Emerging biomarkers for non-invasive diagnosis and treatment of cancer: a systematic review.

Cancer remains a global health challenge, necessitating continuous advancements in diagnostic and treatment strategies. This review focuses on the utility of non-invasive biomarkers in cancer diagnosis and treatment, their role in early detection, disease monitoring, and personalized therapeutic interventions. Through a systematic review of the literature, we identified 45 relevant studies that highlight the potential of these biomarkers across various cancer types, such as breast, prostate, lung, and colorectal cancers. The non-invasive biomarkers discussed include liquid biopsies, epigenetic markers, non-coding RNAs, exosomal cargo, and metabolites. Notably, liquid biopsies, particularly those based on circulating tumour DNA (ctDNA), have emerged as the most promising method for early, non-invasive cancer detection due to their ability to provide comprehensive genetic and epigenetic information from easily accessible blood samples. This review demonstrates how non-invasive biomarkers can facilitate early cancer detection, accurate subtyping, and tailored treatment strategies, thereby improving patient outcomes. It underscores the transformative potential of non-invasive biomarkers in oncology, highlighting their application for enhancing early detection, survival rates, and treatment precision in cancer care. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023474749 PROSPERO, identifier CRD42023474749.

Clinical utility of a rapid two-dimensional balanced steady-state free precession sequence with deep learning reconstruction.

BACKGROUND: Cardiovascular magnetic resonance (CMR) cine imaging is still limited by long acquisition times. This study evaluated the clinical utility of an accelerated two-dimensional (2D) cine sequence with deep learning reconstruction (Sonic DL) to decrease acquisition time without compromising quantitative volumetry or image quality. METHODS: A sub-study using 16 participants was performed using Sonic DL at two different acceleration factors (8× and 12×). Quantitative left-ventricular volumetry, function, and mass measurements were compared between the two acceleration factors against a standard cine method. Following this sub-study, 108 participants were prospectively recruited and imaged using a standard cine method and the Sonic DL method with the acceleration factor that more closely matched the reference method. Two experienced clinical readers rated images based on their diagnostic utility and performed all image contouring. Quantitative contrast difference and endocardial border sharpness were also assessed. Left- and right-ventricular volumetry, left-ventricular mass, and myocardial strain measurements were compared between cine methods using Bland-Altman plots, Pearson's correlation, and paired t-tests. Comparative analysis of image quality was measured using Wilcoxon-signed-rank tests and visualized using bar graphs. RESULTS: Sonic DL at an acceleration factor of 8 more closely matched the reference cine method. There were no significant differences found across left ventricular volumetry, function, or mass measurements. In contrast, an acceleration factor of 12 resulted in a 6% (5.51/90.16) reduction of measured ejection fraction when compared to the standard cine method and a 4% (4.32/88.98) reduction of measured ejection fraction when compared to Sonic DL at an acceleration factor of 8. Thus, Sonic DL at an acceleration factor of 8 was chosen for downstream analysis. In the larger cohort, this accelerated cine sequence was successfully performed in all participants and significantly reduced the acquisition time of cine images compared to the standard 2D method (reduction of 37% (5.98/16) p < 0.0001). Diagnostic image quality ratings and quantitative image quality evaluations were statistically not different between the two methods (p > 0.05). Left- and right-ventricular volumetry and circumferential and radial strain were also similar between methods (p > 0.05) but left-ventricular mass and longitudinal strain were over-estimated using the proposed accelerated cine method (mass over-estimated by 3.36 g/m2, p < 0.0001; longitudinal strain over-estimated by 1.97%, p = 0.001). CONCLUSION: This study found that an accelerated 2D cine method with DL reconstruction at an acceleration factor of 8 can reduce CMR cine acquisition time by 37% (5.98/16) without significantly affecting volumetry or image quality. Given the increase of scan time efficiency, this undersampled acquisition method using deep learning reconstruction should be considered for routine clinical CMR.

An original study assessing biomarker success rate in breast cancer recurrence biomarker research.

