The Roots of Genetic Coding in Aminoacyl-tRNA Synthetase Duality.

Codon-dependent translation underlies genetics and phylogenetic inferences, but its origins pose two challenges. Prevailing narratives cannot account for the fact that aminoacyl-tRNA synthetases (aaRSs), which translate the genetic code, must collectively enforce the rules used to assemble themselves. Nor can they explain how specific assignments arose from rudimentary differentiation between ancestral aaRSs and corresponding transfer RNAs (tRNAs). Experimental deconstruction of the two aaRS superfamilies created new experimental tools with which to analyze the emergence of the code. Amino acid and tRNA substrate recognition are linked to phase transfer free energies of amino acids and arise largely from aaRS class-specific differences in secondary structure. Sensitivity to protein folding rules endowed ancestral aaRS-tRNA pairs with the feedback necessary to rapidly compare alternative genetic codes and coding sequences. These and other experimental data suggest that the aaRS bidirectional genetic ancestry stabilized the differentiation and interdependence required to initiate and elaborate the genetic coding table.

Reward expectations direct learning and drive operant matching in Drosophila.

Foraging animals must use decision-making strategies that dynamically adapt to the changing availability of rewards in the environment. A wide diversity of animals do this by distributing their choices in proportion to the rewards received from each option, Herrnstein's operant matching law. Theoretical work suggests an elegant mechanistic explanation for this ubiquitous behavior, as operant matching follows automatically from simple synaptic plasticity rules acting within behaviorally relevant neural circuits. However, no past work has mapped operant matching onto plasticity mechanisms in the brain, leaving the biological relevance of the theory unclear. Here, we discovered operant matching in Drosophila and showed that it requires synaptic plasticity that acts in the mushroom body and incorporates the expectation of reward. We began by developing a dynamic foraging paradigm to measure choices from individual flies as they learn to associate odor cues with probabilistic rewards. We then built a model of the fly mushroom body to explain each fly's sequential choice behavior using a family of biologically realistic synaptic plasticity rules. As predicted by past theoretical work, we found that synaptic plasticity rules could explain fly matching behavior by incorporating stimulus expectations, reward expectations, or both. However, by optogenetically bypassing the representation of reward expectation, we abolished matching behavior and showed that the plasticity rule must specifically incorporate reward expectations. Altogether, these results reveal the first synapse-level mechanisms of operant matching and provide compelling evidence for the role of reward expectation signals in the fly brain.

Science, evidence, law, and justice.

For nearly 25 y, the Committee on Science, Technology, and Law (CSTL), of the National Academies of Sciences, Engineering, and Medicine, has brought together distinguished members of the science and law communities to stimulate discussions that would lead to a better understanding of the role of science in legal decisions and government policies and to a better understanding of the legal and regulatory frameworks that govern the conduct of science. Under the leadership of recent CSTL co-chairs David Baltimore and David Tatel, and CSTL director Anne-Marie Mazza, the committee has overseen many interdisciplinary discussions and workshops, such as the international summits on human genome editing and the science of implicit bias, and has delivered advisory consensus reports focusing on topics of broad societal importance, such as dual use research in the life sciences, voting systems, and advances in neural science research using organoids and chimeras. One of the most influential CSTL activities concerns the use of forensic evidence by law enforcement and the courts, with emphasis on the scientific validity of forensic methods and the role of forensic testimony in bringing about justice. As coeditors of this Special Feature, CSTL alumni Tom Albright and Jennifer Mnookin have recruited articles at the intersection of science and law that reveal an emerging scientific revolution of forensic practice, which we hope will engage a broad community of scientists, legal scholars, and members of the public with interest in science-based legal policy and justice reform.

Cortical-subcortical interactions underlie processing of auditory predictions measured with 7T fMRI.

Perception integrates both sensory inputs and internal models of the environment. In the auditory domain, predictions play a critical role because of the temporal nature of sounds. However, the precise contribution of cortical and subcortical structures in these processes and their interaction remain unclear. It is also unclear whether these brain interactions are specific to abstract rules or if they also underlie the predictive coding of local features. We used high-field 7T functional magnetic resonance imaging to investigate interactions between cortical and subcortical areas during auditory predictive processing. Volunteers listened to tone sequences in an oddball paradigm where the predictability of the deviant was manipulated. Perturbations in periodicity were also introduced to test the specificity of the response. Results indicate that both cortical and subcortical auditory structures encode high-order predictive dynamics, with the effect of predictability being strongest in the auditory cortex. These predictive dynamics were best explained by modeling a top-down information flow, in contrast to unpredicted responses. No error signals were observed to deviations of periodicity, suggesting that these responses are specific to abstract rule violations. Our results support the idea that the high-order predictive dynamics observed in subcortical areas propagate from the auditory cortex.

