Predictive Testing Research Articles

IDE-Net: Interactive Driving Event and Pattern Extraction From Human Data

Autonomous vehicles (AVs) need to share the road with multiple, heterogeneous road users in a variety of driving scenarios. It is overwhelming and unnecessary to carefully interact with all observed agents, and AVs need to determine whether and when to interact with each surrounding agent. In order to facilitate the design and testing of prediction and planning modules of AVs, in-depth understanding of interactive behavior is expected with proper representation, and events in behavior data need to be extracted and categorized automatically. Answers to what are the essential patterns of interactions are also crucial for these motivations in addition to answering whether and when . Thus, learning to extract interactive driving events and patterns from human data for tackling the whether-when-what tasks is of critical importance for AVs. There is, however, no clear definition and taxonomy of interactive behavior, and most of the existing works are based on either manual labelling or hand-crafted rules and features. In this letter, we propose the I nteractive D riving event and pattern E xtraction Net work (IDE-Net), which is a deep learning framework to automatically extract interaction events and patterns directly from vehicle trajectories. In IDE-Net, we leverage the power of multi-task learning and proposed three auxiliary tasks to assist the pattern extraction in an unsupervised fashion. We also design a unique spatial-temporal block to encode the trajectory data. Experimental results on the INTERACTION dataset verified the effectiveness of such designs in terms of better generalizability and effective pattern extraction. We find three interpretable patterns of interactions, bringing insights for driver behavior representation, modeling and comprehension. Both objective and subjective evaluation metrics are adopted in our analysis of the learned patterns.

Breast cancer in multiple endocrine neoplasia type 1 (MEN1).

SummaryA 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy).Learning pointsWe describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen.Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3.Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .

Modeling changes in land use using the integration of MLP-NN, CA-Markov models and GIS for settlement development in Tembalang District

The effects of dynamic land use change can be modeled by Artificial Neural Network (ANN) models with Multi-layer Perceptron (MLP) network architecture and backpropagation algorithms. The setting process and predictive capabilities testing will be generated by the models with a combination of MLP-NN, CA-Markov methods and Geographic Iinformation System (GIS) from several previous studies so the results is accurate. This study aims to analisys land use change in Tembalang District in 2010 as first period models, 2014 as period models, and land use in 2018 as validation data, make a model of land use change with ANN methods and projection land use in Tembalang District in 2026. CA-Markov models are used for future projections. In modeling land use change, several driving force variables are used, namely distance to roads, rivers, settlements, and population density. This research are using maps for 2010, 2014 and 2018 from digitization process of hight resolution satellite imagery and validation land use in the field. In this research, data on land use change from 2010 to 2018 is dominated by land use changes from vacant land to settlements and housing. Settlement increased by 2,13%, housing increased by 102,69%, and vacant land already allocate increased by 47,32% and vacant land decreased by -61,18%. The results of modeling validation have a Kappa index of 0.959, an the root mean square value is 2.579 m that means this value is accepted, and 85% of the area between the prediction map and the digitization map are said to be appropriate, so this model is classified as having very good similarities with existing land use conditions in 2018. Overall prediction results show that land suitability is 70.52% and 29.48% of land is not in accordance with Semarang City RTRW map for 2011-2031.

Public attitudes towards the genetic testing in Georgia.

The aim of this study is to assess attitudes towards genetic testing in Georgian public. We used a Likert-scale written questionnaire. The survey was completed by 480 respondents. A majority of respondents (75.3%) curious about predictive genetic testing and 40.6% of participants preferred to be tested only for disorders that are treatable or preventable. Approximately 65% of the participants would like to test their newborn children for late-onset disorders and undergo preconception carrier screening (73%). In addition, the majority (59%) of our respondents were not worried that genetic testing would further stigmatize people with disabilities. These results indicate that the respondents surveyed in our study may have placed particularly high importance on the availability of genetic testing and greatly valued access to genomic information.

