Among 205,760,936 individuals in the database for the study period, 2,435 had an index diagnosis of achondroplasia of whom 530 met all other criteria for inclusion and were matched with 1,060 non-achondroplasia controls (Additional file 1: Table S1). The cohorts were 44.2% male and consisted of 47.7% pediatric and 52.3% adult patients, predominantly with commercial insurance (58.1%-60.3%) (Table 1).

Among the 253 pediatric individuals with achondroplasia, the comorbidity burden was higher relative to the 506 pediatric controls as indicated by mean (SD) PCI scores of 0.95 (1.61) and 0.36 (1.02), respectively. In the achondroplasia cohort, 40.3% had any of the PCI comorbidities vs 20.2% of controls. The PCI comorbidities that were more prevalent in the achondroplasia cohort relative to controls were congenital malformations (18.2% vs 2.2%), developmental delays (6.7% vs 1.4%), joint disorder (3.2% vs 1.0%), sleep disorders (3.2% vs 0.4%), and anemia (1.2% vs 0%).

Among the 10 most frequent CCSR comorbid conditions in the achondroplasia cohort, five overlapped with the 10 most frequent among controls (Additional file 1: Fig. S1) Among the 5 overlapping conditions, otitis media and respiratory signs and symptoms had a higher prevalence in the achondroplasia cohort, 6.7% vs 4.7%, and 5.5% vs 3.4%, respectively.

Use of all categories of healthcare resources was higher in the achondroplasia cohort (Fig. 1A). The most frequently used resource category was outpatient visits, 97.6% (95% CI: 95.7, 99.5) in the achondroplasia cohort and 86.2% (95% CI: 83.8, 89.7) in controls, followed by prescriptions, 69.2% (95% CI: 63.4, 74.9) and 60.7% (95% CI: 56.4, 64.9) in the two cohorts, respectively. While the proportion with inpatient visits was approximately 7-fold higher in the achondroplasia cohort relative to controls (5.5% [95% CI: 2.7, 8.4) vs 0.8% [95% CI: 0, 1.6]), those with achondroplasia also had substantially higher use of home healthcare (17.8% [95% CI: 13.0, 22.5] vs 4.2% [95% CI: 2.4, 5.9]) and surgery (27.7% [95% CI: 22.1, 33.2] vs 11.5% [95% CI: 8.7, 14.3]). Units of use were higher in the achondroplasia cohort for all resource categories except ER, which was similar between the cohorts (Fig. 1B); home healthcare and outpatient visits were the categories with the highest utilization per individual in both groups. Mean length of inpatient stay was 8.9 days (SD 23.0; 95% CI -4.4, 22.2) in the achondroplasia cohort and 2.0 days (SD 0.8; 95% CI: 0.7, 3.3) in controls. Of the 10 most commonly seen outpatient specialties in the achondroplasia cohort, most of these specialist visits were also among the 10 most commonly seen specialties by controls, although controls had a lower rate of utilization except for general/family practice, which was the only category with an incrementally higher rate (Fig. 1C). Orthopedic surgery and anesthesiology were among the top 10 specialties in the achondroplasia cohort, 26.6% and, 19.7%, respectively, but not in controls (Fig. 1C).

Healthcare resource utilization in the 12-month follow-up period among pediatric individuals with achondroplasia and matched controls. A Resource categories. B Units of resource use. C The 10 most frequently seen outpatient visit specialties in the achondroplasia cohort among pediatric individuals with outpatient visits. Values for controls in panel C reflect specialties in the top 10 for this group, with NA indicating “not available” but imputed as < 8% based on the 10th most frequently seen specialty

The most frequent surgical procedures in the achondroplasia cohort were related to ear, nose, and throat, and included tympanostomy (8.3%), removal of impacted cerumen (4.0%), and tonsillectomy/adenoidectomy (3.2%). Destruction of benign lesions was the most frequent surgical procedure in the control cohort (1.8%), with all other procedures, most of which appeared to be related to injuries, occurring in <1% of individuals (data not shown).

When HCRU was stratified by age groups (Additional file 1: Fig. S2), rates of use were substantially higher in the achondroplasia cohort relative to controls across age groups for inpatient visits, home healthcare, and any surgery. Outpatient visits were similar to or incrementally higher in the achondroplasia cohort relative to controls, and ER use was higher in the achondroplasia cohort among those 0 to < 2 years and 6 to < 11 years but was similar to controls in the other age groups. Use of prescription medications was incrementally higher in the achondroplasia cohort for all pediatric age groups except 0 to < 2 years old. Among the individuals with achondroplasia, inpatient stays were higher in the younger age groups, and while the percentage with outpatient visits was similar across age groups, home healthcare, ER, and surgeries were highest among those aged 0 to < 2 years and tended to decrease with increasing age (Additional file 1: Fig. S2). The proportion of individuals with prescription medication use was generally similar across age categories. The number of units of use of each resource category varied by age, with higher units of use generally observed in the achondroplasia cohort; the exceptions were for home healthcare and ER, which were both higher in the controls for individuals 6 to < 11 years old, and prescriptions, which were similar in the two cohorts for individuals 6 to < 11 years old (Additional file 1: Fig. S3). The only clear age-related trends appeared to be higher use of inpatient stays, outpatient visits, and any surgery in the younger age groups of the achondroplasia cohort.

Mean (SD) total costs were approximately 14-fold higher in the achondroplasia cohort than controls, $28,386 (SD $259,858; 95% CI: $-3,789, $60,561) vs $2,031 (SD $5,418; 95% CI: $1,559, $2,504) (Table 2), with inpatient costs the primary cost driver in the achondroplasia cohort, accounting for 71.6% of total costs; non-ER outpatient visits was the primary cost driver in the control cohort (69.0% of total costs). Prescription costs comprised < 5% of total costs in the achondroplasia cohort, but accounted for 17.5% of total costs in controls.

