencing |
NPV | Negative Preditive Value |
OR | Odds Ratio |
PPV | Positive Predictive Value |
SAA | Serum Amyloid A |
Se | Sensibility |
Sp | Specificity |
VUS | Variant of Unknown Significance |
WES | Whole Exome Sequencing |
WGS | Whole Genome Sequencing |
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Characteristics | Cases n (%) | Controls n (%) | p | Characteristics | Cases n (%) | Controls n (%) | p |
---|---|---|---|---|---|---|---|
Age of onset | Digestive | ||||||
mean (months), 95% CI | 96 (61; 131) | 137 (106; 168) | 0.09 | abscess | 2 (1.7) | 4 (3.4) | 0.68 |
neonatal (<30 days old) § | 12/104 (11.5) | 1/107 (0.9) | 0.001 | hepatic cytolysis | 11 (9.2) | 14 (11.8) | 0.53 |
early childhood (≤3 years old) § | 56/104 (53.8) | 30/107 (28.0) | 0.0001 | IBD | 2 (1.7) | 6 (5.0) | 0.28 |
childhood (<18 years old) § | 94/104 (90.4) | 87/107 (81.3) | 0.06 | diarrhea/vomiting | 34 (28.6) | 34 (28.6) | 1 |
adult (≥18 years old) § | 10/104 (9.6) | 20/107 (18.7) | 0.06 | abdominal pain | 47 (39.5) | 52 (43.7) | 0.51 |
Inflammation | hemorrhage | 3 (2.5) | 7 (5.9) | 0.20 | |||
fever | 86 (72.3) | 87 (73.1) | 0.88 | Cutaneous | |||
crisis CRP elevation | 102 (85.7) | 98 (82.4) | 0.48 | aphthous ulceration * | 42 (35.3) | 42 (35.3) | 1 |
Thoracic | erythema nodosum | 4 (3.4) | 7 (5.9) | 0.34 | |||
chest pain | 25 (21.0) | 25 (21.0) | 1 | folliculitis, acne, HS | 18 (15.1) | 19 (16.0) | 0.86 |
pleuro-pericarditis | 9 (7.6) | 9 (7.6) | 1 | lipodystrophia | 4 (3.4) | 4 (3.4) | 1 |
pneumonia | 8 (6.7) | 8 (6.7) | 1 | livedo | 6 (5.0) | 6 (5.0) | 1 |
Neurologic and sensorineural | maculopapular rash/urticaria | 42 (35.3) | 33 (27.7) | 0.21 | |||
stroke | 3 (2.5) | 7 (5.9) | 0.20 | necrosis | 4 (3.4) | 6 (5.0) | 0.52 |
cerebral calcifications | 2 (1.7) | 1 (0.8) | 1 | edema | 8 (6.7) | 9 (7.6) | 0.80 |
headaches | 26 (21.8) | 36 (30.3) | 0.14 | pseudoerysipelas | 9 (7.6) | 7 (5.9) | 0.60 |
conjunctivitis | 21 (17.6) | 13 (10.9) | 0.14 | psoriasis | 6 (5.0) | 4 (3.4) | 0.52 |
encephalitis | 1 (0.8) | 2 (1.7) | 1 | pyoderma | 0 (0.0) | 3 (2.5) | 0.25 |
epilepsy | 1 (0.8) | 3 (2.5) | 0.62 | tenosynovitis | 6 (5.0) | 6 (5.0) | 1 |
meningitis | 8 (6.7) | 3 (2.5) | 0.12 | vasculitis/Raynaud | 14 (11.8) | 10 (8.4) | 0.39 |
papillitis | 5 (4.2) | 0 (0.0) | 0.06 | Diverse | |||
uveitis | 11 (9.2) | 9 (7.6) | 0.64 | failure to thrive | 24 (20.2) | 12 (10.1) | 0.03 |
deafness | 19 (16.0) | 2 (1.7) | 0.0001 | adenopathy | 26 (21.8) | 30 (25.2) | 0.54 |