BACKGROUND: Breast cancer is the second most common cause of cancer mortality worldwide. Biomarker discovery has led to advances in understanding molecular phenotyping and thus has a great potential for precision management of this diverse disease. Despite increased interest in the biomarker field, only a small number of breast cancer biomarkers are known to be clinically useful. Therefore, it is very important to characterise the success rate of biomarkers in this field and study potential reasons for the deficit. We therefore aim to achieve quantitative characterisation of the biomarker translation gap by tracking the progress of prognostic biomarkers associated with breast cancer recurrence. METHODS: An electronic systematic search was conducted in Medline and Embase databases using keywords and mesh headings associated with breast cancer recurrence biomarkers (1940-2023). Abstracts were screened, and primary clinical studies involving breast cancer recurrence biomarkers were selected. Upon identification of relevant literature, we extracted the biomarker name, date of publication and journal name. All analyses were performed using IBM SPSS Statistics and GraphPad prism (La Jolla, California, USA). RESULTS: A total of 19,195 articles were identified, from which 4597 articles reported breast cancer biomarkers associated with recurrence. Upon data extraction, 2437 individual biomarkers were identified. Out of these, 23 are currently recommended for clinical use, which corresponds to only 0.94% of all discovered biomarkers. CONCLUSIONS: This study characterised for the first time the translational gap in the field of recurrence-related breast cancer biomarkers, indicating that only 0.94% of identified biomarkers were recommended for clinical use. This denotes an evident barrier in the biomarker research field and emphasises the need for a clearer route from biomarker discovery through to implementation.

On the Boundary of Exploratory Genomics and Translation in Sequential Glioblastoma.

OMICS methods brought significant advancements to the understanding of tumor cell biology, which transformed the treatment and prognosis of several cancers. Clinical practice and outcomes, however, changed significantly less in the case of glioblastoma (GBM). In this study, we aimed to assess the utility of whole exome (WES) sequencing in the clinical setting. Ten pairs of formalin-fixed, paraffin-embedded (FFPE) GBM specimens were obtained at onset (GBM-P) and at recurrence (GBM-R). Histopathological and molecular features of all samples supported the diagnosis of GBM based on WHO CNS5. WES data were filtered, applying a strict and custom-made pipeline, and occurrence of oncogenic and likely oncogenic variants in GBM-P, GBM-R or both were identified by using the VarSeq program version 2.5.0 (Golden Helix, Inc.). Characteristics and recurrence of the variants were analyzed in our own cohort and were also compared to those available in the COSMIC database. The lists of oncogenic and likely oncogenic variants corresponded to those identified in other studies. The average number of these variants were 4 and 5 out of all detected 24 and 34 variants in GBM-P and GBM-R samples, respectively. On average, one shared oncogenic/likely oncogenic variant was found in the pairs. We assessed the identified variants' therapeutic significance, also taking into consideration the guidelines by the Association for Molecular Pathology (AMP). Our data support that a thorough WES analysis is suitable for identifying oncogenic and likely oncogenic variants in an individual clinical sample or a small cohort of FFPE glioma specimens, which concur with those of comprehensive research studies. Such analyses also allow us to monitor molecular dynamics of sequential GBM. In addition, careful evaluation of data according to the AMP guideline reveal that though therapeutic applicability of the variants is generally limited in the clinic, such information may be valuable in selected cases, and can support innovative preclinical and clinical trials.

Applications of MRI in Schizophrenia: Current Progress in Establishing Clinical Utility.