When stratified by age, costs in the achondroplasia cohort were consistently and substantially higher than controls across pediatric age groups and resource categories (Additional file 1: Table S2). The highest total costs in the achondroplasia cohort were among those 0 to < 2 years old ($172,602 [SD $831,390; 95% CI: $-171,972, $530,159), and while these costs were driven by inpatient costs that accounted for 94.5% of the total, the large SD indicates that a small subset had high inpatient utilization. Costs in other age groups in the achondroplasia cohort, as well as in controls, were primarily driven by non-ER outpatient costs.

The OOP costs were ~3.5-fold higher among the achondroplasia cohort relative to controls ($1,522 [SD $3,879; 95% CI $1,042, $2,003] vs $439 [SD $974; 95% CI $353, $524), and were generally similar across age groups.

In the adult population, the mean CCI suggested an overall greater comorbidity burden in the achondroplasia cohort than the control cohort, 0.26 (0.86) and 0.15 (0.49), respectively. Five of the 10 most prevalent CCSR comorbidities in the achondroplasia cohort overlapped with the top 10 comorbidities of controls, and all had a higher prevalence than in controls (Additional file 1: Fig. S4). Among these comorbidities, the achondroplasia cohort had more pain-related conditions than controls including musculoskeletal other than low back pain (14.8% vs 9.4%), spondylopathy/spondyloarthropathy (11.2% vs 5.8%), low back pain (9.4% vs 4.5%), and headache/migraines (7.2% vs 3.3%).

Across all healthcare resource categories, the proportion of individuals who used these resources was consistently higher in the achondroplasia cohort relative to controls (Fig. 2A). While the most frequently used resource category was outpatient visits, almost 1 out of 5 individuals with achondroplasia had an inpatient stay for a rate that was more than 4-fold higher than controls (19.1% [95% CI: 14.5, 23.8] vs 4.3% [95% CI: 2.6, 6.0]. Units of use among individuals who used each resource was substantially higher for outpatient visits and incrementally higher for other resource categories (Fig. 2B). Most of the 10 most frequently seen outpatient specialties in the achondroplasia cohort were also observed among controls who had lower rates of utilization except for obstetrics/gynecology, which was higher among the controls (25.9% vs 18.1%) (Fig. 2C). Mean length of inpatient stay was 5.0 days (SD 4.9; 95% CI 3.6, 6.3) and 2.3 days (SD 2.5, 95% CI: 1.2, 3.3) in the achondroplasia and control cohorts, respectively, and individuals with achondroplasia were also more likely than controls to have an inpatient readmission within 30 days (3.6% [95% CI: 1.4, 5.8] vs 0%), 90 days (4.0% [95% CI: 1.7, 6.3] vs 0%), and 365 days (4.7% [95% CI: 2.2, 7.2] vs 0.2% [95% CI: 0, 0.5]) after the first admission (data not shown).

Healthcare resource utilization in the 12-month follow-up period among adults with achondroplasia and matched controls. A Resource categories. B Units of resource use. C The 10 most frequently seen outpatient visit specialties in the adult achondroplasia cohort among individuals with outpatient visits. NA, not available but < 8% based on frequency of the 10 most frequently seen specialties in the control group

The three most common surgical procedures among adults in the achondroplasia cohort were “arterial catheterization or cannulation for sampling, monitoring, or transfusion” (7.2%) followed by “arthrocentesis, aspiration, and/or injection, major joint or bursa, without ultrasound” (4.3%) and “laminectomy, facetectomy, foraminotomy” (3.2%). In the control cohort, the three most common procedures were “arthrocentesis, aspiration, and/or injection, major joint or bursa, without ultrasound” (2.3%), “esophagogastroduodenoscopy, flexible, transoral; with biopsy” (2.3%), and “colonoscopy, flexible, with biopsy” (1.1%).

Higher rates of HCRU across resource categories were also observed in the achondroplasia cohort relative to controls when stratified by age (Additional file 1: Fig. S5). While all individuals with achondroplasia who were ≥65 years old had ER, surgeries, and prescription medications, these individuals had a low rate of inpatient stays, albeit this age group was characterized by a small number of individuals. Units of outpatient visits was substantially higher in the achondroplasia cohort relative to controls across age categories, but other resource categories were generally similar between the cohorts or incrementally higher, and were characterized by wide variability in units of use (Additional file 1: Fig. S6).

Mean total costs were approximately 4-fold higher in the achondroplasia cohort than controls, $21,579 (SD $58,817; 95% CI: $14,622, $28,536) vs $4,951 (SD $13,020; 95% CI: $3,864, $6,037), with these costs driven by inpatient costs and non-ER outpatient costs in the two cohorts, respectively (Table 3). While prescription costs were similar between the achondroplasia and control cohorts, they comprised 7.4% and 25.3% of total costs, respectively. Similar results were observed when stratified by age (Additional file 1: Table S3); total costs in the achondroplasia cohort were 3.3-4.5-fold higher relative to controls, with inpatient costs and non-ER outpatient costs the primary cost drivers in the achondroplasia and control cohorts, respectively, across all age groups. The highest total costs in the achondroplasia cohort were for individuals 41-<65 years old, driven by the high inpatient costs relative to the other age groups.

The OOP costs were almost 3-fold higher among the achondroplasia cohort relative to controls ($2,805 [SD $9,770; 95% CI: $1,650, $3,961] vs $970 [SD $2,385; 95% CI: $772, $1,170]). The mean OOP costs were generally similar among the age groups in the achondroplasia cohort and were higher than controls (data not shown).