Incidental Detection of Maternal Neoplasia in Noninvasive Prenatal Testing.

BACKGROUND: Noninvasive prenatal testing (NIPT) uses cell-free DNA (cfDNA) as an analyte to detect copy-number alterations in the fetal genome. Because maternal and fetal cfDNA contributions are comingled, changes in the maternal genome can manifest as abnormal NIPT results. Circulating tumor DNA (ctDNA) present in cases of maternal neoplasia has the potential to distort the NIPT readout to a degree that prevents interpretation, resulting in a nonreportable test result for fetal aneuploidy. METHODS: NIPT cases that showed a distortion from normal euploid genomic representation were communicated to the caregiving physician as nonreportable for fetal aneuploidy. Follow-up information was subsequently collected for these cases. More than 450000 pregnant patients who submitted samples for clinical laboratory testing >3 years are summarized. Additionally, in-depth analysis was performed for >79000 research-consented samples. RESULTS: In total, 55 nonreportable NIPT cases with altered genomic profiles were cataloged. Of these, 43 had additional information available to enable follow-up. A maternal neoplasm was confirmed in 40 of these cases: 18 malignant, 20 benign uterine fibroids, and 2 with radiological confirmation but without pathological classification. CONCLUSIONS: In a population of pregnant women who submitted a blood sample for cfDNA testing, an abnormal genomic profile not consistent with fetal abnormalities was detected in about 10 out of 100000 cases. A subset of these observations (18 of 43; 41.9%) was attributed to maternal malignant neoplasms. These observational results suggest the need for a controlled trial to evaluate the potential of using cfDNA as an early biomarker of cancer.

Genome-wide cfDNA screening: clinical laboratory experience with the first 10,000 cases.

PurposeInvasive diagnostic prenatal testing can provide the most comprehensive information about the genetic status of a fetus. Noninvasive prenatal screening methods, especially when using cell-free DNA (cfDNA), are often limited to reporting only on trisomies 21, 18, and 13 and sex chromosome aneuploidies. This can leave a significant number of chromosomal and subchromosomal copy-number variations undetected. In 2015, we launched a new genome-wide cfDNA screening test that has the potential to narrow this detection gap.MethodsHere, we review the results from the first 10,000 cases submitted to the Sequenom clinical laboratory for genome-wide cfDNA screening.ResultsThe high-risk indication for this cohort differed compared with standard cfDNA screening. More samples were submitted with ultrasound indications (25% compared with 13% for standard cfDNA screening) and fewer for advanced maternal age (51% for genome-wide screening versus 68% for standard cfDNA screening). A total of 554 positive calls were made, of which 164 were detectable only via genome-wide analysis.ConclusionThis reports indicates a difference in utilization compared with standard cfDNA screening, where positivity rates are higher and a large subset of positive calls could not have been made using standard cfDNA screening.

Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants.

BACKGROUND: Current cell-free DNA assessment of fetal chromosomes does not analyze and report on all chromosomes. Hence, a significant proportion of fetal chromosomal abnormalities are not detectable by current noninvasive methods. Here we report the clinical validation of a novel noninvasive prenatal test (NIPT) designed to detect genomewide gains and losses of chromosomal material ≥7 Mb and losses associated with specific deletions <7 Mb. OBJECTIVE: The objective of this study is to provide a clinical validation of the sensitivity and specificity of a novel NIPT for detection of genomewide abnormalities. STUDY DESIGN: This retrospective, blinded study included maternal plasma collected from 1222 study subjects with pregnancies at increased risk for fetal chromosomal abnormalities that were assessed for trisomy 21 (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies (SCAs), fetal sex, genomewide copy number variants (CNVs) ≥7 Mb, and select deletions <7 Mb. Performance was assessed by comparing test results with findings from G-band karyotyping, microarray data, or high coverage sequencing. RESULTS: Clinical sensitivity within this study was determined to be 100% for T21 (95% confidence interval [CI], 94.6-100%), T18 (95% CI, 84.4-100%), T13 (95% CI, 74.7-100%), and SCAs (95% CI, 84-100%), and 97.7% for genomewide CNVs (95% CI, 86.2-99.9%). Clinical specificity within this study was determined to be 100% for T21 (95% CI, 99.6-100%), T18 (95% CI, 99.6-100%), and T13 (95% CI, 99.6-100%), and 99.9% for SCAs and CNVs (95% CI, 99.4-100% for both). Fetal sex classification had an accuracy of 99.6% (95% CI, 98.9-99.8%). CONCLUSION: This study has demonstrated that genomewide NIPT for fetal chromosomal abnormalities can provide high resolution, sensitive, and specific detection of a wide range of subchromosomal and whole chromosomal abnormalities that were previously only detectable by invasive karyotype analysis. In some instances, this NIPT also provided additional clarification about the origin of genetic material that had not been identified by invasive karyotype analysis.