#75: Microbial Cell-free DNA Sequencing for Prediction of Culture-Negative Infection Events in Children with Cancer

Abstract Background New culture-independent diagnostics are being investigated for diagnosis and prediction of infection. One method is microbial cell-free DNA sequencing (mcfDNA-seq), which can detect a wide range of pathogens directly from plasma. Immunocompromised children who develop febrile neutropenia (FN) without documented bloodstream infection (BSI) may have an undiagnosed bacterial infection, but identification of this subset is difficult. The percentage of episodes of FN caused by bacterial pathogens that did not grow in culture is unknown, as is the relative contribution of other specific etiologies such as viruses, fungi, immunotherapies, and immune reconstitution or graft vs. host disease. The value of mcfDNA-seq in FN patients is also unknown. As part of a larger study evaluating the ability of mcfDNA-seq to predict BSI in a cohort of pediatric patients with relapsed or refractory leukemia, we analyzed mcfDNA-seq results in a sample of cases of FN for which the definitive etiology was unknown. Methods Eligible participants were &amp;lt;25 years of age and undergoing treatment for cancer. Remnant plasma from clinical testing was prospectively obtained and stored. Samples collected on the day of onset of FN (Day 0) and the day prior (Day –1) underwent mcfDNA-seq by Karius Inc. in a CLIA and CAP-accredited laboratory. Pathogen detection results were reported in molecules per microliter (MPM) of plasma. Negative control samples from study participants without impending or recent fever or infection were also obtained. Testing was batched and blinded, so results were not clinically available. Results mcfDNA-seq results were obtained from eight episodes of FN in seven patients. Five episodes occurred in participants awaiting engraftment after HCT and three were receiving chemotherapy only. All participants receiving chemotherapy were receiving antibacterial prophylaxis with vancomycin and ciprofloxacin, antifungal prophylaxis with micafungin or voriconazole, and PJP prophylaxis with TMP-SMX or pentamidine. No HCT recipients were receiving antibacterial prophylaxis, but all received PJP prophylaxis, antifungal prophylaxis or treatment, and antiviral prophylaxis or treatment. Of 8 FN episodes, 4 (50%) had a common bacterial pathogen identified by mcfDNA-seq on Day 0 (Table 1). In 2 (50%) of these cases, the same organism was also identified on Day –1, at a lower concentration. One fungal pathogen was identified prior to and at the onset of FN. A common bacterial pathogen was identified in 3/64 (5%) control samples from the study population. Culture-negative sepsis was the final diagnosis in one episode; in this case, Streptococcus mitis, an important cause of sepsis in neutropenic patients, was identified in both Day 0 and Day –1 samples. In another episode where E. coli was identified, antibiotics were discontinued after 48 hours, but the patient was re-admitted within 24 hours for recurrent FN. Conclusions In this sample of culture-negative FN episodes in pediatric patients with relapsed or refractory leukemia, mcfDNA-seq identified a common bacterial pathogen in 50% of cases. The same organism was identifiable on the day prior to FN in 50% of cases, suggesting that predictive testing might be feasible. More data regarding sensitivity and specificity of mcfDNA-seq to diagnose and predict FN are needed.

Immune Checkpoint Inhibitors in Urothelial Carcinoma: Recommendations for Practical Approaches to PD-L1 and Other Potential Predictive Biomarker Testing

