Machine learning models are increasingly applied to biomedical data, yet their adoption in high stakes domains remains limited by poor robustness, limited interpretability, and instability of learned features under realistic data perturbations, such as missingness. In particular, models that achieve high predictive performance may still fail to inspire trust if their key features fluctuate when data completeness changes, undermining reproducibility and downstream decision-making. Here, we present CACTUS (Comprehensive Abstraction and Classification Tool for Uncovering Structures), an explainable machine learning framework explicitly designed to address these challenges in small, heterogeneous, and incomplete clinical datasets. CACTUS integrates feature abstraction, interpretable classification, and systematic feature stability analysis to quantify how consistently informative features are preserved as data quality degrades. Using a real-world haematuria cohort comprising 568 patients evaluated for bladder cancer, we benchmark CACTUS against widely used machine learning approaches, including random forests and gradient boosting methods, under controlled levels of randomly introduced missing data. We demonstrate that CACTUS achieves competitive or superior predictive performance while maintaining markedly higher stability of top-ranked features as missingness increases, including in sex-stratified analyses. Our results show that feature stability provides information complementary to conventional performance metrics and is essential for assessing the trustworthiness of machine learning models applied to biomedical data. By explicitly quantifying robustness to missing data and prioritising interpretable, stable features, CACTUS offers a generalizable framework for trustworthy data-driven decision support.
Figures & tables
Figure 1: Stability of features across ML methods . Average relative change in feature importance calculated for the 10 most important features for classification obtained by each method for: the total dataset (top), the male subjects in the dataset (middle), and the female subjects in the dataset (bottom).
Figure 2: Overlapping features . Graphs plotted for each subset from the total population, males and females, presenting percentage of overlapping features from the top 10 most important features for classification with increasing number of missing values in the dataset.
rank
complete
rank
complete +10%
rank
complete +20%
rank
complete +30%
rank
number
value
missing values
value
missing values
value
missing values
value
1
haematuria
0.304
clusterin
0.317
clusterin
0.253
clusterin
0.220
2
clusterin
0.297
nse
0.295
fas
0.219
cystatin-b
0.220
3
nse
0.279
haematuria
0.257
tar expos.
0.215
nse
0.210
4
tar expos.
0.252
microalbumin
0.248
nse
0.214
vegf
0.208
5
il- 1 α
0.242
(s)pai- 1 /tpa
0.241
(s)pai- 1 /tpa
0.213
haematuria
0.206
Table 1: The most important 10 features for classification obtained through CACTUS analysis for the combined dataset (total population). The prefix (s) indicates that the biomarker is measured in blood rather than in urine (default).
rank
complete
rank
complete +10%
rank
complete +20%
rank
complete +30%
rank
number
value
missing values
value
missing values
value
missing values
value
1
nse
318.2
nse
228.3
nse
166.7
nse
207.9
2
yrs of smoking
172.5
psa/tpsa
151.2
psa/tpsa
127.4
psa/tpsa
136.2
3
prolactin
127.3
tnf- α
115.2
yrs of smoking
102.5
prolactin
119.9
4
psa/tpsa
123.3
prolactin
114.7
clusterin
91.8
tar expos.
111.6
5
egf
98.3
(s)pai- 1 /tpa
107.4
il- 8
88.9
tgf- β 1
89.8
Table 4: The most important 10 features for classification obtained through LGBM analysis for the male dataset. The prefix (s) indicates that the biomarker is measured in blood rather than in urine (default).
Figure 3: Balanced Accuracy (BA) . BA calculated for each subset (total, males and females) with increasing number of missing values in the dataset.
Figure 4: Recall (sensitivity) . Sensitivity calculated for each subset (total, males and females) with increasing number of missing values in the dataset.
Figure 5: Heatmap for males subset . A heatmap showing the 10 most important features for BC/non-BC case classification in the male subset, with thresholds and significance values used to produce the ranks. Note: the thresholds shown on the graph represent the best value that separates the two classes (BC and non-BC cases) and do not correspond to thresholds set by medical institutions for diagnosis.