Translational utility of next-generation sequencing.

The development of next-generation sequencing (NGS) technology has made DNA sequencing not only rapid and cost-effective, but also highly accurate and reproducible. The translational utility of genomic sequencing is clear, from understanding of human genetic variation and its association with disease risk and individual response to treatment, to the interpretation and translation of the data for clinical decision making. It will be a critical technology for disease characterization and monitoring in molecular pathology and is expected to become a central piece of routine healthcare management which will result in accurate and reliable reporting, a prerequisite for physicians to practice genomic medicine.

Parallel Maximum Cardinality Matching for General Graphs on GPUs.

The matching problem formulated as Maximum Cardinality Matching in General Graphs (MCMGG) finds the largest matching on graphs without restrictions. The Micali-Vazirani algorithm has the best asymptotic complexity for solving MCMGG when the graphs are sparse. Parallelizing matching in general graphs on the GPU is difficult for multiple reasons. First, the augmenting path procedure is highly recursive, and NVIDIA GPUs use registers to store kernel arguments, which eventually spill into cached device memory, with a performance penalty. Second, extracting parallelism from the matching process requires partitioning the graph to avoid any overlapping augmenting paths. We propose an implementation of the Micali-Vazirani algorithm which identifies bridge edges using thread-parallel breadth-first search, followed by block-parallel path augmentation and blossom contraction. Augmenting path and Union-find methods were implemented as stack-based iterative methods, with a stack allocated in shared memory. Our experimentation shows that compared to the serial implementation, our approach results in up to 15-fold speed-up for very sparse regular graphs, up to 5-fold slowdown for denser regular graphs, and finally a 50-fold slowdown for power-law distributed Kronecker graphs. This implementation has been open-sourced for further research on developing combinatorial graph algorithms on GPUs.

Shared-Memory Parallel Edmonds Blossom Algorithm for Maximum Cardinality Matching in General Graphs.

The Edmonds Blossom algorithm is implemented here using depth-first search, which is intrinsically serial. By streamlining the code, our serial implementation is consistently three to five times faster than the previously fastest general graph matching code. By extracting parallelism across iterations of the algorithm, with coarse-grain locking, we are able to further reduce the run time on random regular graphs four-fold and obtain a two-fold reduction of run time on real-world graphs with similar topology. Solving very sparse graphs (average degree less than four) exhibiting community structure with eight threads led to a slow down of three-fold, but this slow down is replaced by marginal speed up once the average degree is greater than four. We conclude that our parallel coarse-grain locking implementation performs well when extracting parallelism from this augmenting-path-based algorithm and may work well for similar algorithms.

Proof-of-concept evaluation of next-generation sequencing-based liquid biopsy for non-invasive cancer detection in cats.

This proof-of-concept evaluation demonstrates that next-generation sequencing-based liquid biopsy can detect genomic alterations in the blood of cats with cancer and the absence of such alterations in the blood of presumably cancer-free cats. Two cats with cytologically confirmed lymphoma and nine presumably cancer-free cats were included in this analysis. Whole blood was collected from each subject and samples were subjected to DNA extraction, library preparation, and next-generation sequencing. Both cancer-diagnosed subjects had somatic copy number variants (a "cancer signal") identified in cell-free DNA, suggesting the current presence of cancer in these subjects. All nine presumably cancer-free subjects had unremarkable genomic profiles, suggesting the absence of cancer in these subjects. Liquid biopsy using next-generation sequencing of cell-free DNA allows for blood-based detection of cancer-associated genomic alterations in cats. Such technology has the potential to offer considerable utility in veterinary medicine, particularly for the non-invasive prioritization of small cell intestinal lymphoma versus inflammatory bowel disease in cats with gastrointestinal signs. This study lays the foundation for future studies to fully validate this type of testing for use in clinical practice.

Clinical validation of a blood-based liquid biopsy test integrating cell-free DNA quantification and next-generation sequencing for cancer screening in dogs.

