scholarly journals A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259178
Author(s):  
José L. Jiménez ◽  
Julia Niewczas ◽  
Alexander Bore ◽  
Carl-Fredrik Burman
Keyword(s):  
Statistical Power ◽  
Experimental Treatment ◽  
Hazard Ratio ◽  
Rank Test ◽  
Control Group ◽  
Potential Hazard ◽  
Intention To Treat ◽  
Treatment Switching ◽  
Log Rank Test ◽  
The Impact

In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.

Palliative medicine consultation impacts DNR designation and length of stay for terminal medical MICU patients

2011 ◽  
Vol 9 (4) ◽  
pp. 401-406 ◽  
Author(s):  
Dana Lustbader ◽  
Renee Pekmezaris ◽  
Michael Frankenthaler ◽  
Rajni Walia ◽  
Frederick Smith ◽  
...  
Keyword(s):  
Length Of Stay ◽  
Palliative Medicine ◽  
Intervention Group ◽  
Hospital Length Of Stay ◽  
Rank Test ◽  
Control Group ◽  
Do Not Resuscitate ◽  
Log Rank Test ◽  
The Impact ◽  
Reduced Time

AbstractObjective:The purpose of this study was to assess the impact of a palliative medicine consultation on medical intensive care unit (MICU) and hospital length of stay, Do Not Resuscitate (DNR) designation, and location of death for MICU patients who died during hospitalization.Method:A comparison of two retrospective cohorts in a 17-bed MICU in a tertiary care university-affiliated hospital was conducted. Patients admitted to the MICU between January 1, 2003 and June 30, 2004 (N = 515) were compared to MICU patients who had had a palliative medicine consultation between January 1, 2005 and June 1, 2009 (N = 693). To control for disease severity, only patients in both cohorts who died during their hospitalization were considered for this study.Results:Palliative medicine consultation reduced time until death during the entire hospitalization (log-rank test,p < 0.01). Time from MICU admission until death was also reduced (log-rank test,p < 0.01), further demonstrating the impact of the palliative care consultation on the duration of dying for hospitalized patients. The intervention group contained a significantly higher percentage of patients with a DNR designation at death than did the control group (86% vs. 68%, χ2test,p < 0.0001).Significance of results:Palliative medicine consultation is associated with an increased rate of DNR designation and reduced time until death. Patients in the intervention group were also more likely to die outside the MICU as compared to controls in the usual care group.

scholarly journals TREATMENT SWITCHING: STATISTICAL AND DECISION-MAKING CHALLENGES AND APPROACHES

2016 ◽  
Vol 32 (3) ◽  
pp. 160-166 ◽  
Author(s):  
Nicholas R. Latimer ◽  
Chris Henshall ◽  
Uwe Siebert ◽  
Helen Bell
Keyword(s):  
Statistical Methods ◽  
Failure Time ◽  
Controlled Trial ◽  
International Workshop ◽  
Experimental Treatment ◽  
Decision Makers ◽  
Control Group ◽  
Intention To Treat ◽  
Treatment Switching ◽  
New Treatment

Objectives: Treatment switching refers to the situation in a randomized controlled trial where patients switch from their randomly assigned treatment onto an alternative. Often, switching is from the control group onto the experimental treatment. In this instance, a standard intention-to-treat analysis does not identify the true comparative effectiveness of the treatments under investigation. We aim to describe statistical methods for adjusting for treatment switching in a comprehensible way for nonstatisticians, and to summarize views on these methods expressed by stakeholders at the 2014 Adelaide International Workshop on Treatment Switching in Clinical Trials.Methods: We describe three statistical methods used to adjust for treatment switching: marginal structural models, two-stage adjustment, and rank preserving structural failure time models. We draw upon discussion heard at the Adelaide International Workshop to explore the views of stakeholders on the acceptability of these methods.Results: Stakeholders noted that adjustment methods are based on assumptions, the validity of which may often be questionable. There was disagreement on the acceptability of adjustment methods, but consensus that when these are used, they should be justified rigorously. The utility of adjustment methods depends upon the decision being made and the processes used by the decision-maker.Conclusions: Treatment switching makes estimating the true comparative effect of a new treatment challenging. However, many decision-makers have reservations with adjustment methods. These, and how they affect the utility of adjustment methods, require further exploration. Further technical work is required to develop adjustment methods to meet real world needs, to enhance their acceptability to decision-makers.

Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5520-5520 ◽  
Author(s):  
Myong Cheol Lim ◽  
Suk-Joon Chang ◽  
Heong Jong Yoo ◽  
Byung-Ho Nam ◽  
Robert Bristow ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cytoreductive Surgery ◽  
Residual Tumor ◽  
Study Endpoint ◽  
Rank Test ◽  
Control Group ◽  
Term Survival ◽  
Log Rank Test ◽  
And Control ◽  
The Impact

5520 Background: Cytoreductive surgery followed by taxane and platinum-based chemotherapy is standard treatment for advanced ovarian cancer. We compared results of randomly allocated HIPEC in primary advanced epithelial ovarian cancer who have optimal cytoreductive surgery in this prospective randomized multicenter trial. The study endpoint is to evaluate progression free survival (PFS) and overall survival (OS). Methods: 184 patients staged III and IV were randomly allocated to trial arm (HIPEC, cisplatin 75 mg/m2, 90 min) or control arm (no HIPEC), intraoperatively based on residual tumor (size <1cm) from July 2010 to January 2016. The groups were well balanced according to the age, body mass index, performance status, stage, histology, serum CA125 level, and use of neoadjuvant chemotherapy (NAC) at study entry. Results: 184 pts (HIPEC, 92; control, 92) were included in this preplanned analysis. No mortality after surgery ± HIPEC was identified in both groups. Postoperative outcomes including extent of surgery, estimated blood loss, residual tumor, and hospitalization day were not different between both group, except operation time (487 vs. 404 min, p<0.001) due to HIPEC procedure. The most common adverse event was anemia: 67.4% in HIPEC and 50% in control group (p=0.025). The other toxicity common in HIPEC group is the elevation of creatinine (15.2% vs. 4.3%, p=0.026). There were no differences between both groups for transfusion (35.9 vs. 29.3, p=0.432), neutropenia (19.6 vs. 10.9%, p=0.151), and thrombocytopenia (9.8 vs. 3.3%, p=0.136). Two-year PFS was 43.2% and 43.5% and 5-year PFS was 20.9% and 16.0% in HIPEC and control group, respectively (p=0.569). Five-year OS was 51.0% and 49.4% in HIPEC and control group, respectively (p=0.574). In women who received NAC, the median PFS for HIPEC and control group were 20 and 19 months, respectively (log-rank test, p = 0.137) and the median OS for HIPEC and control group were 54 and 51 months, respectively (log-rank test, p = 0.407). In the subgroup with NAC, 2-year PFS was 37.2% in HIPEC group and 29.5% in control group and 5-year OS was 47.9% in HIPEC group and 27.7% in control group. After 20 months in PFS and 30 months in OS, two survival curves in women who received NAC showed the trend of gradual distinction, favoring HIPEC group. Conclusions: No mortality was identified and postoperative morbidities were not statistically different between two groups except anemia and creatinine elevation in HIPEC group. The survival analysis did not show the statistical superiority of the HIPEC arm. More follow-up is required to confirm the impact of HIPEC on long-term survival outcome in ovarian cancer, especially in NAC group. Clinical trial information: NCT01091636.

scholarly journals Assessing methods for dealing with treatment switching in clinical trials: A follow-up simulation study

2016 ◽  
Vol 27 (3) ◽  
pp. 765-784 ◽  
Author(s):  
Nicholas R Latimer ◽  
Keith R Abrams ◽  
Paul C Lambert ◽  
James P Morden ◽  
Michael J Crowther
Keyword(s):  
Sample Size ◽  
Treatment Effect ◽  
Failure Time ◽  
Control Group ◽  
Structural Failure ◽  
Inverse Probability ◽  
Intention To Treat ◽  
Treatment Switching ◽  
Randomised Controlled ◽  
The Impact