Can the potential benefit of individualizing treatment be assessed using trial summary statistics alone?

Individualizing treatment assignment can improve outcomes for diseases with patient-to-patient variability in comparative treatment effects. When a clinical trial demonstrates that some patients improve on treatment while others do not, it is tempting to assume that treatment effect heterogeneity exists. However, if outcome variability is mainly driven by factors other than variability in the treatment effect, investigating the extent to which covariate data can predict differential treatment response is a potential waste of resources. Motivated by recent meta-analyses assessing the potential of individualizing treatment for major depressive disorder using only summary statistics, we provide a method that uses summary statistics widely available in published clinical trial results to bound the benefit of optimally assigning treatment to each patient. We also offer alternate bounds for settings in which trial results are stratified by another covariate. Our upper bounds can be especially informative when they are small, as there is then little benefit to collecting additional covariate data. We demonstrate our approach using summary statistics from a depression treatment trial. Our methods are implemented in the rct2otrbounds R package.

Learning Optimal Dynamic Treatment Regimes from Longitudinal Data.

Studies often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual's information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR). Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments' benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments' benefits vary as relevant circumstances evolve within an individual. The goal of this paper is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. We describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. We then learn a time-varying ODTR for when to increase buprenorphine-naloxone (BUP-NX) dose to minimize return-to-regular-opioid-use among patients with opioid use disorder. Our analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy.

Personality heterophily and friendship as drivers for successful cooperation.

Cooperation is widespread and arguably a pivotal evolutionary force in maintaining animal societies. Yet, proximately, what underlying motivators drive individuals to cooperate remains relatively unclear. Since 'free-riders' can exploit the benefits by cheating, selecting the right partner is paramount. Such decision rules need not be based on complex calculations and can be driven by cognitively less-demanding mechanisms, like social relationships (e.g. kinship, non-kin friendships, dyadic tolerance), social status (e.g. dominance hierarchies) and personalities (social and non-social traits); however, holistic evidence related to those mechanisms is scarce. Using the classical 'loose-string paradigm', we tested cooperative tendencies of a hierarchical primate, the long-tailed macaque (Macaca fascicularis). We studied three groups (n = 21) in their social settings, allowing partner choice. We supplemented cooperation with observational and experimental data on social relationships, dominance hierarchies and personality. Friendship and dissimilarities in non-social 'exploration' and 'activity-sociability' personality traits predicted the likelihood of cooperative dyad formation. Furthermore, the magnitude of cooperative success was positively associated with friendship, low rank-distance and dissimilarity in the activity-sociability trait. Kinship did not affect cooperation. While some findings align with prior studies, the evidence of (non-social) personality heterophily promoting cooperation may deepen our understanding of the proximate mechanisms and, broadly, the evolution of cooperation.

G × E × M analysis to define allometric rules between leaves and stems in wheat.

Allometric rules provide insights into the structure-function relationships across species and scales and are commonly used in ecology. The fields of agronomy, plant phenotyping and modeling also need simplifications such as allometric rules to reconcile data at different temporal and spatial levels (organs/canopy). This paper explores the variations in relationships for wheat regarding (i) the distribution of crop green area between leaves and stems, and (ii) the allocation of above-ground biomass between leaves and stems during the vegetative period, using a large dataset covering different years, countries, genotypes and management practices. Our results show that the relationship between leaf and stem area was linear, genotype-specific, and sensitive to radiation. The relationship between leaf and stem biomass depended on genotype and nitrogen fertilization. The mass per area, associating area and biomass for both leaf and stem, varied strongly by developmental stage and was significantly affected by environment and genotype. These allometric rules were evaluated with satisfactory performance, and their potential use is discussed with regard to current phenotyping techniques and plant/crop models. Our results enable the definition of models and minimum datasets required for characterizing diversity panels and making predictions in various G × E × M contexts.

