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Intensive Care Medicine Mar 2020Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed their performance by carrying out a systematic review and meta-analysis.
METHODS
A systematic search was performed in PubMed, Embase.com and Scopus. Studies targeting sepsis, severe sepsis or septic shock in any hospital setting were eligible for inclusion. The index test was any supervised machine learning model for real-time prediction of these conditions. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, with a tailored Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist to evaluate risk of bias. Models with a reported area under the curve of the receiver operating characteristic (AUROC) metric were meta-analyzed to identify strongest contributors to model performance.
RESULTS
After screening, a total of 28 papers were eligible for synthesis, from which 130 models were extracted. The majority of papers were developed in the intensive care unit (ICU, n = 15; 54%), followed by hospital wards (n = 7; 25%), the emergency department (ED, n = 4; 14%) and all of these settings (n = 2; 7%). For the prediction of sepsis, diagnostic test accuracy assessed by the AUROC ranged from 0.68-0.99 in the ICU, to 0.96-0.98 in-hospital and 0.87 to 0.97 in the ED. Varying sepsis definitions limit pooling of the performance across studies. Only three papers clinically implemented models with mixed results. In the multivariate analysis, temperature, lab values, and model type contributed most to model performance.
CONCLUSION
This systematic review and meta-analysis show that on retrospective data, individual machine learning models can accurately predict sepsis onset ahead of time. Although they present alternatives to traditional scoring systems, between-study heterogeneity limits the assessment of pooled results. Systematic reporting and clinical implementation studies are needed to bridge the gap between bytes and bedside.
Topics: Diagnostic Tests, Routine; Humans; Machine Learning; Retrospective Studies; Sepsis; Shock, Septic
PubMed: 31965266
DOI: 10.1007/s00134-019-05872-y -
Journal of Cachexia, Sarcopenia and... Feb 2023Muscle ultrasound is an emerging tool for diagnosing sarcopenia. This review aims to summarize the current knowledge on the diagnostic test accuracy of ultrasound for... (Meta-Analysis)
Meta-Analysis Review
Muscle ultrasound is an emerging tool for diagnosing sarcopenia. This review aims to summarize the current knowledge on the diagnostic test accuracy of ultrasound for the diagnosis of sarcopenia. We collected data from Ovid Medline, Embase and the Cochrane Central Register of Controlled Trials. Diagnostic test accuracy studies using muscle ultrasound to detect sarcopenia were included. Bivariate random-effects models based on sensitivity and specificity pairs were used to calculate the pooled estimates of sensitivity, specificity and the area under the curves (AUCs) of summary receiver operating characteristic (SROC), if possible. We screened 7332 publications and included 17 studies with 2143 participants (mean age range: 52.6-82.8 years). All included studies had a high risk of bias. The study populations, reference standards and ultrasound measurement methods varied across the studies. Lower extremity muscles were commonly studied, whereas muscle thickness (MT) was the most widely measured parameter, followed by the cross-sectional area (CSA). The MTs of the gastrocnemius, rectus femoris, tibialis anterior, soleus, rectus abdominis and geniohyoid muscles showed a moderate diagnostic accuracy for sarcopenia (SROC-AUC 0.83, 8 studies; SROC-AUC 0.78, 5 studies; AUC 0.82, 1 study; AUC 0.76-0.78, 2 studies; AUC 0.76, 1 study; and AUC 0.79, 1 study, respectively), whereas the MTs of vastus intermedius, quadriceps femoris and transversus abdominis muscles showed a low diagnostic accuracy (AUC 0.67-0.71, 3 studies; SROC-AUC 0.64, 4 studies; and AUC 0.68, 1 study, respectively). The CSA of rectus femoris, biceps brachii muscles and gastrocnemius fascicle length also showed a moderate diagnostic accuracy (AUC 0.70-0.90, 3 studies; 0.81, 1 study; and 0.78-0.80, 1 study, respectively), whereas the echo intensity (EI) of rectus femoris, vastus intermedius, quadriceps femoris and biceps brachii muscles showed a low diagnostic accuracy (AUC 0.52-0.67, 2 studies; 0.48-0.50, 1 study; 0.43-0.49, 1 study; and 0.69, 1 study, respectively). The combination of CSA and EI of biceps brachii or rectus femoris muscles was better than either CSA or EI alone for diagnosing sarcopenia. Muscle ultrasound shows a low-to-moderate diagnostic test accuracy for sarcopenia diagnosis depending on different ultrasound parameters, measured muscles, reference standards and study populations. The combination of muscle quality indicators (e.g., EI) and muscle quantity indicators (e.g., MT) might provide better diagnostic test accuracy.