When patients randomised to the control group of a randomised controlled trial are allowed to switch onto the experimental treatment, intention-to-treat analyses of the treatment effect are confounded because the separation of randomised groups is lost. Previous research has investigated statistical methods that aim to estimate the treatment effect that would have been observed had this treatment switching not occurred and has demonstrated their performance in a limited set of scenarios. Here, we investigate these methods in a new range of realistic scenarios, allowing conclusions to be made based upon a broader evidence base. We simulated randomised controlled trials incorporating prognosis-related treatment switching and investigated the impact of sample size, reduced switching proportions, disease severity, and alternative data-generating models on the performance of adjustment methods, assessed through a comparison of bias, mean squared error, and coverage, related to the estimation of true restricted mean survival in the absence of switching in the control group. Rank preserving structural failure time models, inverse probability of censoring weights, and two-stage methods consistently produced less bias than the intention-to-treat analysis. The switching proportion was confirmed to be a key determinant of bias: sample size and censoring proportion were relatively less important. It is critical to determine the size of the treatment effect in terms of an acceleration factor (rather than a hazard ratio) to provide information on the likely bias associated with rank-preserving structural failure time model adjustments. In general, inverse probability of censoring weight methods are more volatile than other adjustment methods.

CDKN2A or CDKN2B homozygous deletion with high-immune infiltration as a favorable prognostic factor for lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20543-e20543
Author(s):  
Benxu Tan ◽  
Yonghong Chen ◽  
Lei Xia ◽  
Xian Yu ◽  
Yusheng Huang ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Lung Adenocarcinoma ◽  
Homozygous Deletion ◽  
Hazard Ratio ◽  
Gene Set Enrichment Analysis ◽  
Rank Test ◽  
Immune Infiltration ◽  
Log Rank Test ◽  
Significant Difference ◽  
Wild Group

e20543 Background: CDKN2A and CDKN2B both acted as tumor suppressor genes by regulating the cell cycle, which in humans were located at chromosome 9, band p21.3. The frequencies of homozygous deletion (HomDel) in CDKN2A and CDKN2B in lung adenocarcinoma (LUAD) were 12.5% and 12.1%, respectively. However, the genomic, immunogenomic features and impact on the prognosis of LUAD patients with CDKN2A/B HomDel were still unclear. Methods: The cohort of this study was from The Cancer Genome Atlas (TCGA). A total of 508 LUAD patients, including 99 CDKN2A/B HomDel (homdel) and 509 CDKN2A/B wild (wild). This study explored the difference of genomic and immunogenomic landscape between homdel and wild by analysis of whole-exome sequencing (WES) and RNA sequencing data. Results: The most frequently mutated genes were TP53, TTN, MUC16, and CSMD3. Their frequencies in homdel and wild are 46% and 48%, 43% and 46%, 35% and 41%, 33% and 38%, respectively. There was no significant difference of tumor mutational burden (TMB) between homdel and wild (median TMB, 133 in homdel vs 177 in wild; Wilcoxon test, p = 0.11), and clinical characteristics including age, gender, smoking history, and tumor stage were not significantly different between homdel and wild. Homdel had a shorter overall survival (OS) than wild (Log-rank test, p = 0.04, Hazard Ratio: 0.7, 95% CI: 0.49-1.02), but there was no significant difference in progression-free survival (PFS) (Log-rank test, p = 0.05, Hazard Ratio: 0.73, 95% CI: 0.51-1.04). We used single sample gene set enrichment analysis (ssGSEA) to calculate the enrichment score (ES) of 25 immune-related pathways such as antigen presentation and T cell-mediated immunity, and then used the consensus clustering algorithm (ConsensusClusterPlus) to cluster homdel and wild respectively, and both clustered into low and high immune infiltration groups. For the high immune infiltration and low immune infiltration in homdel and wild, high immune infiltration had a longer OS (Log-rank test, p = 0.009, Hazard Ratio: 2.19, 95% CI: 1.22-3.94) and PFS (Log-rank test, p = 0.044, Hazard Ratio: 1.8, 95% CI: 1.01-3.2) than low immune infiltration in homdel. However, there was no significant heterogeneity between high and immune infiltration in terms of PFS (Log-rank test, p = 0.28, Hazard Ratio: 1.21, 95% CI: 0.87-1.68) and OS (Log-rank test, p = 0.96, Hazard Ratio: 1.01, 95% CI: 0.71-1.44) in the wild group, the wild group had longer OS than homdel group with low immune infiltration (Log-rank test, p = 0.003, Hazard Ratio: 0.5, 95% CI: 0.29-0.88), while had the same OS with homdel with high immune infiltration, irrespective of immune infiltration. And so was PFS (Log-rank test, p = 0.005, Hazard Ratio: 0.48, 95% CI: 0.27-0.82). Conclusions: CDKN2A/B homdel was an unfavorable prognostic factor for LUAD, but which with high immune infiltration might improve patient survival time.