Spin-Vibronic Coupling Controls the Intersystem Crossing of Iodine-Substituted BODIPY Triplet Chromophores.

4,4-Difluoro-4-borata-3a-azonia-4a-aza-s-indacene (BODIPY) dyes are extensively used in various applications of their triplet states, ranging from photoredox catalysis, through triplet sensitization to photodynamic therapy. However, the rational design of BODIPY triplet chromophores by ab initio modelling is limited by their strong interactions of spin, electronic and vibrational dynamics. In particular, spin-vibronic coupling is often overlooked when estimating intersystem crossing (ISC) rates. In this study, a combined experimental and theoretical approach using spin-vibronic coupling to correctly describe ISC in BODIPY dyes was developed. For this purpose, seven π-extended BODIPY derivatives with iodine atoms in different positions were examined. It was found that the heavy-atom effect of iodine atoms is site specific, causing high triplet yields in only some positions. This site-specific ISC was explained by El-Sayed rules, so both the contribution and character of the molecular orbitals involved in the excitation must be considered when predicting the ISC rates. Overall, the rational design of BODIPY triplet chromophores requires using (i) the high-quality electronic structure theory, including both static and dynamical correlations; and (ii) the two-component wave function Hamiltonian, and rationalizing; and (iii) ISC based on the character of the molecular orbitals of heavy atoms involved in the excitation, expanding El-Sayed rules beyond their traditional applications.

Gold-catalyzed endo-selective Ring-opening of Epoxides and its Application in Construction of Poly-ethers.

Tetrahydropyran and tetrahydropyran-fused poly-ethers scaffolds are found in many classes of natural products and medicinally relevant small molecules. Here we describe a catalytic system for 6-endo selective ring-opening of epoxides by Au(I) or Au(III) catalyst that provides rapid access to various tetrahydropyran-derived motifs. It also could efficiently construct the subunits of marine ladder-like poly-ethers through emulating the Nakanishi's hypothesis on the biosynthesis of these toxins. The synthetic utility of this method is also demonstrated in the preparation of the tricyclic core of tetrahydropyran-containing macrolide natural products lituarines A-C.

Bending Relaxation of H2 O by Collision with Para- and Ortho-H2.

We extend our recent theoretical work on the bending relaxation of H2 O in collisions with H2 by including the three water modes of vibration coupled with rotation, as well as the rotation of H2 . Our full quantum close-coupling method (excluding the H2 vibration) is combined with a high-accuracy nine-dimensional potential energy surface. The collisions of para-H2 O and ortho-H2 O with the two spin modifications of H2 are considered and compared for several initial states of H2 O. The convergence of the results as a function of the size of the rotational basis set of the two colliders is discussed. In particular, near-resonant energy transfer between H2 O and H2 is found to control the vibrational relaxation process, with a dominant contribution of transitions with Δ j 2 = j 2 f - j 2 i ${{\rm{\Delta }}j_2 = j_2^f - j_2^i }$ = + 2 , + 4 ${ + 2, + 4}$ , j 2 i ${j_2^i }$ and j 2 f ${j_2^f }$ being respectively the H2 initial and final rotational quantum numbers. Finally, the calculated value of the H2 O bending relaxation rate coefficient at 295 K is found to be in excellent agreement with its experimental estimate.

Woodward-Hoffmann or Hoffmann-Woodward? Cycloadditions and the Transformation of Roald Hoffmann from a "Calculator" to an "Explainer".

On May 1, 1965, Roald Hoffmann and R. B. Woodward published their second joint communication, Selection Rules for Concerted Cycloaddition Reactions, in the Journal of the American Chemical Society. Herein is presented a historical analysis of Woodward and Hoffmann's determination of the mechanism of cycloadditions. This analysis is based on thorough analyses with Roald Hoffmann of his 1964 and 1965 laboratory notebooks and his archived documents and on numerous in-person, video, and email interviews. This historical research pinpoints several seminal moments in chemistry and in the professional career of Hoffmann. For example, now documented is the fact that Woodward and Hoffmann had no anticipation that their collaboration would continue after the publication of their first 1965 communication on electrocyclizations. Also pinpointed is the moment in Hoffmann's professional and intellectual trajectories that he became a full-fledged, equal collaborator with Woodward and Hoffmann's transition from a "calculator" to an "explainer."

