**Purpose**:
In Germany, approximately one-third of the harvested donor corneas are not suitable for transplantation, mostly due to insufficient endothelial cell density (ECD). The ECD can only be reliably determined after harvesting and processing of the cornea. Our group has previously developed a predictive model for corneal ECD: \( {Predicted\, ECD} = 2919-6^{\ast}\;{age}\; [{years}]-189\; [{if\, male}]\\
-7^{\ast}\;{death-to-explantation\, interval\,} [{hours}]\\
- 378\; [{if\, pseudophakic}] \;{cells/mm}^2 \)

**Methods**:
A total of 2.999 consecutive donor corneas harvested between 2017 and 2021 from the Eye Bank of Rhineland-Palatinate in Mainz, Germany, were included. An actual ECD of >2000 cells/mm^{2} was defined as the cutoff value. To evaluate the clinical utility of the prognostic model as a screening instrument for transplant eligibility in an independent cohort, we performed a decision curve analysis.

**Results**:
The median predicted ECD was 2061 cells/mm^{2} (interquartile range [IQR] = 1834 to 2221), whereas the median actual ECD was 2377 cells/mm^{2} (IQR = 1907 to 2624). There was a positive correlation between predicted and actual ECD (correlation coefficient = 0.411; *P* < 0.01). Our predictive model for ECD is a strong predictor for an actual ECD greater than 2000 (odds ratio = 1.374, 95% confidence interval [CI]) per 100 cells; *P* < 0.001, area under the curve [AUC] of 0.73). Decision curve analysis showed that the predictive model yielded a positive net benefit in clinical settings.

**Conclusions**:
Decision curve analysis demonstrated a positive net benefit of the ECD predictive model in clinical settings with limited eye bank resources.

**Translational Relevance**:
In possible scenarios where a choice between corneal grafts is required, or in countries with limited eye bank infrastructure and staff, the initial estimate of ECD from the formula may be beneficial.

^{1}The increasing number of keratoplasties is accompanied by a corresponding demand for suitable donor corneas. Despite a leading share of donor corneas of about 90 percent of all donated tissues and an increasing number of donors each year, the growing demand for corneal tissue cannot be fully met.

^{2}In Germany, approximately one third of donor corneas harvested are not suitable for transplantation.

^{3}

^{,}

^{4}The most common reason for corneal exclusion is a low endothelial cell density (ECD).

^{5}

^{–}

^{7}Further reasons for exclusion include lack of valid blood sample, exceeding the maximum death-to-explantation interval (DEI) limited to 72 hours in Germany, inaccessibility of relatives, lack of consent for tissue donation, logistical problems, and others. Previous studies reported on an association between advanced donor age and pseudophakic lens status,

^{7}

^{–}

^{13}cause of death, such as cardiovascular disease,

^{14}cancer,

^{8}or sepsis,

^{15}and an increased postmortem interval

^{16}with endothelial cell loss, but some other studies could not confirm these associations.

^{5}

^{,}

^{13}

^{,}

^{17}

^{–}

^{22}Usually, the ECD of the cornea is measured between the third and fifth day after explantation of the cornea and organ culture.

^{23}DEI was calculated for each corneal donor using the time of death from the donor’s death certificate and the eye bank’s records of processing dates and times. Lens status (phakic, pseudophakic, or aphakic) was assessed at explantation. They developed a predictive model for the expected ECD from predefined potential predictors:

^{24}All data in this retrospective study were obtained from deceased donors; therefore, no ethics vote was obtained in this study.

^{2}as a clinically relevant cutoff value for transplantability. To evaluate the clinical utility of the expected ECD, we performed a decision curve analysis. For this, we estimated the corresponding net benefit of the expected ECD model in predicting if a harvested cornea is transplantable at a wide range of threshold probabilities. The threshold probability is defined as the minimum probability of an event at which a decision-maker would choose to harvest the cornea. Selection of a higher threshold probability would, for instance, imply limited eye bank resources, whereas selection of a lower threshold probability implies, for instance, a higher demand on transplantable corneas than available organ donors. The net benefit is defined as the proportion of correct positive classifications subtracted from the proportion of false negatives, weighted by the risk threshold. The decision curve analysis is presented as a graphical plot of net benefit against threshold probability.

^{2}(interquartile range [IQR] = 1834 to 2221) compared to the median measured ECD of 2377 cells/mm

^{2}(IQR = 1907 to 2624). The predicted ECD underestimates the actual measured ECD translating to a significant difference in the paired

*t*-test. There was a positive correlation between the predicted and actual ECD (correlation coefficient = 0.411;

*P*< 0.01; Fig. 1).

^{2}. The prognostic model significantly predicts probability of ECD > 2000 cells/mm

^{2}with an area under the curve (AUC) of 0.73 (odds ratio = 1.374, 95% confidence interval [CI] per 100 cells;

*P*< 0.001; Fig. 2).

^{25}Many potential donors are already out of question before tissue collection because of their medical history, infectious pre-existing conditions, cause of death, DEI, or lack of consent. Furthermore, about one third of the harvested corneas are not suitable for transplantation. The most common reason for the discard is a low ECD.

^{5}

^{–}

^{7}

^{,}

^{26}

^{5}

^{–}

^{7}the donor with the highest possible ECD should be chosen to obtain the best condition for its upcoming use.

^{22}To the best of our knowledge, this is the first investigation to validate such a predictive model on a large cohort of almost 3000 harvested corneas. The results show that the predicted ECD by the model correlates with the actual ECD (correlation coefficient = 0.411;

*P*< 0.01). We have shown that this model, in fact, is an acceptable predictor of an actual ECD of over 2000 cells/mm

^{2}as this number is considered to be the threshold for cornea transplantation involving the endothelium. The median ECD predicted with the formula was 2061 cells/mm

^{2}(IQR = 1834 to 2221) compared to the median measured ECD of 2377 cells/mm

^{2}(IQR = 1907 to 2624). A tendency to underestimate the ECD compared to the actual measured ECD is more likely to be beneficial for the upcoming corneal transplant and overall graft survival than the other way around. The results of our ROC curve suggest that our predictive model predicts an ECD > 2000 cells/mm

^{2}with an AUC of 73% (see Fig. 2). To evaluate the clinical utility of the expected ECD as a screening tool to best manage reprocessing capacities of cornea donor banks when it is limited, we performed a decision curve analysis (see Fig. 3). In clinical settings with a high reprocessing capacity, a low-risk threshold of, for example, 30% for an ECD > 2000 may be sufficient for tissue explantation. In this case, the approach to examine all corneas (see the blue line in the decision curve analysis) has an identical net benefit compared to the ECD predictive model. But in a clinical setting that requires a higher risk threshold for a transplantable donor cornea of, for example, 45% for an ECD > 2000 and above, for example, due to limited processing capacity, our prognostic model shows a higher net benefit (see the red line in the decision curve analysis; see Fig. 3).

**Data Availability Statements:**The data used to support the findings of this study are available from the corresponding author upon request.

**J.B. Bu**, None;

**S.D. Grabitz**, None;

**F. Schön**, None;

**M. Apel**, None;

**T. Pusch**, None;

**A. Gericke**, None;

**A. Poplawski**, None;

**N. Pfeiffer**, None;

**J. Wasielica-Poslednik**, None

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