Schizophrenia is a severe mental illness that significantly impacts the lives of affected individuals and with increasing mortality rates. Early detection and intervention are crucial for improving outcomes but the lack of validated biomarkers poses great challenges in such efforts. The use of magnetic resonance imaging (MRI) in schizophrenia enables the investigation of the disorder's etiological and neuropathological substrates in vivo. After decades of research, promising findings of MRI have been shown to aid in screening high-risk individuals and predicting illness onset, and predicting symptoms and treatment outcomes of schizophrenia. The integration of machine learning and deep learning techniques makes it possible to develop intelligent diagnostic and prognostic tools with extracted or selected imaging features. In this review, we aimed to provide an overview of current progress and prospects in establishing clinical utility of MRI in schizophrenia. We first provided an overview of MRI findings of brain abnormalities that might underpin the symptoms or treatment response process in schizophrenia patients. Then, we summarized the ongoing efforts in the computer-aided utility of MRI in schizophrenia and discussed the gap between MRI research findings and real-world applications. Finally, promising pathways to promote clinical translation were provided. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Case report: Early use of whole exome sequencing unveils HNRNPU-related neurodevelopmental disorder and answers additional clinical questions through reanalysis.

This case report chronicles the diagnostic odyssey and resolution of a 27-year-old female with a complex neurodevelopmental disorder (NDD) using Whole Exome Sequencing (WES). The patient presented to a precision medicine clinic with multiple diagnoses including intellectual disability, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), tics, seizures, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although this patient previously had chromosomal microarray and several single-gene tests, the underlying cause of this patient's symptoms remained elusive. WES revealed a pathogenic missense mutation in the HNRNPU gene, associated with HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) and developmental and epileptic encephalopathy-54 (DEE54, OMIM: # 617391). Following this diagnoses, other treating clinicians identified additional indications for genetic testing, however, as the WES data was readily available, the clinical team was able to re-analyze the WES data to address their inquiries without requiring additional tests. This emphasizes the pivotal role of WES in expediting diagnoses, reducing costs, and providing ongoing clinical utility throughout a patient's life. Accessible WES data in primary care settings can enhance patient care by informing future genetic inquiries, enhancing coordination of care, and facilitating precision medicine interventions, thereby mitigating the burden on families and the healthcare system.

The Impact of Polymerase Chain Reaction Urine Testing on Clinical Decision-Making in the Management of Complex Urinary Tract Infections.

While urinary polymerase chain reaction (PCR) testing is effective in organism identification in patients with complex urinary tract infections (cUTI), limited data exists on the clinical usefulness of this test. We serially surveyed physicians treating symptomatic patients with cUTI both at presentation and after PCR, and urine culture (UC) results were available to ascertain how the test results modified the therapy. A total of 96 unique surveys completed by 21 providers were included in the data analysis. The mean age for female and male patients was 69.4 ± 15.5 and 71.6 ± 12.7 years, respectively. The test positivity and line-item concordance for UC and PCR were consistent with prior reports. The PCR results modified or confirmed treatment in 59/96 (61.5%) and 25/96 (26.0%) of the cases, respectively, with 12/29 (41.4%) and 47/67 (70.1%) having negative and positive PCR results, respectively, resulting in treatment change (difference 28.7%, p < 0.01). Of these, 55/59 (57.3%) were alterations in the antibiotic regimen. PCR use to modify treatment was similar across providers and not statistically different when stratified by patient age, gender, or prior empiric therapy. In 31/59 (52.5%) of the cases, the PCR results modified the treatment where UC would not; conversely, UC would have modified the treatment in 3/37 (8.1%) of the cases where PCR did not (difference 44.4%, p < 0.01). We find that PCR test results are used by clinicians in managing cUTI, and use of this test provides an opportunity to improve antibiotic stewardship in this difficult-to-treat subset of patients.

Fit-for-Purpose Ki-67 Immunohistochemistry Assays for Breast Cancer.

New therapies are being developed for breast cancer, and in this process, some "old" biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory-developed tests (LDTs) of relevance for the LDTs' clinical utility. Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays with 32 cases and performed their in-house Ki-67 assays. The results were assessed using QuPath, an open-source software application for bioimage analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20%, and 30% cutoffs. Overall, PPA and NPA varied depending on the selected cutoff; participants were more successful with 5% and 10%, than with 20% and 30% cutoffs. Only 4 of 16 laboratories had robust IHC protocols with acceptable PPA for all cutoffs. The lowest PPA for the 5% cutoff was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cutoff was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%. Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cutoffs. The poor agreement was not due to the readout but rather due to IHC protocol conditions. International Ki-67 in Breast Cancer Working Group (IKWG) recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing.