Simple SummaryThe predominant histologic type of bladder cancer is urothelial carcinoma (UC). Programmed cell death-ligand 1 (PD-L1) expression levels in UC tumors help clinicians determine which patients are more likely to respond to immuno-oncology (IO) therapies; as such, the harmonization of PD-L1 testing in evaluating patients is increasingly important. A series of international workshops, involving renowned pathologists and oncologists, were held to develop best practice approaches to PD-L1 testing in UC. It was agreed that robust control of analytical standards is required to obtain quality PD-L1 results and that interpretation and reporting of PD-L1 require clear inter-clinician communication. Recommendations for the best practices for PD-L1 testing in UC are provided. A PD-L1 test request form for pathology laboratories was also developed and included here, encouraging communication between clinicians and pathologists, and ensuring fast and high-quality test results. Novel biomarkers being evaluated for immuno-oncology agents in UC are also briefly discussed.Immuno-oncology (IO) agents (anti–programmed cell death 1 (PD-1) and anti–programmed cell death-ligand 1 (PD-L1)) are approved as first- and second-line treatments for metastatic UC. PD-L1 expression levels in UC tumors help clinicians determine which patients are more likely to respond to IO therapies. Assays for approved IO agents use different antibodies, immunohistochemical protocols, cutoffs (defining “high” vs. “low” PD-L1 expression), and scoring algorithms. The robust control of pre-analytical and analytical standards is needed to obtain high-quality PD-L1 results. To better understand the status and perspectives of biomarker-guided patient selection for anti–PD-1 and anti–PD-L1 agents in UC, three workshops were held from December 2018 to December 2019 in Italy, Malaysia, and Spain. The primary goal was to develop recommendations for best practice approaches to PD-L1 testing in UC. Recommendations pertaining to the interpretation and reporting of the results of PD-L1 assays from experienced pathologists and oncologists from around the globe are included. A test request form for pathology laboratories was developed as a critical first step for oncologists/urologists to encourage communication between clinicians and pathologists, ensuring fast and high-quality test results. In this era of personalized medicine, we briefly discuss novel biomarkers being evaluated for IO agents in UC.

A distinct APC pathogenic germline variant identified in a southern Thai family with familial adenomatous polyposis

BackgroundFamilial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the APC gene. To date, multiple pathogenic variants in coding regions, splice sites, and deep intronic regions have been revealed. However, there are still pathogenic variants that remain unidentified.MethodsTwenty-nine primer pairs flanking exons 2–16 (i.e., coding exons 1–15) of APC and their exon–intron junctions were used for germline pathogenic variant screening in Southern Thai patients with familial adenomatous polyposis (FAP). Transcription analysis was performed to confirm the pathogenicity of a splice site deletion of intron 10. Family members were interviewed for clinical histories. Blood samples were collected from 18 family members for a segregation study. Subsequently, clinical data of affected members were collected from the hospital databases.ResultsWe found a distinct heterozygous 16-bp deletion at the splice donor site of intron 10 leading to a skipping of exon 10 which was confirmed by transcript analysis (APC: c 1312 + 4_1312 + 19del, r.934_1312del). Predictive testing for the pathogenic APC variant in 18 of the proband’s family members (ten healthy and eight affected) from three generations showed the same heterozygous germline pathogenic variant in eight affected adult members (15–62 years old) and two children (7 and 10 years old). Seven of the ten carriers of the disease-causing variant had undergone colonoscopy, and colonic polyps were found in all cases, which confirmed the segregation of the inherited pathogenic variant. The phenotypic spectrum was found to vary within the family; and some affected family members exhibited extracolonic manifestations.ConclusionsTo our knowledge, the pathogenic APC variant, c.1312 + 4_1312 + 19del, r.934_1312del, has not previously been reported. This study is one of the few reports describing the phenotypic consequences of a pathogenic APC variant in a high number of affected family members.

FRAGSITE: A Fragment-Based Approach for Virtual Ligand Screening.