intellectual disabilities | 6 (5.0) | 4 (3.4) | 0.52 | immunodeficiency | 6 (5.0) | 2 (1.7) | 0.28 |
Locomotor | hepatomegaly | 3 (2.5) | 4 (3.4) | 1 | |||
arthralgia | 73 (61.3) | 80 (67.2) | 0.34 | splenomegaly | 9 (7.6) | 5 (4.2) | 0.27 |
arthritis | 42 (35.3) | 29 (24.4) | 0.07 | recurrent infections | 10 (8.4) | 14 (11.8) | 0.39 |
myalgia/myositis | 32 (26.9) | 35 (29.4) | 0.67 | pharyngitis | 14 (11.8) | 26 (21.8) | 0.04 |
distorting arthropathy | 5 (4.2) | 3 (2.5) | 0.72 | polychondritis | 2 (1.7) | 0 (0.0) | 0.50 |
osteitis | 3 (2.5) | 6 (5.0) | 0.50 | HLH | 1 (0.8) | 6 (5.0) | 0.12 |
Renal | MDS | 2 (1.7) | 1 (0.8) | 1 | |||
amyloidosis | 6 (5.0) | 2 (1.7) | 0.28 | obesity | 4 (3.4) | 4 (3.4) | 1 |
kidney failure | 10 (8.4) | 4 (3.4) | 0.10 | ||||
proteinuria | 11 (9.2) | 5 (4.2) | 0.12 |
Combinations | Cases n (%) | Controls n (%) | p |
---|---|---|---|
NO fever and/or NO CRP elevation | 39 (32.8) | 38 (31.9) | 0.89 |
NO fever and NO CRP elevation | 11 (9.2) | 15 (12.6) | 0.41 |
Bipolar aphthosis | 8 (6.7) | 17 (14.3) | 0.06 |
Hepatosplenomegaly | 14 (11.8) | 5 (4.2) | 0.03 |
No other system than inflammatory | 1 (0.8) | 2 (1.7) | 1 |
At least 1 system (except inflammatory) | 118 (99.2) | 117 (98.3) | 1 |
At least 2 systems (except inflammatory) | 108 (90.9) | 109 (91.6) | 0.82 |
At least 3 systems (except inflammatory) | 86 (72.3) | 93 (78.2) | 0.29 |
At least 4 systems (except inflammatory) | 56 (47.1) | 55 (46.2) | 0.90 |
At least 5 systems (except inflammatory) | 29 (24.4) | 30 (25.2) | 0.88 |
At least 6 systems (except inflammatory) | 9 (7.6) | 8 (6.7) | 0.80 |
All 7 systems (except inflammatory) | 2 (1.7) | 0 (0.0) | 0.50 |
Mean of the number of systems involved (except inflammatory), 95% CI | 3.43 (0.51; 6.35) | 3.47 (0.74; 6.20) | 0.82 |
Characteristics | Cases n (%) | Controls n (%) | OR (95% CI) | Se (%) (95% CI) | Sp (%) (95% CI) | PPV (%) * (95% CI) | NPV (%) * (95% CI) | Accuracy (%) * (95% CI) |
---|---|---|---|---|---|---|---|---|
Neonatal onset § | 12/104 (11.5) | 1/107 (0.9) | 13.83 (1.76; 108.38) | 11.5 (6.1; 19.3) | 99.1 (94.9; 100.0) | 48.2 (11.0; 87.5) | 93.7 (93.3; 94.1) | 92.9 (88.6; 96.0) |
Early childhood onset § | 56/104 (53.8) | 30/107 (28.0) | 2.99 (1.69; 5.30) | 53.9 (43.8; 63.7) | 72.0 (62.5; 80.2) | 12.6 (9.2; 17.1) | 95.4 (94.2; 96.34) | 70.7 (64.1; 76.7) |
Fever | 86 (72.3) | 87 (73.1) | 0.96 (0.54; 1.70) | 72.3 (63.3; 80.1) | 26.9 (19.2; 35.8) | 6.9 (6.0; 8.0) | 92.8 (89.5; 95.12) | 30.1 (24.3; 36.30) |