OBJECTIVE: To validate the performance of a novel, integrated test for canine cancer screening that combines cell-free DNA quantification with next-generation sequencing (NGS) analysis. SAMPLE: Retrospective data from a total of 1,947 cancer-diagnosed and presumably cancer-free dogs were used to validate test performance for the detection of 7 predefined cancer types (lymphoma, hemangiosarcoma, osteosarcoma, leukemia, histiocytic sarcoma, primary lung tumors, and urothelial carcinoma), using independent training and testing sets. METHODS: Cell-free DNA quantification data from all samples were analyzed using a proprietary machine learning algorithm to determine a Cancer Probability Index (High, Moderate, or Low). High and Low Probability of Cancer were final result classifications. Moderate cases were additionally analyzed by NGS to arrive at a final classification of High Probability of Cancer (Cancer Signal Detected) or Low Probability of Cancer (Cancer Signal Not Detected). RESULTS: Of the 595 dogs in the testing set, 89% (n = 530) received a High or Low Probability result based on the machine learning algorithm; 11% (65) were Moderate Probability, and NGS results were used to assign a final classification. Overall, 87 of 122 dogs with the 7 predefined cancer types were classified as High Probability and 467 of 473 presumably cancer-free dogs were classified as Low Probability, corresponding to a sensitivity of 71.3% for the predefined cancer types at a specificity of 98.7%. CLINICAL RELEVANCE: This integrated test offers a novel option to screen for cancer types that may be difficult to detect by physical examination at a dog's wellness visit.

Next-generation sequencing-based liquid biopsy may be used for detection of residual disease and cancer recurrence monitoring in dogs.

OBJECTIVE: The purpose of this study was to evaluate the performance of a next-generation sequencing-based liquid biopsy test for cancer monitoring in dogs. SAMPLES: Pre- and postoperative blood samples were collected from dogs with confirmed cancer diagnoses originally enrolled in the CANcer Detection in Dogs (CANDiD) study. A subset of dogs also had longitudinal blood samples collected for recurrence monitoring. METHODS: All cancer-diagnosed patients had a preoperative blood sample in which a cancer signal was detected and had at least 1 postoperative sample collected. Clinical data were used to assign a clinical disease status for each follow-up visit. RESULTS: Following excisional surgery, in the absence of clinical residual disease at the postoperative visit, patients with Cancer Signal Detected results at that visit were 1.94 times as likely (95% CI, 1.21 to 3.12; P = .013) to have clinical recurrence within 6 months compared to patients with Cancer Signal Not Detected results. In the subset of patients with longitudinal liquid biopsy samples that had clinical recurrence documented during the study period, 82% (9/11; 95% CI, 48% to 97%) had Cancer Signal Detected in blood prior to or concomitant with clinical recurrence; in the 6 patients where molecular recurrence was detected prior to clinical recurrence, the median lead time was 168 days (range, 47 to 238). CLINICAL RELEVANCE: Next-generation sequencing-based liquid biopsy is a noninvasive tool that may offer utility as an adjunct to current standard-of-care clinical assessment for cancer monitoring; further studies are needed to confirm diagnostic accuracy in a larger population.

Age at cancer diagnosis by breed, weight, sex, and cancer type in a cohort of more than 3,000 dogs: Determining the optimal age to initiate cancer screening in canine patients.

The goal of cancer screening is to detect disease at an early stage when treatment may be more effective. Cancer screening in dogs has relied upon annual physical examinations and routine laboratory tests, which are largely inadequate for detecting preclinical disease. With the introduction of non-invasive liquid biopsy cancer detection methods, the discussion is shifting from how to screen dogs for cancer to when to screen dogs for cancer. To address this question, we analyzed data from 3,452 cancer-diagnosed dogs to determine the age at which dogs of certain breeds and weights are typically diagnosed with cancer. In our study population, the median age at cancer diagnosis was 8.8 years, with males diagnosed at younger ages than females, and neutered dogs diagnosed at significantly later ages than intact dogs. Overall, weight was inversely correlated with age at cancer diagnosis, and purebred dogs were diagnosed at significantly younger ages than mixed-breed dogs. For breeds represented by ≥10 dogs, a breed-based median age at diagnosis was calculated. A weight-based linear regression model was developed to predict the median age at diagnosis for breeds represented by ≤10 dogs and for mixed-breed dogs. Our findings, combined with findings from previous studies which established a long duration of the preclinical phase of cancer development in dogs, suggest that it might be reasonable to consider annual cancer screening starting 2 years prior to the median age at cancer diagnosis for dogs of similar breed or weight. This logic would support a general recommendation to start cancer screening for all dogs at the age of 7, and as early as age 4 for breeds with a lower median age at cancer diagnosis, in order to increase the likelihood of early detection and treatment.