To reduce time and cost, virtual ligand screening (VLS) often precedes experimental ligand screening in modern drug discovery. Traditionally, high-resolution structure-based docking approaches rely on experimental structures, while ligand-based approaches need known binders to the target protein and only explore their nearby chemical space. In contrast, our structure-based FINDSITEcomb2.0 approach takes advantage of predicted, low-resolution structures and information from ligands that bind distantly related proteins whose binding sites are similar to the target protein. Using a boosted tree regression machine learning framework, we significantly improved FINDSITEcomb2.0 by integrating ligand fragment scores as encoded by molecular fingerprints with the global ligand similarity scores of FINDSITEcomb2.0. The new approach, FRAGSITE, exploits our observation that ligand fragments, e.g., rings, tend to interact with stereochemically conserved protein subpockets that also occur in evolutionarily unrelated proteins. FRAGSITE was benchmarked on the 102 protein DUD-E set, where any template protein whose sequence identify >30% to the target was excluded. Within the top 100 ranked molecules, FRAGSITE improves VLS precision and recall by 14.3 and 18.5%, respectively, relative to FINDSITEcomb2.0. Moreover, the mean top 1% enrichment factor increases from 25.2 to 30.2. On average, both outperform state-of-the-art deep learning-based methods such as AtomNet. On the more challenging unbiased set LIT-PCBA, FRAGSITE also shows better performance than ligand similarity-based and docking approaches such as two-dimensional ECFP4 and Surflex-Dock v.3066. On a subset of 23 targets from DEKOIS 2.0, FRAGSITE shows much better performance than the boosted tree regression-based, vScreenML scoring function. Experimental testing of FRAGSITE's predictions shows that it has more hits and covers a more diverse region of chemical space than FINDSITEcomb2.0. For the two proteins that were experimentally tested, DHFR, a well-studied protein that catalyzes the conversion of dihydrofolate to tetrahydrofolate, and the kinase ACVR1, FRAGSITE identified new small-molecule nanomolar binders. Interestingly, one new binder of DHFR is a kinase inhibitor predicted to bind in a new subpocket. For ACVR1, FRAGSITE identified new molecules that have diverse scaffolds and estimated nanomolar to micromolar affinities. Thus, FRAGSITE shows significant improvement over prior state-of-the-art ligand virtual screening approaches. A web server is freely available for academic users at http:/sites.gatech.edu/cssb/FRAGSITE.

Germline FFPE inherited cancer panel testing in deceased family members: implications for clinical management of unaffected relatives

Where previously, germline genetic testing in deceased affected relatives was not possible due to the absence of lymphocytic DNA, the North-West-Genomic-Laboratory Hub (NWGLH) has developed and validated next-generation sequencing based gene panels utilising formalin-fixed-paraffin-embedded (FFPE) tissue DNA from deceased individuals. This technology has been utilised in the clinical setting for the management of unaffected relatives seen in the Clinical Genetics Service (CGS). Here we assess the clinical impact. At the time of data collection, the NWGLH had analysed 180 FFPE tissue samples from deceased affected individuals: 134 from breast and/or ovarian cancer cases for germline variants in the BRCA1/BRCA2 genes and 46 from colorectal, gastric, ovarian and endometrial cancer cases for germline variants in a panel of 13 genes implicated in inherited colorectal cancer and gastric cancer conditions. Successful analysis was achieved in 140/180 cases (78%). In total, 29 germline pathogenic/likely pathogenic variants were identified in autosomal dominant cancer predisposition genes where the gene was pertinent to the cancer family history (including BRCA1/BRCA2, the mismatch-repair genes and APC). Of the 180 cases, the impact of the result on clinical management of unaffected relatives was known in 143 cases. Of these, the results in 54 cases (38%) directly impacted the clinical management of relatives seen by the CGS. This included changes to risk assessments, screening recommendations and the availability of predictive genetic testing to unaffected relatives. Our data demonstrate how FFPE testing in deceased relatives is an accurate and informative tool in the clinical management of patients referred to the CGS.

Genetic counseling and testing practices for late-onset neurodegenerative disease: a systematic review.

ObjectiveTo understand contemporary genetic counseling and testing practices for late-onset neurodegenerative diseases (LONDs), and identify whether practices address the internationally accepted goals of genetic counseling: interpretation, counseling, education, and support.MethodsFour databases were systematically searched for articles published from 2009 to 2020. Peer-reviewed research articles in English that reported research and clinical genetic counseling and testing practices for LONDs were included. A narrative synthesis was conducted to describe different practices and map genetic counseling activities to the goals. Risk of bias was assessed using the Qualsyst tool. The protocol was registered with PROSPERO (CRD42019121421).ResultsSixty-one studies from 68 papers were included. Most papers focused on predictive testing (58/68) and Huntington’s disease (41/68). There was variation between papers in study design, study population, outcomes, interventions, and settings. Although there were commonalities, novel and inconsistent genetic counseling practices were identified. Eighteen papers addressed all four goals of genetic counseling.ConclusionContemporary genetic counseling and testing practices for LONDs are varied and informed by regional differences and the presence of different health providers. A flexible, multidisciplinary, client- and family-centered care continues to emerge. As genetic testing becomes a routine part of care for patients (and their relatives), health providers must balance their limited time and resources with ensuring clients are safely and effectively counseled, and all four genetic counseling goals are addressed. Areas of further research include diagnostic and reproductive genetic counseling/testing practices, evaluations of novel approaches to care, and the role and use of different health providers in practice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-021-10461-5.