Crisis CRP elevation | 102 (85.7) | 98 (82.4) | 1.29 (0.64; 2.58) | 85.7 (78.1; 91.5) | 17.7 (11.3; 25.7) | 7.3 (6.6; 8.1) | 94.3 (90.1; 96.72) | 22.4 (17.3; 28.3) |
Deafness | 19 (16.0) | 2 (1.7) | 11.12 (2.53; 48.89) | 16.0 (9.9; 23.8) | 98.3 (94.1; 99.8) | 41.7 (14.6; 75.0) | 94.0 (93.8; 94.4) | 92.6 (88.5; 95.6) |
Failure to thrive | 24 (20.2) | 12 (10.1) | 2.25 (1.07; 4.75) | 20.2 (13.4; 28.5) | 89.9 (83.1; 94.7) | 13.1 (7.3; 22.3) | 93.7 (93.1; 94.3) | 85.0 (79.9; 89.3) |
Pharyngitis | 14 (11.8) | 26 (21.8) | 0.48 (0.24; 0.97) | 11.8 (6.6; 19.0) | 78.2 (69.7; 85.2) | 3.9 (2.2; 6.9) | 92.2 (91.3; 93.0) | 73.5 (67.4; 79.0) |
Hepatosplenomegaly | 14 (11.8) | 5 (4.2) | 3.04 (1.06; 8.73) | 11.8 (6.6; 19.0) | 95.8 (90.5; 98.6) | 17.4 (7.3; 36.2) | 93.5 (93.0; 94.0) | 89.9 (85.4; 93.4) |
Characteristics | 32-Gene Panel Subgroup | 55-Gene Panel Subgroup | 62-Gene Panel Subgroup | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Cases, n (%) | Controls, n (%) | p | Cases, n (%) | Controls, n (%) | p | Cases, n (%) | Controls, n (%) | p | |||||
Significantly associated variables | |||||||||||||
neonatal onset § | 0/4 (0.0) | 1/5 (20.0) | 1 | 1/14 (7.1) | 0/17 (0.0) | 0.45 | 8/49 (16.3) | 0/49 (0.0) | 0.006 | ||||
early childhood onset § | 2/4 (50.0) | 2/5 (40.0) | 1 | 7/14 (50.0) | 7/17 (41.2) | 0.62 | 30/49 (61.2) | 17/49 (34.7) | 0.009 | ||||
deafness | 1 (20.0) | 0 (0.0) | 1 | 5 (29.4) | 1 (5.9) | 0.17 | 8 (14.0) | 1 (1.8) | 0.03 | ||||
failure to thrive | 2 (40.0) | 0 (0.0) | 0.44 | 2 (11.8) | 3 (17.6) | 1 | 14 (24.6) | 7 (12.3) | 0.09 | ||||
pharyngitis | 0 (0.0) | 2 (40.0) | 0.44 | 3 (17.6) | 4 (23.5) | 1 | 7 (12.3) | 16 (28.1) | 0.04 | ||||
hepatosplenomegaly | 1 (20.0) | 1 (20.0) | 1 | 4 (23.5) | 0 (0.0) | 0.10 | 7 (12.3) | 1 (1.8) | 0.06 | ||||
Trend variables | |||||||||||||
childhood onset § | 4/4 (100.0) | 4/5 (80.0) | 1 | 13/14 (92.9) | 17/17 (1.0) | 0.26 | 45/49 (91.8) | 40/49 (81.6) | 0.14 | ||||
adulthood onset § | 0/4 (0.0) | 1/5 (20.0) | 1 | 1/14 (7.1) | 0/17 (0.0) | 0.45 | 4/49 (8.2) | 9/49 (18.4) | 0.14 | ||||
papillitis | 1 (20.0) | 0 (0.0) | 1 | 2 (11.8) | 0 (0.0) | 0.48 | 1 (1.8) | 0 (0.0) | 1 | ||||
arthritis | 3 (60.0) | 0 (0.0) | 0.17 | 7 (41.2) | 5 (29.4) | 0,47 | 20 (35,1) | 16 (28.1) | 0.42 | ||||
bipolar aphthosis | 1 (20.0) | 0 (0.0) | 1 | 0 (0.0) | 2 (11.8) | 0.48 | 1 (1.8) | 8 (14.0) | 0.03 | ||||
Characteristics | 114-Gene Panel Subgroup | 302-Gene Panel Subgroup | |||||||||||
Cases, n (%) | Controls, n (%) | p | Cases, n (%) | Controls, n (%) | p | ||||||||
Significantly associated variables | |||||||||||||