Topics: Humans; Middle Aged; Aged; Aged, 80 and over; Sarcopenia; Quadriceps Muscle; Ultrasonography; Rectus Abdominis; Diagnostic Tests, Routine
PubMed: 36513380
DOI: 10.1002/jcsm.13149 -
European Urology Oncology Dec 2021During the past decade, several urinary biomarker tests (UBTs) for bladder cancer have been developed and made commercially available. However, none of these is... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
During the past decade, several urinary biomarker tests (UBTs) for bladder cancer have been developed and made commercially available. However, none of these is recommended by international guidelines so far.
OBJECTIVE
To assess the diagnostic estimates of novel commercially available UBTs for diagnosis and surveillance of non-muscle-invasive bladder cancer (NMIBC) using diagnostic test accuracy (DTA) and network meta-analysis (NMA).
EVIDENCE ACQUISITION
PubMed, Web of Science, and Scopus were searched up to April 2021 to identify studies addressing the diagnostic values of UBTs: Xpert bladder cancer, Adxbladder, Bladder EpiCheck, Uromonitor and Cxbladder Monitor, and Triage and Detect. The primary endpoint was to assess the pooled diagnostic values for disease recurrence in NMIBC patients using a DTA meta-analysis and to compare them with cytology using an NMA. The secondary endpoints were the diagnostic values for high-grade (HG) recurrence as well as for the initial detection of bladder cancer.
EVIDENCE SYNTHESIS
Twenty-one studies, comprising 7330 patients, were included in the quantitative synthesis. In most of the studies, there was an unclear risk of bias. For NMIBC surveillance, novel UBTs demonstrated promising pooled diagnostic values with sensitivities up to 93%, specificities up to 84%, positive predictive values up to 67%, and negative predictive value up to 99%. Pooled estimates for the diagnosis of HG recurrence were similar to those for the diagnosis of any-grade recurrence. The analysis of the number of cystoscopies potentially avoided during the follow-up of 1000 patients showed that UBTs might be efficient in reducing the number of avoidable interventions with up to 740 cystoscopies. The NMA revealed that diagnostic values (except specificity) of the novel UBTs were significantly higher than those of cytology for the detection of NMIBC recurrence. There were too little data on UBTs in the primary diagnosis setting to allow a statistical analysis.
CONCLUSIONS
Our analyses support high diagnostic accuracy of the studied novel UBTs, supporting their utility in the NMIBC surveillance setting. All of these might potentially help prevent unnecessary cystoscopies safely. There are not enough data to reliably assess their use in the primary diagnostic setting. These results have to be confirmed in a larger cohort as well as in head-to-head comparative studies. Nevertheless, our study might help policymakers and stakeholders evaluate the clinical and social impact of the implementation of these tests into daily practice.
PATIENT SUMMARY
Novel urinary biomarker tests outperform cytology with the potential of improving routine clinical practice by preventing unnecessary cystoscopic examinations during the surveillance of non-muscle-invasive bladder cancer.