The acceptability and clinical impact of using polygenic scores for risk-estimation of common cancers in primary care: a systematic review.

BACKGROUND: Polygenic scores (PGS) have been developed for cancer risk-estimation and show potential as tools to prompt earlier referral for high-risk individuals and aid risk-stratification within cancer screening programmes. This review explores the potential for using PGS to identify individuals at risk of the most common cancers seen in primary care. METHODS: Two electronic databases were searched up until November 2023 to identify quantitative, qualitative, and mixed methods studies that reported on the acceptability and clinical impact of using PGS to identify individuals at highest risk of breast, prostate, colorectal and lung cancer in primary care. The Mixed Methods Appraisal Tool (MMAT) was used to assess the quality of included studies and a narrative synthesis was used to analyse data. RESULTS: A total of 190 papers were identified, 18 of which were eligible for inclusion. A cancer risk-assessment tool incorporating PGS was acceptable to the general practice population and their healthcare providers but major challenges to implementation were identified, including lack of evidence for PGS in non-European ancestry and a need for healthcare provider education in genomic medicine. A PGS cancer risk-assessment had relatively limited impact on psychosocial outcomes and health behaviours. However, for prostate cancer, potential applications for its use in primary care were shown. CONCLUSIONS: Cancer risk assessment incorporating PGS in primary care is acceptable to patients and healthcare providers but there is a paucity of research exploring clinical impact. Few studies were identified, and more research is required before clinical implementation of PGS can be recommended.

A clinical impact study of dermatologists' use of diagnostic gene expression profile testing to guide patient management.

Aim: Cutaneous melanocytic neoplasms with diagnostic and/or clinical ambiguity pose patient management challenges. Methods: Six randomized case scenarios with diagnostic/clinical uncertainty were described with/without a benign or malignant diagnostic gene expression profile (GEP) result. Results: Clinical impact was assessed by reporting the mean increase/decrease of management changes normalized to baseline (n = 32 dermatologists). Benign GEP results prompted clinicians to decrease surgical margins (84.2%). Malignant GEP results escalated surgical excision recommendations (100%). A majority (72.2%) reduced and nearly all (98.9%) increased follow-up frequency for benign or malignant GEP results, respectively. There was an overall increase in management plan confidence with GEP results. Conclusion: Diagnostic GEP tests help guide clinical decision-making in a variety of diagnostically ambiguous or clinicopathologically discordant scenarios.

Dermatologists' use of diagnostic gene expression profiles for personalized patient care. When your doctor takes a piece of a mole, that mole is looked at under the microscope by a pathologist. The pathologist is responsible for figuring out if the mole is dangerous or not. Dangerous moles are removed with surgery to make sure all the dangerous tissue is gone. Moles without a health threat are left alone. Sometimes figuring out how dangerous a mole is is difficult. The pathologist may not provide the doctor with enough information for them to know how to treat your mole. There is a test that can provide information on whether your mole is unsafe. This test is called diagnostic gene expression profiling or GEP. In this study, GEP is used to help doctors figure out how to treat a mole and how often the patient should be seen in the office for skin checks. With GEP, important changes in patient treatment were identified. These include the need for an additional surgery, how much healthy tissue should be removed during surgery and how often the patient should be seen in the office. For suspicious moles where the pathology report is unclear, GEP can provide information that leads to more appropriate and personalized patient care.

Ancillary diagnostic gene expression profile testing for ambiguous cutaneous melanocytic lesions helps optimize dermatologist recommendations for excision margin and follow-up.

External Validation of the Kidney Failure Risk Equation Among Urban Community-Based Chinese Patients With CKD.