Detection of Age-Related Somatic Alterations in Canine Blood Using Next-Generation Sequencing-Based Liquid Biopsy: An Analysis of over 4800 Dogs.

Age-related somatic genomic alterations in hematopoietic cell lines have been well characterized in humans; however, this phenomenon has not been well studied in other species. Next-generation sequencing-based liquid biopsy testing for cancer detection was recently developed for dogs and has been used to study the genomic profiles of blood samples from thousands of canine patients since 2021. In this study, 4870 client-owned dogs with and without a diagnosis or suspicion of cancer underwent liquid biopsy testing by this method. Copy number variants detected exclusively in genomic DNA derived from white blood cells (WBC gDNA-specific CNVs) were observed in 126 dogs (2.6%; 95% CI: 2.2-3.1); these copy number variants were absent from matched plasma cell-free DNA, and from tumor tissue in dogs with concurrent cancer. These findings were more common in older dogs and were persistent in WBC gDNA in over 70% of patients, with little to no change in the amplitude of the signal across longitudinal samples. Many of these alterations were observed at recurrent locations in the genome across subjects; the most common finding was a partial loss on CFA25, typically accompanied by a partial gain on the same chromosome. These early findings suggest that age-related somatic alterations may be present at an appreciable frequency in the general canine population. Further research is needed to determine the clinical significance of these findings.

Cancer detection in clinical practice and using blood-based liquid biopsy: A retrospective audit of over 350 dogs.

BACKGROUND: Guidelines-driven screening protocols for early cancer detection in dogs are lacking, and cancer often is detected at advanced stages. HYPOTHESIS/OBJECTIVES: To examine how cancer typically is detected in dogs and whether the addition of a next-generation sequencing-based "liquid biopsy" test to a wellness visit has the potential to enhance cancer detection. ANIMALS: Client-owned dogs with definitive cancer diagnoses enrolled in a clinical validation study for a novel blood-based multicancer early detection test. METHODS: Retrospective medical record review was performed to establish the history and presenting complaint that ultimately led to a definitive cancer diagnosis. Blood samples were subjected to DNA extraction, library preparation, and next-generation sequencing. Sequencing data were analyzed using an internally developed bioinformatics pipeline to detect genomic alterations associated with the presence of cancer. RESULTS: In an unselected cohort of 359 cancer-diagnosed dogs, 4% of cases were detected during a wellness visit, 8% were detected incidentally, and 88% were detected after the owner reported clinical signs suggestive of cancer. Liquid biopsy detected disease in 54.7% (95% confidence interval [CI], 49.5%-59.8%) of patients, including 32% of dogs with early-stage cancer, 48% of preclinical dogs, and 84% of dogs with advanced-stage disease. CONCLUSIONS/CLINICAL IMPORTANCE: Most cases of cancer were diagnosed after the onset of clinical signs; only 4% of dogs had cancer detected using the current standard of care (i.e., wellness visit). Liquid biopsy has the potential to increase detection of cancer when added to a dog's wellness visit.

Clinical experience with next-generation sequencing-based liquid biopsy testing for cancer detection in dogs: a review of 1,500 consecutive clinical cases.

OBJECTIVE: To review ordering patterns, positivity rates, and outcome data for a subset of consecutive samples submitted for a commercially available, blood-based multicancer early-detection liquid biopsy test for dogs using next-generation sequencing at 1 laboratory. SAMPLE: 1,500 consecutively submitted blood samples from client-owned dogs with and without clinical suspicion and/or history of cancer for prospective liquid biopsy testing between December 28, 2021, and June 28, 2022. PROCEDURES: We performed a retrospective observational study, reviewing data from 1,500 consecutive clinical samples submitted for liquid biopsy testing. Outcome data were obtained via medical record review, direct communication with the referring clinic, and/or a patient outcome survey through October 16, 2022. RESULTS: Sixty-four percent (910/1,419) of reportable samples were submitted for cancer screening, 26% (366/1,419) for aid in diagnosis, and 10% (143/1,419) for other indications. The positivity rate was 25.4% (93/366) in aid-in-diagnosis patients and 4.5% (41/910) in screening patients. Outcome data were available for 33% (465/1,401) of patients, and outcomes were classifiable for 428 patients. The relative observed sensitivity was 61.5% (67/109) and specificity was 97.5% (311/319). The positive predictive value was 75.0% (21/28) for screening patients and 97.7% (43/44) for aid-in-diagnosis patients, and the time to diagnostic resolution following a positive result was < 2 weeks in most cases. CLINICAL RELEVANCE: Liquid biopsy using next-generation sequencing represents a novel tool for noninvasive detection of cancer in dogs. Real-world clinical performance meets or exceeds expectations established in the test's clinical validation study.