Topics: Biomarkers, Tumor; Cystoscopy; Humans; Neoplasm Recurrence, Local; Network Meta-Analysis; Urinary Bladder Neoplasms
PubMed: 34753702
DOI: 10.1016/j.euo.2021.10.003 -
Journal of General Internal Medicine Mar 2020Eating disorders affect upwards of 30 million people worldwide and often go undertreated and underdiagnosed. The purpose of this systematic review and meta-analysis was... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Eating disorders affect upwards of 30 million people worldwide and often go undertreated and underdiagnosed. The purpose of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of the Sick, Control, One, Fat and Food (SCOFF) questionnaire for DSM-5 eating disorders in the general population.
METHOD
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) were followed. A PubMed search was conducted among peer-reviewed articles. Information regarding validation of the SCOFF was required for inclusion. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool.
RESULTS
The final analysis included 25 studies. The validity of the SCOFF was high across samples with a pooled sensitivity of 0.86 (95% CI, 0.78-0.91) and specificity of 0.83 (95% CI, 0.77-0.88). Subgroup analyses were conducted to examine the impact of methodology, study quality, and clinical characteristics on diagnostic accuracy. Studies with the highest sensitivity tended to be case-control studies of young women with anorexia nervosa (AN) and bulimia nervosa (BN). Studies which included more men, included those diagnosed with binge eating disorder, and recruited from large community samples tended to have lower sensitivity. Few studies reported on BMI and race/ethnicity; thus, subgroups for these factors could not be examined. No studies used reference standards which assessed all DSM-5 eating disorders.
CONCLUSION
This meta-analysis of 25 validation studies demonstrates that the SCOFF is a simple and useful screening tool for young women at risk for AN and BN. However, there is not enough evidence to support utilizing the SCOFF for screening for the range of DSM-5 eating disorders in primary care and community-based settings. Further examination of the validity of the SCOFF or development of a new screening tool, or multiple tools, to screen for the range of DSM-5 eating disorders heterogenous populations is warranted.
TRIAL REGISTRATION
This study is registered online with PROSPERO (CRD42018089906).
Topics: Anorexia Nervosa; Diagnostic Tests, Routine; Feeding and Eating Disorders; Female; Humans; Male; Mass Screening; Surveys and Questionnaires
PubMed: 31705473
DOI: 10.1007/s11606-019-05478-6 -
Endocrine Aug 2023To summarize the more robust evidence about the performance of tools useful for diagnosis of medullary thyroid carcinoma (MTC) such as calcitonin (Ctn) and other... (Review)
Review
PURPOSE
To summarize the more robust evidence about the performance of tools useful for diagnosis of medullary thyroid carcinoma (MTC) such as calcitonin (Ctn) and other circulating markers, ultrasound (US), fine-needle aspiration (FNA), and other imaging procedures.
METHODS
This systematic review of systematic reviews was carried out according to a predefined protocol. A search string was created. An electronical comprehensive search of literature was performed on December 2022. Quality assessment of eligible systematic reviews was performed and main findings were described.
RESULTS
Twenty-three systematic reviews were included and several findings were achieved. Ctn is the most reliable diagnostic marker of MTC with no evidence of improvement with stimulation test. CEA doubling time is more reliable than Ctn in identifying MTC with poorer prognosis. US sensitivity is suboptimal in MTC and only just over half of cases are at high risk according to Thyroid Imaging And Reporting Data Systems. Cytology can correctly detect MTC in just over half of cases and measuring Ctn in washout fluid from FNA is necessary. PET/CT is useful for detecting recurrent MTC.
CONCLUSIONS
Future guidelines of both thyroid nodule management and MTC diagnosis should consider these evidence-based data.
Topics: Thyroid Neoplasms; Thyroid Nodule; Positron Emission Tomography Computed Tomography; Diagnostic Tests, Routine; Calcitonin; Systematic Reviews as Topic; Biopsy, Fine-Needle
PubMed: 36877452
DOI: 10.1007/s12020-023-03326-6 -
Clinical Journal of the American... Nov 2020Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
This is a systematic review and meta-analysis of the literature published from January 1983 to March 2018. The initial PubMed search yielded 1139 manuscripts. Using predetermined selection criteria, 87 manuscripts were included in the final analysis. A random effects meta-analysis for proportions was used to obtain combined estimates of complication rates. Freeman-Tukey double-arcsine transformations were used to stabilize variance as complications were rare.