neonatal onset § | 1/9 (11.1) | 0/6 (0.0) | 1 | 2/28 (7.1) | 0/30 (0.0) | 0.23 | |||||||
early childhood onset § | 5/9 (55.6) | 1/6 (16.7) | 0.29 | 12/28 (42.9) | 6/30 (20.0) | 0.06 | |||||||
deafness | 1 (11.1) | 0 (0.0) | 1 | 4 (12.9) | 0 (0.0) | 0.11 | |||||||
failure to thrive | 1 (11.1) | 0 (0.0) | 1 | 5 (16.1) | 2 (6.5) | 0.42 | |||||||
pharyngitis | 1 (11.1) | 1 (11.1) | 1 | 3 (9.7) | 3 (9.7) | 1 | |||||||
hepatosplenomegaly | 0 (0.0) | 2 (22.2) | 0.47 | 2 (6.5) | 2 (6.5) | 1 | |||||||
Trend variables | |||||||||||||
childhood onset § | 8/9 (88.9) | 4/6 (66.7) | 0.53 | 24/28 (85.7) | 22/30 (73.3) | 0.24 | |||||||
adulthood onset § | 1/9 (11.1) | 2/6 (33.3) | 0.53 | 4/28 (14.3) | 8/30 (26.7) | 0.24 | |||||||
papillitis | 0 (0.0) | 0 (0;0) | 1 | 0 (0.0) | 0 (0.0) | 1 | |||||||
arthritis | 3 (33.3) | 1 (11.1) | 0.58 | 9 (29.0) | 7 (22.6) | 0.56 | |||||||
bipolar aphthosis | 1 (11.1) | 1 (11.1) | 1 | 5 (16.1) | 6 (19.4) | 0.74 |
Characteristics | Cases, n (%) | Controls, n (%) | OR (95% CI) | p-Value |
---|---|---|---|---|
Fever § | 86/110 (78.2) | 84/116 (72.4) | 1.37 (0.74; 2.51) | 0.32 |
Crisis CRP elevation § | 102/105 (97.1) | 92/113 (81.4) | 7.76 (2.24; 26.88) | 0.002 |
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Heiser, L.; Broly, M.; Rittore, C.; Touitou, I.; Georgin-Lavialle, S.; Boursier, G. Predictive Clinical and Biological Criteria for Gene Panel Positivity in Suspected Inherited Autoinflammatory Diseases: Insights from a Case–Control Study. Genes 2023, 14, 1939. https://doi.org/10.3390/genes14101939
Heiser L, Broly M, Rittore C, Touitou I, Georgin-Lavialle S, Boursier G. Predictive Clinical and Biological Criteria for Gene Panel Positivity in Suspected Inherited Autoinflammatory Diseases: Insights from a Case–Control Study. Genes. 2023; 14(10):1939. https://doi.org/10.3390/genes14101939
Chicago/Turabian StyleHeiser, Lionel, Martin Broly, Cécile Rittore, Isabelle Touitou, Sophie Georgin-Lavialle, and Guilaine Boursier. 2023. "Predictive Clinical and Biological Criteria for Gene Panel Positivity in Suspected Inherited Autoinflammatory Diseases: Insights from a Case–Control Study" Genes 14, no. 10: 1939. https://doi.org/10.3390/genes14101939
APA StyleHeiser, L., Broly, M., Rittore, C., Touitou, I., Georgin-Lavialle, S., & Boursier, G. (2023). Predictive Clinical and Biological Criteria for Gene Panel Positivity in Suspected Inherited Autoinflammatory Diseases: Insights from a Case–Control Study. Genes, 14(10), 1939. https://doi.org/10.3390/genes14101939