Constructing the first comorbidity networks in companion dogs in the Dog Aging Project

Abstract

Comorbidity and its association with age are of great interest in geroscience. However, there are few model organisms that are well-suited to study comorbidities that will have high relevance to humans. In this light, we turn our attention to the companion dog. The companion dog shares many morbidities with humans. Thus, a better understanding of canine comorbidity relationships could benefit both humans and dogs. We present an analysis of canine comorbidity networks from the Dog Aging Project, a large epidemiological cohort study of companion dogs in the United States. We included owner-reported health conditions that occurred in at least 60 dogs (n=160) and included only dogs that had at least one of those health conditions (n=26,614). We constructed an undirected comorbidity network using a Poisson binomial test, adjusting for age, sex, sterilization status, breed background (i.e., purebred vs. mixed-breed), and weight. The comorbidity network reveals well-documented comorbidities, such as diabetes with cataracts and blindness, and hypertension with chronic kidney disease (CKD). In addition, this network also supports less well-studied comorbidity relationships, such as proteinuria with anemia. A directed comorbidity network accounting for time of reported condition onset suggests that diabetes precedes cataracts, elbow/hip dysplasia before osteoarthritis, and keratoconjunctivitis sicca before corneal ulcer, which are consistent with the canine literature. Analysis of age-stratified networks reveals that global centrality measures increase with age and are the highest in the Senior group compared to the Young Adult and Mature Adult groups. Only the Senior group identified the association between hypertension and CKD. Our results suggest that comorbidity network analysis is a promising method to enhance clinical knowledge and canine healthcare management.

Figure 1.. Undirected comorbidity network.

Nodes are health conditions, and edges are statistically significant comorbidity connections (at a Bonferroni adjusted P-value < 0.001). Node sizes represent lifetime prevalence, with more common health conditions having larger nodes. Nodes with degrees greater than 10 are outlined in bold. Additionally, several health conditions or health condition groups of interest in geroscience, as outlined by the National Institute of Aging, as well as their first-order neighbors are highlighted with shaded boxes [44]. These health condition groups as well as the five health condition categories with the highest number of affected dogs have colored nodes. All other categories have gray nodes. Health condition categories were created using the categorization system in the DAP survey and the majority of the categories highlighted in the network can best be described as organ systems (i.e., respiratory, cardiac) as opposed to pathophysiological processes (i.e., trauma, infection) [45]. Refer to Table S1b for the corresponding health condition name associated with each numeric code.

Figure 2.. Age-stratified comorbidity networks.

(a) Young Adult, (b) Mature Adult, and (c) Senior dog networks. In each network, nodes represent health conditions with node size proportional to condition prevalence, and edges represent statistically significant comorbidity associations (Bonferroni-adjusted P < 0.01). Nodes with the highest degree in each network are indicated with bold outlines, and the largest connected subnetwork is highlighted with a dotted shaded box. No network is shown for the Puppy stratum as no significant comorbidities were detected in this age group. (d) Heatmap displaying edge overlap between disease networks across age groups. Numbers indicate shared edges between a pair of networks, with diagonal values showing total edges per network.

Figure 3.. Time-directed network using a window size of 12 months.

Nodes are health conditions, and edges are statistically significant comorbidity connections (at a Bonferroni-adjusted P-value < 0.01). Arrowheads point from the health condition that occurs earlier in time to the health condition that occurs later. Node sizes represent prevalence, with more common health conditions having larger nodes. Nodes with total node degree greater than 10 are outlined in bold. Additionally, several health conditions or health condition groups of interest in geroscience, as well as their first-order neighbors are highlighted with shaded boxes [44]. These health condition categories as well as the top five best-represented health condition categories also have colored nodes. All other categories have gray nodes. Refer to Table S1b for the corresponding health condition name associated with each numeric code.