RESULTS
A total of 118,064 biopsies were included in this study. Patient age ranged from 30 to 79 years, and 45% of patients were women. On the basis of our meta-analysis, pain at the site of biopsy is estimated to occur in 4.3% of biopsied patients, hematomas are estimated to occur in 11%, macroscopic hematuria is estimated to occur in 3.5%, bleeding requiring blood transfusions is estimated to occur in 1.6%, and interventions to stop bleeding are estimated to occur in only 0.3%. Death attributed to native kidney biopsy was a rare event, occurring only in an estimated 0.06% of all biopsies but only 0.03% of outpatient biopsies. Complication rates were higher in hospitalized patients and in those with acute kidney disease. The reported complications varied on the basis of study type and geographic location.
CONCLUSIONS
Although the native kidney biopsy is an invasive diagnostic procedure, the rates of bleeding complications are low. Albeit rare, death can occur postbiopsy. Complications are more frequently seen after kidney biopsies of hospitalized patients with AKI.
Topics: Blood Transfusion; Hematoma; Hematuria; Hemostasis, Surgical; Hospitalization; Humans; Image-Guided Biopsy; Kidney; Kidney Diseases; Pain; Risk Factors
PubMed: 33060160
DOI: 10.2215/CJN.04710420 -
Neurology(R) Neuroimmunology &... Nov 2021To facilitate and improve the diagnostic and therapeutic process by systematically reviewing studies on patients with primary angiitis of the CNS (PACNS). (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
To facilitate and improve the diagnostic and therapeutic process by systematically reviewing studies on patients with primary angiitis of the CNS (PACNS).
METHODS
We searched PubMed, looking at the period between 1988 and February 2020. Studies with adult patients with PACNS were included. We extracted and pooled proportions using fixed-effects models. Main outcomes were proportions of patients with certain clinical, imaging, and laboratory characteristics and neurologic outcomes.
RESULTS
We identified 46 cohort studies including a total of 911 patients (41% biopsy confirmed, 43% angiogram confirmed, and 16% without clear assignment to the diagnostic procedure). The most frequent onset symptoms were focal neurologic signs (63%), headache (51%), and cognitive impairment (41%). Biopsy- compared with angiogram-confirmed cases had higher occurrences of cognitive impairment (55% vs 39%) and seizures (36% vs 16%), whereas focal neurologic signs occurred less often (56% vs 95%). CSF abnormalities were present in 75% vs 65% and MRI abnormalities in 97% vs 98% of patients. Digital subtraction angiography was positive in 33% of biopsy confirmed, and biopsy was positive in 8% of angiogram-confirmed cases. In 2 large cohorts, mortality was 23% and 8%, and the relapse rate was 30% and 34%, during a median follow-up of 19 and 57 months, respectively. There are no randomized trials on the treatment of PACNS. The initial treatment usually includes glucocorticoids and cyclophosphamide.
DISCUSSION
PACNS is associated with disabling symptoms, frequent relapses, and significant mortality. Differences in symptoms and neuroimaging results and low overlap between biopsy and angiogram suggest that biopsy- and angiogram-confirmed cases represent different histopathologic types of PACNS. The optimal treatment is unknown.
Topics: Humans; Vasculitis, Central Nervous System
PubMed: 34663675
DOI: 10.1212/NXI.0000000000001093 -
Ultrasound in Obstetrics & Gynecology :... Jul 2019Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to...
OBJECTIVE
Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre-eclampsia, to identify high-value avenues for future research and to minimize future research waste in this field.