Scoring System to Evaluate Risk of Nonoperative Management Failure in Children With Intussusception.

INTRODUCTION: Typical first-line management of children with intussusception is enema reduction; however, failure necessitates surgical intervention. The number of attempts varies by clinician, and predictors of failed nonoperative management are not routinely considered in practice. The purpose of this study is to create a scoring system that predicts risk of nonoperative failure and need for surgical intervention. METHODS: Children diagnosed with intussusception upon presentation to the emergency department of a tertiary children's hospital between 2019 and 2022 were retrospectively identified. Univariable logistic regression identified predictors of nonoperative failure used as starting covariates for multivariable logistic regression with final model determined by backwards elimination. Regression coefficients for final predictors were used to create the scoring system and optimal cut-points were delineated. RESULTS: We identified 143 instances of ultrasound-documented intussusception of which 28 (19.6%) required operative intervention. Predictors of failed nonoperative management included age ≥4 y (odds ratio [OR] 32.83, 95% confidence interval [CI]: 1.91-564.23), ≥1 failed enema reduction attempts (OR 189.53, 95% CI: 19.07-1884.11), presenting heart rate ≥128 (OR 3.38, 95% CI: 0.74-15.36), presenting systolic blood pressure ≥115 mmHg (OR 6.59, 95% CI: 0.93-46.66), and trapped fluid between intussuscepted loops on ultrasound (OR 17.54, 95% CI: 0.77-397.51). Employing these factors, a novel risk scoring system was developed (area under the curve 0.96, 95% CI: 0.93-0.99). Scores range from 0 to 8; ≤2 have low (1.1%), 3-4 moderate (50.0%), and ≥5 high (100%) failure risk. CONCLUSIONS: Using known risk factors for enema failure, we produced a risk scoring system with outstanding discriminate ability for children with intussusception necessitating surgical intervention. Prospective validation is warranted prior to clinical integration.

Valence-state mixing and reduced magnetic moment inFe3-δGeTe2single crystals with varying Fe content probed by x-ray spectroscopy.

We present a spectroscopic study of the magnetic properties ofFe3-δGeTe2single crystals with varying Fe content, achieved by tuning the stoichiometry of the crystals. We carried out x-ray absorption spectroscopy and analyzed the x-ray circular magnetic dichroism spectra using the sum rules, to determine the orbital and spin magnetic moments of the materials. We find a clear reduction of the spin and orbital magnetic moment with increasing Fe deficiency. Magnetic susceptibility measurements show that the reduction in magnetization is accompanied by a reduced Curie temperature. Multiplet calculations reveal that the Fe2+state increasingly mixes with a higher valence state when the Fe deficiency is increased. This effect is correlated with the weakening of the magnetic moment. As single crystals are the base material for exfoliation processes, our results are relevant for the assembly of 2D magnetic heterostructures.

Prospective external validation of IOTA methods for classifying adnexal masses and retrospective assessment of two-step strategy using benign descriptors and ADNEX: a Portuguese multicenter study.