Blood-Based Liquid Biopsy for Comprehensive Cancer Genomic Profiling Using Next-Generation Sequencing: An Emerging Paradigm for Non-invasive Cancer Detection and Management in Dogs.

This proof-of-concept study demonstrates that blood-based liquid biopsy using next generation sequencing of cell-free DNA can non-invasively detect multiple classes of genomic alterations in dogs with cancer, including alterations that originate from spatially separated tumor sites. Eleven dogs with a variety of confirmed cancer diagnoses (including localized and disseminated disease) who were scheduled for surgical resection, and five presumably cancer-free dogs, were enrolled. Blood was collected from each subject, and multiple spatially separated tumor tissue samples were collected during surgery from 9 of the cancer subjects. All samples were analyzed using an advanced prototype of a novel liquid biopsy test designed to non-invasively interrogate multiple classes of genomic alterations for the detection, characterization, and management of cancer in dogs. In five of the nine cancer patients with matched tumor and plasma samples, pre-surgical liquid biopsy testing identified genomic alterations, including single nucleotide variants and copy number variants, that matched alterations independently detected in corresponding tumor tissue samples. Importantly, the pre-surgical liquid biopsy test detected alterations observed in spatially separated tissue samples from the same subject, demonstrating the potential of blood-based testing for comprehensive genomic profiling of heterogeneous tumors. Among the three patients with post-surgical blood samples, genomic alterations remained detectable in one patient with incomplete tumor resection, suggesting utility for non-invasive detection of minimal residual disease following curative-intent treatment. Liquid biopsy allows for non-invasive profiling of cancer-associated genomic alterations with a simple blood draw and has potential to overcome the limitations of tissue-based testing posed by tissue-level genomic heterogeneity.

Genome-wide Sequencing of Cell-free DNA Enables Detection of Copy-number Alterations in Patients with Cancer Where Tissue Biopsy is Not Feasible.

When tissue biopsy is not medically prudent or tissue is insufficient for molecular testing, alternative methods are needed. Because cell-free DNA (cfDNA) has been shown to provide a representative surrogate for tumor tissue, we sought to evaluate its utility in this clinical scenario. cfDNA was isolated from the plasma of patients and assayed with low-coverage (∼0.3×), genome-wide sequencing. Copy-number alterations (CNA) were identified and characterized using analytic methods originally developed for noninvasive prenatal testing (NIPT) and quantified using the genomic instability number (GIN), a metric that reflects the quantity and magnitude of CNAs across the genome. The technical variability of the GIN was first evaluated in an independent cohort comprising genome-wide sequencing results from 27,754 women who consented to have their samples used for research and whose NIPT results yielded no detected CNAs to establish a detection threshold. Subsequently, cfDNA sequencing data from 96 patients with known cancers but for whom a tissue biopsy could not be obtained are presented. An elevated GIN was detected in 35% of patients and detection rates varied by tumor origin. Collectively, CNAs covered 96.6% of all autosomes. Survival was significantly reduced in patients with an elevated GIN relative to those without. Overall, these data provide a proof of concept for the use of low-coverage, genome-wide sequencing of cfDNA from patients with cancer to obtain relevant molecular information in instances where tissue is difficult to access. These data may ultimately serve as an informative complement to other molecular tests.

Horizons in Veterinary Precision Oncology: Fundamentals of Cancer Genomics and Applications of Liquid Biopsy for the Detection, Characterization, and Management of Cancer in Dogs.

