Orphanet Journal of Rare Diseases | Assessing Cardiometabolic Risk Using the Lipid- and BMI-Based SPISE Index in Pediatric Bardet-Biedl Syndrome

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This study provides a practical, insulin-free alternative for early cardiometabolic risk monitoring in the rare disease Bardet-Biedl Syndrome, suggesting SPISE as a convenient risk stratification tool in clinical follow-up, especially suitable for resource-limited settings or situations where insulin testing is difficult to obtain.

 

Literature Overview

The article titled 'Assessment of cardiometabolic risk using single point insulin sensitivity estimator (SPISE) in pediatric Bardet–Biedl Syndrome: a pilot study,' published in Orphanet Journal of Rare Diseases, systematically investigates the association between the single-point insulin sensitivity estimator (SPISE) and cardiometabolic risk burden in a molecularly confirmed pediatric Bardet-Biedl Syndrome (BBS) cohort, comparing it with MetS z-score and insulin-derived indices. The study found a significant negative correlation between SPISE and MetS z-score, and SPISE demonstrated superior ability in identifying metabolic syndrome compared to HOMA-IR and TG/HDL in the adolescent subgroup, highlighting its potential utility in rare syndromic obesity.

Background Knowledge

1. Clinical challenges addressed in Bardet-Biedl Syndrome: BBS is a rare autosomal recessive ciliopathy characterized by early-onset obesity, retinal dystrophy, polydactyly, and other features. Patients often develop significant cardiometabolic abnormalities in childhood, including insulin resistance, dyslipidemia, and hypertension. However, due to the confounding effects of growth and puberty on traditional metabolic syndrome (MetS) diagnostic criteria, there is a lack of standardized, continuous risk assessment tools in children, potentially missing early intervention opportunities.
2. Current research bottleneck for SPISE: Conventional insulin sensitivity assessments such as HOMA-IR and Matsuda index rely on fasting or OGTT insulin measurements, which are cumbersome and costly, limiting their routine clinical use. SPISE, an insulin-independent index based on BMI and fasting lipids (HDL, TG), has been validated in general and obese adolescents, but its applicability in monogenic or syndromic obesity such as BBS remains unclear.
3. Research rationale: This study is the first to evaluate the association between SPISE and continuous MetS z-score in a molecularly confirmed pediatric BBS cohort, comparing its performance with insulin-derived indices in identifying MetS. It aims to explore a more feasible, low-cost metabolic risk monitoring strategy. By adopting continuous MetS z-score as a benchmark, the study overcomes the limitations of traditional binary definitions and enhances sensitivity to early risk gradients.

 

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Research Methods and Core Experiments

The authors conducted a single-center retrospective study, enrolling 14 genetically confirmed pediatric/adolescent BBS patients. All participants underwent standardized anthropometric and fasting metabolic profiling (including glucose, insulin, lipids, etc.), with some undergoing OGTT. MetS z-score was used as the continuous benchmark for cardiometabolic risk, incorporating waist circumference, TG, HDL-C, systolic blood pressure, and fasting glucose. The SPISE index was calculated using the formula (600 × HDL^0.185) / (TG^0.2 × BMI^1.338), avoiding insulin measurement. Spearman correlation analysis was used to assess the relationship between SPISE and MetS z-score, and ROC curves were used in the ≥10-year-old subgroup to compare the discriminative performance of SPISE, TG/HDL, and HOMA-IR for MetS. Linear regression models further tested the independent predictive value of SPISE for MetS z-score after adjusting for age, sex, and BMI-SDS.

Key Conclusions and Insights

• In the full cohort, SPISE showed a significant negative correlation with MetS z-score (ρ = -0.57, p = 0.021), which remained statistically significant after adjusting for age, gender, and BMI-SDS, indicating that SPISE independently reflects overall cardiometabolic risk beyond obesity severity, suggesting its utility as a continuous risk tracking tool.
• In the adolescent subgroup (n = 10) aged ≥10 years, SPISE achieved an AUC of 0.95 (95% CI 0.82–1.00) for identifying MetS, outperforming TG/HDL (AUC 0.81) and HOMA-IR (AUC 0.60). Although the differences were not statistically significant, the numerical superiority suggests SPISE may outperform traditional insulin-derived indices in this population.
• The Youden optimal threshold indicated that SPISE ≤ 3.34 could identify MetS status in adolescent BBS patients with high sensitivity, providing a replicable critical value for future multicenter studies and supporting further validation of its utility in clinical monitoring.
• SPISE showed no significant correlation with insulin-derived indices such as HOMA-IR (p > 0.30), suggesting that in Bardet-Biedl Syndrome, SPISE may reflect lipid metabolism disorders more than direct insulin action. The mechanism may involve ciliopathy-induced lipid abnormalities independent of insulin resistance, offering a new perspective on BBS-specific metabolic phenotypes.

Research Significance and Outlook

This study offers a new option for cardiometabolic risk monitoring in rare genetic obesity disorders. Given that Bardet-Biedl Syndrome patients require long-term follow-up and insulin testing is costly and complex, SPISE—a non-invasive index requiring only routine lipids and BMI—significantly lowers the monitoring barrier, especially suitable for clinical centers with limited resources or limited access to frequent insulin testing.

From a drug development perspective, with the emergence of targeted therapies for BBS such as the melanocortin-4 receptor agonist setmelanotide, sensitive and reproducible biomarkers are needed to evaluate treatment efficacy. SPISE can serve as a supplementary indicator to rapidly assess the impact of therapy on overall metabolic status, particularly when insulin data are unavailable.

Additionally, the study emphasizes the advantages of using continuous MetS z-score, avoiding the heterogeneity issues of traditional binary definitions, setting a precedent for establishing standardized risk scoring systems in rare diseases. However, the small sample size and single-center retrospective design limit statistical power and generalizability, necessitating future multicenter prospective studies to validate SPISE thresholds and performance across different BBS genetic subtypes.

 

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Conclusion

This study is the first to validate the significant association between the SPISE index and cardiometabolic risk in a molecularly confirmed pediatric Bardet-Biedl Syndrome cohort. The results show that SPISE not only effectively tracks continuous MetS burden but also demonstrates superior discriminative ability for metabolic syndrome compared to HOMA-IR and TG/HDL in adolescents, although the differences were not statistically significant. This finding provides clinicians with a low-cost, convenient risk assessment tool that does not require insulin testing, particularly suitable for settings where insulin data are difficult to obtain during routine follow-up. The study also reveals a decoupling between SPISE and insulin-derived indices, suggesting that lipid metabolism disorders in Bardet-Biedl Syndrome may be partially independent of the classical insulin resistance pathway, reflecting ciliopathy-specific metabolic dysregulation mechanisms. From a translational medicine perspective, SPISE can serve as an auxiliary biomarker to monitor the metabolic effects of emerging therapies (e.g., setmelanotide), improving clinical trial efficiency. Although further validation in large, multicenter studies is needed, this study lays the foundation for building a standardized, accessible metabolic monitoring system for rare syndromic obesity, with the potential to improve long-term care quality for patients with Bardet-Biedl Syndrome.

 

Tugce Kandemir, Melek Yildiz, Ummahan Tercan, Guven Toksoy, and Firdevs Bas. Assessment of cardiometabolic risk using single point insulin sensitivity estimator (SPISE) in pediatric Bardet–Biedl Syndrome: a pilot study. Orphanet Journal of Rare Diseases.