Rationale & Objective: The Kidney Failure Risk Equations have been proven to perform well in multinational databases, whereas validation in Asian populations is lacking. This study sought to externally validate the equations in a community-based chronic kidney disease cohort in China. Study Design: A retrospective cohort study. Setting & Participants: Patients with and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 dwelling in an industrialized coastal city of China. Exposure: Age, sex, eGFR, and albuminuria were included in the 4-variable model, whereas serum calcium, phosphate, bicarbonate, and albumin levels were added to the previously noted variables in the 8-variable model. Outcome: Initiation of long-term dialysis treatment. Analytical Approach: Model discrimination, calibration, and clinical utility were evaluated by Harrell's C statistic, calibration plots, and decision curve analysis, respectively. Results: A total of 4,587 participants were enrolled for validation of the 4-variable model, whereas 1,414 were enrolled for the 8-variable model. The median times of follow-up were 4.0 (interquartile range: 2.6-6.3) years for the 4-variable model and 3.4 (2.2-5.6) years for the 8-variable model. For the 4-variable model, the C statistics were 0.750 (95% CI: 0.615-0.885) for the 2-year model and 0.766 (0.625-0.907) for the 5-year model, whereas the values were 0.756 (0.629-0.883) and 0.774 (0.641-0.907), respectively, for the 8-variable model. Calibration was acceptable for both the 4-variable and 8-variable models. Decision curve analysis for the models at the 5-year scale performed better throughout different net benefit thresholds than the eGFR-based (<30 mL/min/1.73 m2) strategy. Limitations: A large proportion of patients lack albuminuria measurements, and only a subset of population could provide complete data for the 8-variable equation. Conclusions: The kidney failure risk equations showed acceptable discrimination and calibration and better clinical utility than the eGFR-based strategy for incidence of kidney failure among community-based urban Chinese patients with chronic kidney disease.

Accurate and reliable risk evaluation of chronic kidney disease (CKD) prognosis can be helpful for physicians to make decisions concerning treatment opportunity and therapeutic strategy. The kidney failure risk equation is an outstanding model for predicting risk of kidney failure among patients with CKD. However, the equation is lacking validation among Chinese populations. In the current study, we demonstrated that the equation had good discrimination among an urban community-based cohort of patients with CKD in China. The calibration was also acceptable. Decision curve analysis also showed that the equation performed better than a traditional kidney function-based strategy. The results provide the basis for using predictions derived from the kidney failure risk equation to improve the management of patients with CKD in community settings in China.

Clinical exome sequencing by general pediatricians: high clinical utility and no evidence of inappropriate testing.

Background: Genetic disorders account for a large percentage of admissions and outpatient visits to children's hospitals around the world. Clinical exome sequencing (CES) is a valuable diagnostic tool in the workup of these disorders; however, it is not routinely requested by general pediatricians. This may represent a missed opportunity to increase patient access to this powerful diagnostic tool. In our institution, general pediatricians can directly order CES. In this context, this study aims to evaluate the appropriateness of CES and its clinical utility when ordered by general pediatricians. Methods: We retrospectively reviewed all CES tests ordered by general pediatricians in our institution between 2019 and 2023 and recorded their indications and results. General pediatricians were interviewed to evaluate how CES impacted the domains of clinical utility by assessing changes in management, communication, subsequent testing, and counseling. In addition, feedback was obtained, and barriers faced by general pediatricians to order CES were assessed. Results: The study cohort (n = 30) included children from the inpatient (60%) and outpatient (40%) departments. A positive finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 11 of 30 cases (37%), while 3 (10%) and 16 (53%) received ambiguous (variant of uncertain significance) and negative results, respectively. The indication was deemed appropriate in all 30 cases (100%). Clinical utility was reported in all 11 positive cases (100%). Reproductive counseling is a notable utility in this highly consanguineous population, as all variants identified, in the 11 positive cases, were autosomal recessive. Conclusion: We show that CES ordered by general pediatricians is appropriately indicated and provides a diagnostic yield comparable to that requested by specialists. In addition, we note the high clinical utility of positive results as judged by the ordering pediatricians. The findings of this study can empower general pediatricians to advocate for expanded CES adoption to improve patient access and shorten their diagnostic odyssey.