METHODS
MEDLINE, EMBASE and The Cochrane Library including DARE (Database of Abstracts of Reviews of Effects) databases, from database inception to March 2017, and bibliographies of relevant articles were searched, without language restrictions, for systematic reviews and meta-analyses on the prediction of pre-eclampsia. The quality of the included reviews was assessed using the AMSTAR tool and a modified version of the QUIPS tool. We evaluated the comprehensiveness of search, sample size, tests and outcomes evaluated, data synthesis methods, predictive ability estimates, risk of bias related to the population studied, measurement of predictors and outcomes, study attrition and adjustment for confounding.
RESULTS
From 2444 citations identified, 126 reviews were included, reporting on over 90 predictors and 52 prediction models for pre-eclampsia. Around a third (n = 37 (29.4%)) of all reviews investigated solely biochemical markers for predicting pre-eclampsia, 31 (24.6%) investigated genetic associations with pre-eclampsia, 46 (36.5%) reported on clinical characteristics, four (3.2%) evaluated only ultrasound markers and six (4.8%) studied a combination of tests; two (1.6%) additional reviews evaluated primary studies investigating any screening test for pre-eclampsia. Reviews included between two and 265 primary studies, including up to 25 356 688 women in the largest review. Only approximately half (n = 67 (53.2%)) of the reviews assessed the quality of the included studies. There was a high risk of bias in many of the included reviews, particularly in relation to population representativeness and study attrition. Over 80% (n = 106 (84.1%)) summarized the findings using meta-analysis. Thirty-two (25.4%) studies lacked a formal statement on funding. The predictors with the best test performance were body mass index (BMI) > 35 kg/m , with a specificity of 92% (95% CI, 89-95%) and a sensitivity of 21% (95% CI, 12-31%); BMI > 25 kg/m , with a specificity of 73% (95% CI, 64-83%) and a sensitivity of 47% (95% CI, 33-61%); first-trimester uterine artery pulsatility index or resistance index > 90 centile (specificity 93% (95% CI, 90-96%) and sensitivity 26% (95% CI, 23-31%)); placental growth factor (specificity 89% (95% CI, 89-89%) and sensitivity 65% (95% CI, 63-67%)); and placental protein 13 (specificity 88% (95% CI, 87-89%) and sensitivity 37% (95% CI, 33-41%)). No single marker had a test performance suitable for routine clinical use. Models combining markers showed promise, but none had undergone external validation.
CONCLUSIONS
This review of reviews calls into question the need for further aggregate meta-analysis in this area given the large number of published reviews subject to the common limitations of primary predictive studies. Prospective, well-designed studies of predictive markers, preferably randomized intervention studies, and combined through individual-patient data meta-analysis are needed to develop and validate new prediction models to facilitate the prediction of pre-eclampsia and minimize further research waste in this field. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Adult; Biomarkers; Body Mass Index; Female; Humans; Mass Screening; Meta-Analysis as Topic; Placenta Growth Factor; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Complications; Prospective Studies; Pulsatile Flow; Risk Factors; Sensitivity and Specificity; Ultrasonography; Uterine Artery
PubMed: 30267475
DOI: 10.1002/uog.20117 -
World Journal of Emergency Surgery :... May 2023The diagnosis of cardiac contusion, caused by blunt chest trauma, remains a challenge due to the non-specific symptoms it causes and the lack of ideal tests to diagnose... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The diagnosis of cardiac contusion, caused by blunt chest trauma, remains a challenge due to the non-specific symptoms it causes and the lack of ideal tests to diagnose myocardial damage. A cardiac contusion can be life-threatening if not diagnosed and treated promptly. Several diagnostic tests have been used to evaluate the risk of cardiac complications, but the challenge of identifying patients with contusions nevertheless remains.
AIM OF THE STUDY
To evaluate the accuracy of diagnostic tests for detecting blunt cardiac injury (BCI) and its complications, in patients with severe chest injuries, who are assessed in an emergency department or by any front-line emergency physician.
