Table 1.

Summary of sensitivity analysis results.

Case	Sensitivity Highlights	Values of C	Key Processes
Case 1: All Processes Functioning Properly	• C is not sensitive to RdCVF	• C(t1) = 1.8 × 105	• Aerobic glycolysis
	• C is sensitive to $K_{m_i}$, and $V_{{\max }_i}$ for i = [PYR], [LACT] at all time points considered	• C(t4) = 1.9 × 105	• Cone OS renewal
	• C is sensitive to $\eta$, q, $K_{m_{[\mathrm{G}3\mathrm{P}]}}$, and $V_{{\max }_{[\mathrm{G}3\mathrm{P}]}}$ at all time points considered	• The ratio of rods to cones is approximately 20:1 all time points considered	• Competition for resources
	• C is sensitive to various cell population level parameters at all time points considered
Case 2: Insufficient RdCVF δ = 65 × 10−8	• At t2, t3, and t4, C is sensitive to RdCVF (this is the only case where sensitivity to RdCVF occurs)	• C(t1) = 1.6 × 105	• Cone OS renewal
	• C is not sensitive to $K_{m_i}$ and $V_{{\max }_i}$ for i = [PYR], [LACT] but it is to [G6P]0, $K_{m_{[\mathrm{F}1\mathrm{B}6\mathrm{P}]}}$, $V_{{\max }_{[\mathrm{F}1\mathrm{B}6\mathrm{P}]}}$, and [F16BP]0 at t1	• C(t4) = 3.6 × 103	• Competition for resources
	• C is also sensitive to $\eta$, q, $K_{m_{[\mathrm{G}3\mathrm{P}]}}$, and $V_{{\max }_{[\mathrm{G}3\mathrm{P}]}}$ at t1		Note: At equilibrium, glucose is not entering the cell near its maximum rate indicated by
	• C is sensitive to various cell population level parameters at all time points considered		$\frac{V_{{\max }_{[\mathrm{g}]}}{(\delta R_n)}^2}{K_{m_{[\mathrm{g}]}}^2+{(\delta R_n)}^2}\ll V_{{\max }_{[\mathrm{g}]}}$
Case 3: No RdCVF δ = 0	• C is not sensitive to RdCVF	• C(t1) = 1.6 × 105	• Cone OS renewal
	• C is not sensitive to $K_{m_i}$ and $V_{{\max }_i}$ for i = [PYR], [LACT]	• C(t4) = 1	• Competition for resources
	• At t1 and t2, C is sensitive to [F1B6P]0, $\eta$, q, $K_{m_{[\mathrm{G}3\mathrm{P}]}}$, and $V_{{\max }_{[\mathrm{G}3\mathrm{P}]}}$
	• At t1, C is sensitive to α (this is the only case where sensitivity to α occurs)
	• C is sensitive to various cell population level parameters at all time points considered
Case 4: Inefficient use of glucose for cone OS renewal $ϵ=9.99\times {10}^{-4}$	• The sensitivity highlights are the same as those in case one	• C(t1) = 1.5 × 105	• Aerobic glycolysis
		• C(t4) = 5.7 × 103	• Cone OS renewal
		• C(t4) is smaller in this case compared to case one	• Competition for resources

We used uncertainty and sensitivity analysis (see Section 4.2) to analyze the sensitivity of C (defined in Section 2.3) with respect to the model parameters at four time points (t₁ = 60 min, t₂ = 1 day, t₃ = 7 days, and t₄ = 14 days) to verify the cones’ reliance on rods via RdCVF and to gain insight into an understanding of cone vitality. We considered four cases, two involving RdCVF, and concluded that cone OS production is driven by combinations of three key sets of processes. The first set of processes included sensitivity to [LACT] and [PYR] parameters which indicated a reliance on aerobic glycolysis for cone OS production; see Equations 10 and 11. The second set of processes involved sensitivity to [G3P] parameters; see Equation 8. In this instance, we concluded that cone OS production is supported by cone OS renewal. Finally, the third set of processes involved a reliance on cell population level parameters allowing us to conclude that competition for resources affects cone OS production; see Equations 13–15. When the rods are degenerating, leading to low/insufficient RdCVF (δ) synthesis, trophic factors become crucial in maintaining C. It was in this case, insufficient RdCVF, that we saw C sensitive to RdCVF indicating a reliance of cones on rods via RdCVF. In the absence of RdCVF (δ = 0), glucose uptake diminishes significantly and cone OS production cannot be maintained. All parameters are defined in Sections 2.1–2.3. Parameter values are in Table 2. PRCC values for each case are included in Supplemental Information A.6.