OBJECTIVE: This study aimed to externally and prospectively validate the International Ovarian Tumor Analysis (IOTA) Simple Rules (SRs), Logistic Regression model 2 (LR2) and Assessment of Different NEoplasias in the adneXa (ADNEX) in a Portuguese population, comparing them with operator subjective assessment (SA), Risk-of-Malignancy Index (RMI), as well as with each other. This study also aimed to retrospectively validate IOTA two-step strategy, using modified benign descriptors (MBDs) followed by the application of ADNEX in cases where MBDs were not applicable (MBDs + ADNEX). METHODS: In this multicenter diagnostic accuracy study, conducted between January 2016 and December 2021, three tertiary referral centers prospectively included consecutive patients with ultrasound diagnosis of at least one adnexal tumor who underwent surgery. All ultrasound assessments were performed by level II or III sonologists with IOTA certification. Patient clinical data and serum cancer antigen (CA125) levels were collected from the hospital databases. Each adnexal mass was classified as benign or malignant using SA, RMI, IOTA SRs, LR2 and ADNEX (with and without CA125). The reference standard was histopathological diagnosis. In the second phase, all adnexal tumors were retrospectively classified using the two-step strategy (MBDs + ADNEX). The sensitivity, specificity, positive (PPV) and negative predictive value (NPV), positive (LR+) and negative likelihood ratio (LR-) as well as overall accuracy were determined for SA, RMI, IOTA SRs, LR2, ADNEX and two-step strategy (MBDs + ADNEX). Receiver-operator characteristic curves were constructed and corresponding areas under the curve (AUC) determined for RMI, LR2 and ADNEX and two-step strategy (MBDs + ADNEX). The ADNEX calibration plots were constructed and estimated by LOESS smoother. RESULTS: Of the 571 included patients, 428 had benign disease, 42 borderline ovarian tumors, 93 primary invasive adnexal cancers and 8 metastatic tumors in adnexa (malignancy prevalence: 25.0%). The operator SA had an overall sensitivity of 97.9% and a specificity of 83.6% for distinguishing between benign and malignant lesions. RMI showed high specificity (95.6%) but very low sensitivity (58.7%), with an AUC of 0.913. The IOTA SRs were applicable in 80.0% of patients, with a sensitivity of 94.8% and a specificity of 98.6%. LR2 revealed a sensitivity of 84.6%, a specificity of 86.9% and an AUC of 0.939, at the malignancy risk cut-off of 10%. At the same cut-off, ADNEX with and without CA125 had a sensitivity of 95.8% and 98.6%, respectively, and a specificity of 82.5% and 79.7%, respectively. The AUC of ADNEX with vs. without CA125 was 0.962 vs. 0.960. The ADNEX model provided heterogeneous results in distinguishing between benign and different subtypes of malignancy, with the highest AUC (0.991) for discriminating benign masses from primary adnexal cancer stage II-IV, and the lowest AUC (0.696) for distinguishing primary adnexal cancer stage I and metastatic lesion in adnexa. The ADNEX calibration plots suggested an underestimation of the predicted risk in relation with the observed proportion of malignancies. The MBDs were applicable in 26.3% of cases (150/571 tumors, none of which were malignant). Similar to the ADNEX model applied in all patients, the two-step strategy using ADNEX in the second step only, with and without CA125, had an AUC of 0.964 and 0.961, respectively. CONCLUSIONS: Our results showed a good to excellent performance of the IOTA methods in the studied Portuguese population, outperforming RMI. ADNEX was superior in accuracy, but interpretation of its ability to distinguish malignant subtypes was fundamentally limited not only by sample size but also by large differences in the prevalence of tumor subtypes. The IOTA MBDs have been shown to be reliable in identifying benign disease. The two-step strategy based on the application of MBDs, followed by the ADNEX model if MBDs are not applicable, has proven to be suitable for daily practice circumventing the need to use electronic support in all patients. This article is protected by copyright. All rights reserved.

Sensitivity to moral and conventional rules in temporal lobe epilepsy.

OBJECTIVES: Sensitivity to moral and conventional rules (SMCR) is supported by bilateral brain networks and psychosocial input both of which may be altered in temporal lobe epilepsy (TLE). This study evaluated the components of SMCR in patients with TLE, aiming to clarify their preservation and link to psychopathological and cognitive aspects. METHODS: Adult patients with unilateral TLE and healthy controls were evaluated using neuropsychological tests for SMCR, memory, language, and executive functions, the Empathy Questionnaire (EQ), and the Symptom Checklist-90-R (SCL-90-R). RESULTS: The SMCR test items showed good reliability and validity, yielding the Severity and Rules factors distinct from the Executive, Lexical and Memory factors. Patients with right TLE scored worse in moral rules recognition than controls, but this difference was nullified by a significant influence for age and sex. The Severity and Rules factors related to semantic fluency and age and, respectively, TLE side and psychoticism. However, these factors did predict TLE membership. CONCLUSIONS: In adult patients with TLE, the SMCR test reflects a distinct cognitive domain. Conventional rules are well-retained, while moral reasoning may be only affected in right TLE if unfavorable demographics coexist. Although age, TLE side, semantic abilities, and psychoticism cooperate to determine SMCR, impairment of such domain is not a distinctive feature of TLE.

Characteristics and preventability of medication-related admissions for acute kidney injury and dehydration in elderly patients.