Simple tests for stock return predictability with good size and power properties

We develop easy-to-implement tests for return predictability which, relative to extant tests in the literature, display attractive finite sample size control and power across a wide range of persistence and endogeneity levels for the predictor. Our approach is based on the standard regression t-ratio and a variant where the predictor is quasi-GLS (rather than OLS) demeaned. In the strongly persistent near-unit root environment, the limiting null distributions of these statistics depend on the endogeneity and local-to-unity parameters characterising the predictor. Analysis of the asymptotic local power functions of feasible implementations of these two tests, based on asymptotically conservative critical values, motivates a switching procedure between the two, employing the quasi-GLS demeaned variant unless the magnitude of the estimated endogeneity correlation parameter is small. Additionally, if the data suggests the predictor is weakly persistent, our approach switches to the standard t-ratio test with reference to standard normal critical values.

Surveillance life and the shaping of ‘genetically at risk’ chronicities in Denmark

Today, in the field of hereditary colorectal cancer in Denmark, more than 40,000 identified healthy individuals with an increased risk of cancer are enrolled in a surveillance program aimed at preventing cancer from developing, with numbers still growing. What this group of healthy individuals has in common is lifelong regular interaction with a healthcare system that has traditionally been geared towards treating the acutely and chronically ill. In this article, we explore how people living with an inherited elevated risk of colorectal cancer orient themselves towards their families’ and their own predispositions as well as the lifelong surveillance trajectories that they have embarked upon – what we call surveillance life. Unlike prior critiques of predictive genetic testing as generative of ‘pre-patients’ or ‘pre-symptomatically ill’, we suggest that for those enrolled in lifelong surveillance programmes in welfare state Denmark, the relevance of risk fluctuates according to certain moments in life, e.g. at family reunions, when a close relative falls ill, in the time leading up to a surveillance colonoscopy or when enduring the procedures themselves. As such, rather than characterising surveillance life in terms of ‘living with chronic risk’ we show how ‘genetically at risk’ chronicities take shape as persons come to terms with a disease that possibly awaits them leading them to recalibrate familial bonds and responsibilities while leading lives punctuated by regular medical check-ups.

Clinicopathological and molecular characterization of Brazilian families at risk for Lynch syndrome

Lynch syndrome (LS), is the most common hereditary colorectal cancer syndrome. However, it is poorly characterized in Brazil. Therefore, we aimed to determine the spectrum of pathogenic variants in Mismatch Repair (MMR) genes and investigate the MLH1 promotor methylation role as a second hit in LS tumors. Tumor screening through microsatellite instability and immunohistochemistry for MMR proteins was performed in 323 cases who met clinical criteria. BRAF-V600E and MLH1 promoter methylation were analyzed for all MLH1-deficient tumors. Patients with MMR deficient tumor proceeded to germline genetic testing. MMR deficient tumors were detected in 41% of patients recruited. About half of patients carried a pathogenic germline variant. Two recurrent variants in MLH1 and three novel pathogenic variants were identified. Furthermore, pathogenic germline variants with concomitant somatic MLH1 hypermethylation were found in 6% of cases. Predictive genetic testing was offered to 387 relatives. Overall, 127 tumors were diagnosed in 100 LS patients, from 62 unrelated families. Our molecular data provide new information about the spectrum of MMR mutations, which contributes to a better characterization of LS in Brazil. Furthermore, we call attention to the possibility of failure in the diagnosis of germline MLH1 mutation carriers when somatic MLH1 hypermethylation is used to rule out LS.

Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer

BackgroundLynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today’s clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance.MethodsThis was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994–September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation.ResultsA total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time.ConclusionA high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

Generating the American Shoulder and Elbow Surgeons Score Using Multivariable Predictive Models and Computer Adaptive Testing to Reduce Survey Burden

Background: The preferred patient-reported outcome measure for the assessment of shoulder conditions continues to evolve. Previous studies correlating the Patient-Reported Outcomes Measurement Information System (PROMIS) computer adaptive tests (CATs) to the American Shoulder and Elbow Surgeons (ASES) score have focused on a singular domain (pain or physical function) but have not evaluated the combined domains of pain and physical function that compose the ASES score. Additionally, previous studies have not provided a multivariable prediction tool to convert PROMIS scores to more familiar legacy scores. Purpose: To establish a valid predictive model of ASES scores using a nonlinear combination of PROMIS domains for physical function and pain. Study Design: Cohort study (Diagnosis); Level of evidence, 3. Methods: The Military Orthopaedics Tracking Injuries and Outcomes Network (MOTION) database is a prospectively collected repository of patient-reported outcomes and intraoperative variables. Patients in MOTION research who underwent shoulder surgery and completed the ASES, PROMIS Physical Function, and PROMIS Pain Interference at varying time points were included in the present analysis. Nonlinear multivariable predictive models were created to establish an ASES index score and then validated using “leave 1 out” techniques and minimal clinically important difference /substantial clinical benefit (MCID/SCB) analysis. Results: A total of 909 patients completed the ASES, PROMIS Physical Function, and PROMIS Pain Interference at presurgery, 6 weeks, 6 months, and 1 year after surgery, providing 1502 complete observations. The PROMIS CAT predictive model was strongly validated to predict the ASES (Pearson coefficient = 0.76-0.78; R2 = 0.57-0.62; root mean square error = 13.3-14.1). The MCID/SCB for the ASES was 21.7, and the best ASES index MCID/SCB was 19.4, suggesting that the derived ASES index is effective and can reliably re-create ASES scores. Conclusion: The PROMIS CAT predictive models are able to approximate the ASES score within 13 to 14 points, which is 7 points more accurate than the ASES MCID/SCB derived from the sample. Our ASES index algorithm, which is freely available online (https://osf.io/ctmnd/), has a lower MCID/SCB than the ASES itself. This algorithm can be used to decrease patient survey burden by 11 questions and provide a reliable ASES analog to clinicians.

Predictive Genetic Testing by the U.S. Military: Legal and Ethical Issues.

Precision medicine is a significant component of the military medical vanguard. One area of growing interest involves predictive genetic testing (PGT)-which can be used for both medical evaluation and operational planning. Predictive genetic testing is likely to play an increasingly important role in the military, in terms of both medically related testing to predict the risk of disease or injury and testing for non-medical traits that may be relevant to military performance. This article describes predictive tests that currently are in use by the military or that might be of interest to the military. The article also explores the risks and benefits associated with PGTs, describes the ambiguities in the current laws and directives governing the military use of PGT, and proposes a set of guidelines for the use of PGTs by the military. There is no publicly available law or DoD policy that prevents the military from conducting PGT before or after accession. Currently, the only genetic testing routinely employed by the U.S. military is for medical purposes. In addition to non-routine genetic testing to diagnose genetic diseases and conditions, the military also uses targeted testing for predictive purposes. As additional predictive genetic tests are developed and become widely used, the military can be expected to employ those that are of relevance. Predictive military genetic testing of active duty service members could reduce their risk of illness and injury, improve their physical and mental fitness, enhance the health and well-being of the unit, make mission accomplishment more certain and efficient, and reduce medical and other costs for the military and veterans. Moreover, individuals with genetic variants that might enhance the likelihood of successfully completing a military mission could be preferred for certain positions or assignments, such as special operations. At the same time, there are risks that genetic information may be used for improper purposes or may stigmatize service members. Predictive genetic testing is likely to play an increasingly important role in the military, in terms of both medically related testing to predict the risk of disease or injury and testing for non-medical traits that may be relevant to military performance. In instances where PGT meets standard scientific measures of validity and utility, test results can be used to promote the health and welfare of individual service members, units, and military missions. In cases where PGT does not rise to the level of meeting standard scientific criteria, officials should proceed cautiously in incorporating the information into clinical care and military decision-making. There needs to be an appropriate method of collectively calculating risks and benefits. Moreover, although military directives prohibit "unlawful discrimination," this term has received no elaboration in any publicly available military pronouncements. This lacuna should be rectified to provide proper guidance to service members, medical personnel, and the public. Although the promise of PGT may compel military officials to consider ways to maximize the use of test results, the risk of undermining military goals with unverified uses also should be considered appropriately.

Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations.

Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.

Cases in Precision Medicine: Genetic Testing to Predict Future Risk for Disease in a Healthy Patient.

Genetic testing is performed more routinely in clinical practice, and direct-to-consumer tests are widely available. It has obvious appeal as a preventive health measure. Clinicians and their healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. Despite demonstrated utility for diagnosis in the setting of many diseases, genetic testing still has many limitations as a predictive tool for healthy persons. This article uses a hypothetical case to review key considerations for predictive genetic testing.

Lynch syndrome and Muir-Torre phenotype associated with a recurrent variant in the 3’UTR of the MSH6 gene

A MSH6 3’UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome. This variant, which is very rare in the genomic databases, was absent in healthy controls and strongly segregated with the disease in the studied pedigrees. All tumors were defective for MSH2/MSH6/MSH3 proteins expression, but only MSH2 somatic pathogenic mutations were found in 5 of the 12 sequenced tumors. Moreover, we had no evidence of MSH6 transcript decrease in carriers, whereas MSH2 transcript was downregulated. Additional evaluations performed in representative carriers, including karyotype, arrayCGH and Linked-Reads whole genome sequencing, failed to evidence any MSH2 germline pathogenic variant. Posterior probability of pathogenicity for MSH6 c.*23_26dup was obtained from a multifactorial analysis incorporating segregation and phenotypic data and resulted >0.999, allowing to classify the variant as pathogenic (InSiGHT Class 5). Carriers shared a common haplotype involving MSH2/MSH6 loci, then a cryptic disease-associated variant, linked with MSH6 c.*23_26dup, cannot be completely excluded. Even if it is not clear whether the MSH6 variant is pathogenic per se or simply a marker of a disease-associated MSH2/MSH6 haplotype, all data collected on patients and pedigrees prompted us to manage the variant as pathogenic and to offer predictive testing within these families.

Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective.

Diagnostic germline RET analysis is offered to all patients with a diagnosis of medullary thyroid carcinoma (MTC), or other conditions associated with multiple endocrine neoplasia type 2 (MEN2) in the United Kingdom. Here, we report the experience of a single centre's germline RET analysis over a 21-year period. Retrospective case-note review. All index patients referred to the Exeter Genomics Laboratory for diagnostic germline RET analysis between 1997 and 2018, and unaffected family members, undergoing predictive testing. The rate and nature of pathogenic variant detection were recorded, as well as the indication for testing. 1,058 index patients and 551 unaffected family members were tested. The overall rate of pathogenic variant detection was 10.2% amongst index patients and 29% amongst unaffected family members. The commonest indication was isolated MTC, and amongst the 690 patients with isolated MTC, 68 (9.9%) were found to harbour a RET pathogenic variant. Of those with presumed sporadic MTC, 8.5% were found to harbour germline RET pathogenic variants, compared with 36.4% of those with a family history of MEN2-associated conditions. Pathogenic variants were identified in 3.6% and 0% of patients with isolated phaeochromocytoma and primary hyperparathyroidism, respectively. Although the detection rate of RET germline pathogenic variants in patients with presumed sporadic MTC was significant, the overall detection rate in those with MTC was lower than expected in this series. Advances in RET analysis in response to reports of new variants over the last two decades are likely to have improved the pick-up rate in recent years.