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Peer-reviewedCC BY 4.0Investigative Ophthalmology & Visual Science

Latent Correlations Between Longitudinal Systemic Complement Factors and Geographic Atrophy Growth Rate

  • Talisa E. de Carlo Forest1
  • Nathan C. Grove1
  • Nicholas Cordaro1
  • Yoga Advaith Veturi1
  • Brandie D. Wagner2
  • Niranjan Manoharan1
  • Andres Lisker-Cervantes1
  • Benjamin Bearce1
  • Steve McNamara1
  • Anne Lynch1
  • Jayashree Kalpathy-Cramer1
  • Alan G. Palestine1
3 more authors
  • Marc Mathias1
  • V. Michael Holers3
  • Naresh Mandava1
  1. 1Sue Anschutz-Rodgers Eye Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
  2. 2Colorado School of Public Health, University of Colorado, Aurora, CO, United States
  3. 3Departments of Medicine and Immunology, University of Colorado School of Medicine, Aurora, CO, United States
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Abstract

Purpose: Investigate associations between square root-transformed (SQRT) geographic atrophy (GA) growth rate and longitudinal systemic complement levels in non-neovascular AMD.

Methods: Prospective longitudinal cohort study of patients with GA in the University of Colorado AMD Registry enrolled from August 2014 to September 2022, with ≥1month of follow-up imaging through April 2023. Systemic complement factor level ratios (Bb/Factor B, Ba/Factor B, Factor H, Factor I, C4b/C4, C3a/C3, C3b/C3, sC5b-9/C5) were collected approximately annually. SQRT GA growth rate was quantified on fundus autofluorescence. Correlations between GA growth rate and longitudinal biomarker levels were evaluated using a Bayesian hierarchical joint model.

Results: One hundred fifty-five eyes from 88 patients were included. Average SQRT GA growth rate was 0.27mm/year over a mean of 3.3 years and was positively associated with female sex. Ba/Factor B (correlation [credible interval {CrI}]:0.35, 95% CrI: 0.02 to 0.64), and Bb/Factor B (0.20, 95% CrI: −0.086 to 0.48) demonstrated posterior distributions largely above zero, consistent with a positive association. Posterior distributions for Factor I (−0.08, 95% CrI: −0.35 to 0.20) and C3a/C3 (−0.14, 95% CrI: −0.44 to 0.18) were centered below zero, whereas those for Factor H (0.09, 95% CrI: −0.20 to 0.37) and sC5b-9/C5 (0.09, 95% Crl: −0.19 to 0.37) were centered above zero.

Conclusions: Systemic alternative pathway biomarkers demonstrated the strongest positive associations with GA growth rate. The pattern of associations in this exploratory analysis supports a hypothesis-generating framework in which differences in alternative pathway regulation may be associated with heterogeneity in GA progression. Future larger studies are needed for external validation of this hypothesis-generating work.

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Cite

BibTeXRIS
BibTeX
@article{forest2026latent,
  title = {{Latent Correlations Between Longitudinal Systemic Complement Factors and Geographic Atrophy Growth Rate}},
  author = {Talisa E. de Carlo Forest and Nathan C. Grove and Nicholas Cordaro and Yoga Advaith Veturi and Brandie D. Wagner and Niranjan Manoharan and Andres Lisker-Cervantes and Benjamin Bearce and Steve McNamara and Anne Lynch and Jayashree Kalpathy-Cramer and Alan G. Palestine and Marc Mathias and V. Michael Holers and Naresh Mandava},
  journal = {Investigative Ophthalmology \& Visual Science},
  year = {2026},
  month = oct,
  doi = {10.1167/iovs.67.12.69},
  url = {https://doi.org/10.1167/iovs.67.12.69},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Latent Correlations Between Longitudinal Systemic Complement Factors and Geographic Atrophy Growth Rate
AU  - Talisa E. de Carlo Forest
AU  - Nathan C. Grove
AU  - Nicholas Cordaro
AU  - Yoga Advaith Veturi
AU  - Brandie D. Wagner
AU  - Niranjan Manoharan
AU  - Andres Lisker-Cervantes
AU  - Benjamin Bearce
AU  - Steve McNamara
AU  - Anne Lynch
AU  - Jayashree Kalpathy-Cramer
AU  - Alan G. Palestine
AU  - Marc Mathias
AU  - V. Michael Holers
AU  - Naresh Mandava
PY  - 2026
DA  - 2026/10/27
JO  - Investigative Ophthalmology & Visual Science
DO  - 10.1167/iovs.67.12.69
UR  - https://doi.org/10.1167/iovs.67.12.69
AB  - Purpose: Investigate associations between square root-transformed (SQRT) geographic atrophy (GA) growth rate and longitudinal systemic complement levels in non-neovascular AMD.  Methods: Prospective longitudinal cohort study of patients with GA in the University of Colorado AMD Registry enrolled from August 2014 to September 2022, with ≥1month of follow-up imaging through April 2023. Systemic complement factor level ratios (Bb/Factor B, Ba/Factor B, Factor H, Factor I, C4b/C4, C3a/C3, C3b/C3, sC5b-9/C5) were collected approximately annually. SQRT GA growth rate was quantified on fundus autofluorescence. Correlations between GA growth rate and longitudinal biomarker levels were evaluated using a Bayesian hierarchical joint model.  Results: One hundred fifty-five eyes from 88 patients were included. Average SQRT GA growth rate was 0.27mm/year over a mean of 3.3 years and was positively associated with female sex. Ba/Factor B (correlation [credible interval {CrI}]:0.35, 95% CrI: 0.02 to 0.64), and Bb/Factor B (0.20, 95% CrI: −0.086 to 0.48) demonstrated posterior distributions largely above zero, consistent with a positive association. Posterior distributions for Factor I (−0.08, 95% CrI: −0.35 to 0.20) and C3a/C3 (−0.14, 95% CrI: −0.44 to 0.18) were centered below zero, whereas those for Factor H (0.09, 95% CrI: −0.20 to 0.37) and sC5b-9/C5 (0.09, 95% Crl: −0.19 to 0.37) were centered above zero.  Conclusions: Systemic alternative pathway biomarkers demonstrated the strongest positive associations with GA growth rate. The pattern of associations in this exploratory analysis supports a hypothesis-generating framework in which differences in alternative pathway regulation may be associated with heterogeneity in GA progression. Future larger studies are needed for external validation of this hypothesis-generating work.
SN  - 0146-0404
SN  - 1552-5783
ER  -