PURPOSE: Patients with impaired renal function using medication that affects glomerular filtration rate are at increased risk of developing acute kidney injury (AKI) leading to hospital admissions. The risk increases during periods of dehydration due to diarrhoea, vomiting or fever (so-called "sick days"), or high environmental temperatures (heat wave). This study aims to gain insight into the characteristics and preventability of medication-related admissions for AKI and dehydration in elderly patients. METHODS: Retrospective case series study in patients aged ≥ 65 years with admission for acute kidney injury, dehydration or electrolyte imbalance related to dehydration that was defined as medication-related. General practitioner's (GP) patient records including medication history and hospital discharge letters were available. For each admission, patient and admission characteristics were collected to review the patient journey. A case-by-case assessment of preventability of hospital admissions was performed. RESULTS: In total, 75 admissions were included. Most prevalent comorbidities were hypertension, diabetes, and known impaired renal function. Diuretics and RAS-inhibitors were the most prevalent medication combination. Eighty percent of patients experienced non-acute onset of symptoms and 60% had contacted their GP within 2 weeks prior to admission. Around 40% (n = 29) of admissions were considered potentially preventable if pharmacotherapy had been timely and adequately adjusted. CONCLUSION: A substantial proportion of patients admitted with AKI or dehydration experience non-acute onset of symptoms and had contacted their GP within 2 weeks prior to admission. Timely adjusting of medication in these patients could have potentially prevented a considerable number of admissions.

Interaction Rules Supporting Effective Flocking Behavior.

Several simulation models have demonstrated how flocking behavior emerges from the interaction among individuals that react to the relative orientation of their neighbors based on simple rules. However, the precise nature of these rules and the relationship between the characteristics of the rules and the efficacy of the resulting collective behavior are unknown. In this article, we analyze the effect of the strength with which individuals react to the orientation of neighbors located in different sectors of their visual fields and the benefit that could be obtained by using control rules that are more elaborate than those normally used. Our results demonstrate that considering only neighbors located on the frontal side of the visual field permits an increase in the aggregation level of the swarm. Using more complex rules and/or additional sensory information does not lead to better performance.

Establishment and discussion of autoverification rules for transfusion compatibility testing.

OBJECTIVES: To develop an automated verification workflow for transfusion compatibility testing (TCT) based on the AUTO10-A guidelines and blood group serology characteristics and to conduct a simulated validation of the test and subtest results by assessing the appropriateness of the autoverification rules. BACKGROUND: The accuracy of TCT results is a fundamental prerequisite for ensuring the safety of blood transfusions. However, the verification of these results still requires manual intervention. MATERIALS AND METHODS: Five autoverification rules and their standards were determined: agglutination intensity, normal results, logical relationships, delta checks and interlaboratory test comparisons. The established categories and standards for the five rules were retrospectively validated using 13 506 samples (requests) that had been manually verified in our laboratory from January 2020 to June 2023. RESULTS: A total of 66 638 test items were involved in the autoverification, with 3844 items violating the verification rules, resulting in a pass rate of 96.10%. Considering individual test items, four tests had a pass rate of more than 90% in both the test item result table and the test subitem result table. However, there were significant differences in the pass rates between different tests. The same conclusion can be drawn when the unit is requests. The different standards set for the agglutination intensity and the delta check in the ABO typing testing subitems showed significant differences in pass rates. DISCUSSION: The incorporation of manually verified results into the automated verification simulation indicated that the five rules established in this study have good applicability, and appropriate standards can lead to reasonable pass rates.

The diagnostic accuracy of quality control rules.

Internal quality control in clinical chemistry laboratories are based on analyzing samples of stable control materials among the patient samples. The control results are interpreted by using quality control rules that usually are designed to detect systematic errors. The best rules have a high probability of error detection (Ped), i.e. to detect the maximal allowable (critical) systematic error and a low probability of false rejection (Pfr, false alarm). In this work we show that quality control rules can be represented by points on a ROC curve which appears when Ped is plotted against Pfr and only the control limit is varied. Further, we introduce a new method for choosing the optimal control limit, analogous to choosing the optimal operating point on the ROC curve of a diagnostic test. This decision needs knowledge of the pretest probability of a critical systematic error, the benefit of detecting it when it occurs and the cost of false alarm. The ROC curve analysis showed that if rules based on N = 2 are used, mean rules outperform Westgard rules because the ROC curve of the mean rules was lying above the ROC curves of the Westgard rules. A mean rule also had a lower maximum expected increase in the number of unacceptable patient results reported during the presence of an out-of-control error condition (Max E(NUF)) than comparable Westgard rules.