Clinical Utility and Usability of the Digital Box and Block Test: Mixed Methods Study.

Background: The Box and Block Test (BBT) is a clinical tool used to measure hand dexterity, which is often used for tracking disease progression or the effectiveness of therapy, particularly benefiting older adults and those with neurological conditions. Digitizing the measurement of hand function may enhance the quality of data collection. We have developed and validated a prototype that digitizes this test, known as the digital BBT (dBBT), which automatically measures time and determines and displays the test result. Objective: This study aimed to investigate the clinical utility and usability of the newly developed dBBT and to collect suggestions for future improvements. Methods: A total of 4 occupational therapists participated in our study. To evaluate the clinical utility, we compared the dBBT to the BBT across dimensions such as acceptance, portability, energy and effort, time, and costs. We observed therapists using the dBBT as a dexterity measurement tool and conducted a quantitative usability questionnaire using the System Usability Scale (SUS), along with a focus group. Evaluative, structured, and qualitative content analysis was used for the qualitative data, whereas quantitative analysis was applied to questionnaire data. The qualitative and quantitative data were merged and analyzed using a convergent mixed methods approach. Results: Overall, the results of the evaluative content analysis suggested that the dBBT had a better clinical utility than the original BBT, with ratings of all collected participant statements for the dBBT being 45% (45/99) equal to, 48% (48/99) better than, and 6% (6/99) lesser than the BBT. Particularly in the subcategories "acceptance," "time required for evaluation," and "purchase costs," the dBBT was rated as being better than the original BBT. The dBBT achieved a mean SUS score of 83 (95% CI 76-96). Additionally, several suggested changes to the system were identified. Conclusions: The study demonstrated an overall positive evaluation of the clinical utility and usability of the dBBT. Valuable insights were gathered for future system iterations. These pioneering results highlight the potential of digitizing hand dexterity assessments.

Do PID-5 Trait Scores Predict Symptom Disorders? A Meta-analytic Review.

The Personality Inventory for DSM-5 (PID-5) has become influential in the dimensional assessment of personality dysfunction. Though most studies have examined links between PID-5 trait domains and personality pathology, a number of investigations have assessed relationships between PID-5 scores and symptom disorders (e.g., depression, anxiety). We employed meta-analytic techniques to synthesize findings in this area, identifying 26 publications assessing associations between PID-5 scores and symptom disorders (N of effect sizes across the five trait domains = 260). PID-5 domain score effect sizes (rs) ranged from 0.20 for Antagonism to 0.35 for Negative Affect (all ps < .00001). Relationships between PID-5 scores and specific forms of psychopathology were generally consistent with expectations, with some unanticipated relationships as well. Findings confirm that the pathological personality traits assessed by the PID-5 predict symptom disorders as well as personality dysfunction, extending the heuristic value and clinical utility of the measure.

Polygenic risk and incident coronary heart disease in a large multiethnic cohort.

Objective: Many studies support the notion that polygenic risk scores (PRS) improve risk prediction for coronary heart disease (CHD) beyond conventional risk factors. However, PRS are not yet considered risk-enhancing factor in guidelines. Our objective was to determine the predictive performance of a commercially available PRS (CARDIO inCode-Score®) compared with the Pooled Cohorts Equations (PCE) in a contemporary, multi-ethnic cohort. Methods: Participants (n = 63,070; 67 % female; 18 % non-European) without prior CHD were followed from 2007 through 12/31/2022. The association between the PRS and incident CHD was assessed using Cox regression adjusting for genetic ancestry and risk factors. Event rates were estimated by categories of PCE and by low/intermediate/high genetic risk within PCE categories; risk discrimination and net reclassification improvement (NRI) were also assessed. Results: There were 3,289 incident CHD events during 14 years of follow-up. Adjusted hazard ratio (aHR) for incident CHD per 1 SD increase in PRS was 1.18 (95 % CI:1.14-1.22), and the aHR for the upper vs lower quintile of the PRS was 1.66 (95 % CI:1.49-1.86). The association was consistent in both sexes, in European participants compared with all minority groups combined and was strongest in the first 5 years of follow-up. The increase in the C-statistic was 0.004 (0.747 vs. 0.751; p < 0.0001); the NRI was 2.4 (0.9-3.8) for the entire cohort and 9.7 (7.5-12.0) for intermediate PCE risk individuals. After incorporating high genetic risk, a further 10 percent of participants at borderline/intermediate PCE risk would be candidates for statin therapy. Conclusion: Inclusion of polygenic risk improved identification of primary prevention individuals who may benefit from more intensive risk factor modification.

Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score.

BACKGROUND: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD. METHODS: Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors. FINDINGS: A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4-14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332-1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR]interaction 0.91, 95% CIinteraction 0.88-0.94), increased body mass index (HRinteraction 0.97, 95% CIinteraction 0.96-0.98), and increased C-reactive protein (HRinteraction 0.98, 95% CIinteraction 0.96-0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HRinteraction 1.05, 95% CIinteraction 1.04-1.06) and total cholesterol (HRinteraction 1.05, 95% CIinteraction 1.03-1.06). CONCLUSION: The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors. FUNDING: P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health.

Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

PURPOSE: Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. SUMMARY: Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. CONCLUSION: A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing.

Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing.

Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in our comprehensive inpatient CHD genetics service focusing on neonates and infants admitted to the intensive care unit (ICU). The performance and diagnostic utility of using ECA status to screen for genetic disorders was assessed using decision curve analysis, a statistical tool to assess clinical utility, determining the threshold of phenotypic screening by ECA versus a Test-All approach. Over 24% of infants had genetic diagnoses identified (n = 244/1013), and ECA-positive status indicated a 4-fold increased risk of having a genetic disorder. However, ECA status had low-moderate screening performance based on predictive summary index, a compositive measure of positive and negative predictive values. For those with genetic diagnoses, nearly one-third (32%, 78/244) were ECA-negative but had cytogenetic and/or monogenic disorders identified by genetic testing. Thus, if the presence of multiple congenital anomalies is the phenotypic driver to initiate genetic testing, 13.4% (78/580) of infants with isolated CHD with identifiable genetic causes will be missed. Given the prevalence of genetic disorders and limited screening performance of ECA status, this analysis supports genetic testing in all CHD infants in intensive care settings rather than screening based on ECA.

Development process, clinical utility, and preliminary psychometric evidence of a new tool for screening psychological distress in renal care settings: the Hemodialysis Distress Thermometer (HD-DT).

OBJECTIVE: This study aimed to develop, evaluate the clinical utility, and test the psychometric properties of a new tool - the Hemodialysis Distress Thermometer (HD-DT) - designed to screen self-reported psychological distress and its sources in adults receiving hemodialysis. METHODS AND MEASURES: Phase 1 focused on the process of developing and evaluating the content validity and clinical utility of the HD-DT using a stepwise mixed-methods approach; in Phase 2, the measurement properties of the European Portuguese version of the HD-DT were tested against reference measures in a cross-sectional study (n = 134 people on hemodialysis); while in Phase 3 the HD-DT was translated and culturally adapted into American English using forward-backward translation and review by a panel of experts. RESULTS: Qualitative findings suggested that the HD-DT was perceived by feedback panels as practical and useful for rapidly screening psychological distress in nephrology centers. The European Portuguese version of this new tool showed good test-retest reliability and high diagnostic accuracy using a cutoff point of ≥ 6 for total distress. High convergent validity was found with reference measures that assess psychological health, and symptoms of anxiety and depression. CONCLUSION: This study highlights the potential clinical utility of the HD-DT as an acceptable, reliable, and valid measure that can be used by health psychologists in clinical practice and research in renal care settings. Data collection to validate the American English version of the HD-DT is currently underway.