METHODS
A targeted search strategy was performed using Ovid MEDLINE and Embase databases from 1993 up to October 2022. Data on at least one of the following diagnostic tests: electrocardiogram (ECG), serum creatinine phosphokinase-MB level (CPK-MB), echocardiography (Echo), Cardiac troponin I (cTnI) or Cardiac troponin T (cTnT). Diagnostic tests for cardiac contusion were evaluated for their accuracy in meta-analysis. Heterogeneity was assessed using the I and the QUADAS-2 tool was used to assess bias of the studies.
RESULTS
This systematic review yielded 51 studies (n = 5,359). The weighted mean incidence of myocardial injuries after sustaining a blunt force trauma stood at 18.3% of cases. Overall weighted mean mortality among patients with blunt cardiac injury was 7.6% (1.4-36.4%). Initial ECG, cTnI, cTnT and transthoracic echocardiography TTE all showed high specificity (> 80%), but lower sensitivity (< 70%). TEE had a specificity of 72.1% (range 35.8-98.2%) and sensitivity of 86.7% (range 40-99.2%) in diagnosing cardiac contusion. CK-MB had the lowest diagnostic odds ratio of 3.598 (95% CI: 1.832-7.068). Normal ECG accompanied by normal cTnI showed a high sensitivity of 85% in ruling out cardiac injuries.
CONCLUSION
Emergency physicians face great challenges in diagnosing cardiac injuries in patients following blunt trauma. In the majority of cases, joint use of ECG and cTnI was a pragmatic and cost-effective approach to rule out cardiac injuries. In addition, TEE may be highly accurate in identifying cardiac injuries in suspected cases.
Topics: Humans; Thoracic Injuries; Wounds, Nonpenetrating; Heart Injuries; Myocardial Contusions; Troponin I; Troponin T; Diagnostic Tests, Routine
PubMed: 37245048
DOI: 10.1186/s13017-023-00504-9 -
Neurology and Therapy Aug 2023Alzheimer's disease (AD) is a disease continuum from pathophysiologic, biomarker and clinical perspectives. With the advent of advanced technologies, diagnosing and...
INTRODUCTION
Alzheimer's disease (AD) is a disease continuum from pathophysiologic, biomarker and clinical perspectives. With the advent of advanced technologies, diagnosing and managing patients is evolving.
METHODS
A systematic literature review (SLR) of practice guidelines for mild cognitive impairment (MCI) and AD dementia was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This systematic literature review (SLR) aimed to summarize current clinical practice guidelines for screening, testing, diagnosis, treatment and monitoring in the AD continuum. The results of this SLR were used to propose a way forward for practice guidelines given the possible introduction of biomarker-guided technology using blood- or plasma-based assays and disease-modifying treatments (DMTs) targeted for early disease.
RESULTS
53 clinical practice guidelines were identified, 15 of which were published since 2018. Screening for asymptomatic populations was not recommended. Biomarker testing was not included in routine diagnostic practice. There was no consensus on which neurocognitive tests to use to diagnose and monitor MCI or AD dementia. Pharmacologic therapies were not recommended for MCI, while cholinesterase inhibitors and memantine were recommended for AD treatment.
DISCUSSION
The pre-2018 and post-2018 practice guidelines share similar recommendations for screening, diagnosis and treatment. However, once DMTs are approved, clinicians will require guidance on the appropriate use of DMTs in a clinical setting. This guidance should include strategies for identifying eligible patients and evaluating the DMT benefit-to-risk profile to facilitate shared decision-making among physicians, patients and care partners.
CONCLUSION
Regular evidence-based updates of existing guidelines for the AD continuum are required over the coming decades to integrate rapidly evolving technologic and medical scientific advances and bring emerging approaches for management of early disease into clinical practice. This will pave the way toward biomarker-guided identification and targeted treatment and the realization of precision medicine for AD.
PubMed: 37261607
DOI: 10.1007/s40120-023-00504-6