Figure 6: Heatmap for females subset . A heatmap showing the 10 most important features for BC/non-BC case classification in the male subset, with thresholds and significance values used to produce the ranks. Note: the thresholds shown on the graph represent the best value that separates the two classes (BC and non-BC cases) and do not correspond to thresholds set by medical institutions for diagnosis.
Figure 7: Distribution of the HaBio cohort patients regarding sex . A bar plot illustrating the distribution of bladder cancer (BC) and bladder cancer free (non-BC) patients by sex.
Feature attribution analysis is critical for interpreting machine learning models and supporting reliable data-driven decisions. However, feature attribution measures often exhibit stochastic variation: different train--test splits, random seeds, or model-fitting procedures can produce substantially different attribution values and feature rankings. This paper proposes a framework for incorporating stochastic nature of feature attribution and a robust attribution metric, RoSHAP, for stable feature ranking based on the SHAP metric. The proposed framework models the distribution of feature attribution scores and estimates it through bootstrap resampling and kernel density estimation. We show that, under mild regularity conditions, the aggregated feature attribution score is asymptotically Gaussian, which greatly reduces the computational cost of distribution estimation. The RoSHAP summarizes the distribution of SHAP into a robust feature-ranking criterion that simultaneously rewards features that are active, strong, and stable. Through simulations and real-data experiments, the proposed framework and RoSHAP outperform standard single-run attribution measures in identifying signal features. In addition, models built using RoSHAP-selected features achieve predictive performance comparable to full-feature models while using substantially fewer predictors. The proposed RoSHAP approach improves the stability and interpretability of machine learning models, enabling reliable and consistent insights for analysis.
Lanxin Xiang, Liang Shi, Youhui Ye +3
Department of Statistics Virginia Tech · Department of Statistics Virginia Tech Transportation Institute · Department of Computer Science Virginia Tech
Small-to-medium scientific datasets place machine learning pipelines under two compounding pressures. Single-run feature selection produces feature sets that change substantially under small perturbations of the training data, and any procedure that uses the same data for selection, tuning, and evaluation produces optimistically biased performance estimates. The two failure modes are routinely treated as separable, but in the regimes where scientific data live, they interact: an unstable selection inflates the variance of an already-optimistic score, and standard remedies for one rarely address the other. RobustModelMaker is a Python framework that couples bootstrap stability selection with strict nested cross-validation, performs all preprocessing and selection inside each fold, and produces a stability-tested feature subset together with a leakage-safe performance estimate. The framework supports nine algorithms across binary classification, multiclass classification, and regression. Behaviour is verified by a deterministic test suite spanning unit, performance, and reproducibility checks on three real scientific datasets comparing to three alternative selectors (ANOVA F-test, recursive feature elimination with cross-validation, and Boruta) on both predictive score and a Jaccard measure of selection stability. RobustModelMaker is competitive in score with the best alternative selector on each dataset, and occupies a position on the joint score-stability frontier that none of the alternatives match across all three task types. Two example applications, ovarian cancer biomarker discovery from the PLCO Trial and critical-temperature regression on the UCI Superconductivity Data, illustrate how the framework is used in practice and what trade-offs become visible when stability is treated as a first-class deliverable rather than an emergent property.
Amanda S Barnard
School of Computing Australian National University Acton, ACT 2601
Popular explanation methods often produce unreliable feature importance scores due to missingness bias, a systematic distortion that arises when models are probed with ablated, out-of-distribution inputs. Existing solutions treat this as a deep representational flaw that requires expensive retraining or architectural modifications. In this work, we challenge this assumption and show that missingness bias can be effectively treated as a superficial artifact of the model's output space. We introduce MCal, a lightweight post-hoc method that corrects this bias by fine-tuning a simple linear head on the outputs of a frozen base model. Surprisingly, we find this simple correction consistently reduces missingness bias and is competitive with, or even outperforms, prior heavyweight approaches across diverse medical benchmarks spanning vision, language, and tabular domains.
Shailesh Sridhar, Anton Xue, Eric Wong
University of Pennsylvania · University of Texas at Austin