Cancer is the leading cause of death in dogs, in part because many cases are identified at an advanced stage when clinical signs have developed, and prognosis is poor. Increased understanding of cancer as a disease of the genome has led to the introduction of liquid biopsy testing, allowing for detection of genomic alterations in cell-free DNA fragments in blood to facilitate earlier detection, characterization, and management of cancer through non-invasive means. Recent discoveries in the areas of genomics and oncology have provided a deeper understanding of the molecular origins and evolution of cancer, and of the "one health" similarities between humans and dogs that underlie the field of comparative oncology. These discoveries, combined with technological advances in DNA profiling, are shifting the paradigm for cancer diagnosis toward earlier detection with the goal of improving outcomes. Liquid biopsy testing has already revolutionized the way cancer is managed in human medicine - and it is poised to make a similar impact in veterinary medicine. Multiple clinical use cases for liquid biopsy are emerging, including screening, aid in diagnosis, targeted treatment selection, treatment response monitoring, minimal residual disease detection, and recurrence monitoring. This review article highlights key scientific advances in genomics and their relevance for veterinary oncology, with the goal of providing a foundational introduction to this important topic for veterinarians. As these technologies migrate from human medicine into veterinary medicine, improved awareness and understanding will facilitate their rapid adoption, for the benefit of veterinary patients.

Genome-Wide Sequencing of Cell-Free DNA Identifies Copy-Number Alterations That Can Be Used for Monitoring Response to Immunotherapy in Cancer Patients.

Inhibitors of the PD-1/PD-L1/CTLA-4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. We describe the use of low-coverage, genome-wide sequencing of cfDNA, validated extensively for noninvasive prenatal testing, to detect tumor-specific copy-number alterations, and the development of a new metric-the genome instability number (GIN)-to monitor response to these drugs. We demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease. Finally, we provide evidence for delayed kinetics in responses to checkpoint inhibitors relative to molecularly targeted therapies. Overall, these data demonstrate a proof of concept for using this method for monitoring treatment outcome in patients with cancer receiving immunotherapy.

Clinical and economic impact of falsely decreased calcium values caused by gadoversetamide interference.

OBJECTIVE: Gadolinium is administered as a contrast agent in MRI procedures. Two gadolinium-based contrast agents, gadodiamide and gadoversetamide, interfere with colorimetric total serum calcium methods. The purpose of this prospective observational study was to examine the incidence of calcium interference after gadoversetamide procedures, associated clinical outcomes, and costs 20 months after implementation of quality assurance and physician education programs. MATERIALS AND METHODS: Records of patients who received gadoversetamide from June 24, 2006, to October 7, 2006, were reviewed to determine if a routine calcium test had been performed after the injection. Calcium values were repeated with an alternate method that is less susceptible to gadoversetamide interference. If the difference was > or = 2.0 mg/dL or if the initial test value was < or = 7.0 mg/dL, patient charts were reviewed for any related treatment. Costs associated with this algorithm were tracked. RESULTS: The initial calcium test was performed after gadoversetamide in 766 of 3,439 instances. The alternate test was performed in 633 of 766. One hundred twenty-five of 633 (20%) showed a difference in calcium values that was > or = 0.7 mg/dL, with 16 showing differences of > or = 1.6 mg/dL. Chart review for 56 instances revealed that calcium supplements were administered in 22 of 56 around the time of gadoversetamide injection. However, none appeared to be related to the spurious hypocalcemia. The total additional cost (reagent and technologist) for following this algorithm for just over 3 months was $6,807. CONCLUSION: Approximately 20% of patients receiving gadoversetamide exhibited spurious hypocalcemia. No patients were identified who received inappropriate calcium because of this interference. This may be attributable to the quality assurance and physician education programs.

Algorithmic mechanism design for load balancing in distributed systems.

Computational grids are promising next-generation computing platforms for large-scale problems in science and engineering. Grids are large-scale computing systems composed of geographically distributed resources (computers, storage etc.) owned by self interested agents or organizations. These agents may manipulate the resource allocation algorithm in their own benefit, and their selfish behavior may lead to severe performance degradation and poor efficiency. In this paper, we investigate the problem of designing protocols for resource allocation involving selfish agents. Solving this kind of problems is the object of mechanism design theory. Using this theory, we design a truthful mechanism for solving the static load balancing problem in heterogeneous distributed systems. We prove that using the optimal allocation algorithm the output function admits a truthful payment scheme satisfying voluntary participation. We derive a protocol that implements our mechanism and present experiments to show its effectiveness.