124Impact of intimal tracking for recanalization of CTO lesions on long-term clinical outcomes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Kano ◽  
K Nasu ◽  
M Habara ◽  
T Shimura ◽  
M Yamamoto ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cox Regression ◽  
Target Lesion ◽  
Hazard Ratio ◽  
Rank Test ◽  
Total Occlusion ◽  
Significant Difference ◽  
The Impact

Abstract Background For recanalization of coronary chronic total occlusion (CTO) lesions, subintimal guidewire tracking in both antegrade and retrograde approaches are commonly used. Purpose This study aimed to assess the impact of subintimal tracking on long-term clinical outcomes after recanalization of CTO lesions. Methods Between January 2009 and December 2016, 474 CTO lesions (434patients) were successfully recanalized in our center. After guidewire crossing in a CTO lesion, those lesions were divided into intimal tracking group (84.6%, n=401) and subintimal tracking group (15.4%, n=73) according to intravascular ultrasound (IVUS) findings. Long-term clinical outcomes including death, target lesion revascularization (TLR), target vessel revascularization (TVR) were compared between the two groups. In addition, the rate of re-occlusion after successful revascularization was also evaluated. Results The median follow-up period was 4.7 years (interquartile range, 2.8–6.1). There was no significant difference of the rate of cardiac death between the two groups (intimal tracking vs. subintimal tracking: 7.0% vs. 4.1%; hazard ratio, 0.61; 95% confidence interval [CI], 0.19 to 2.00; p=0.41), TLR (14.3% vs. 16.2%; hazard ratio, 1.34; 95% CI, 0.71 to 2.53; p=0.37), and TVR (17.5% vs. 20.3%; hazard ratio, 1.27; 95% CI, 0.72 to 2.23; p=0.42). However, the rate of re-occlusion was significantly higher in the subintimal tracking group than intimal tracking group at 3-years re-occlusion (4.2% vs. 14.5%; log-rank test, p=0.002, Figure). In the multivariate COX regression, subintimal guidewire tracking was an independent predictor of re-occlusion after CTO recanalization (HR: 5.40; 95% CI: 2.11–13.80; p<0.001). Figure 1 Conclusions Subintimal guidewire tracking for recanalization of coronary CTO was associated with significantly higher incidence of target lesion re-occlusion during long-term follow-up period.

scholarly journals The Impact of Online Computer Assisted Learning at Home for Disadvantaged Children in Taiwan: Evidence from a Randomized Experiment

2020 ◽  
Vol 12 (23) ◽  
pp. 10092
Author(s):  
Bin Tang ◽  
Te-Tien Ting ◽  
Chyi-In Wu ◽  
Yue Ma ◽  
Di Mo ◽  
...  
Keyword(s):  
Academic Performance ◽  
Preliminary Evidence ◽  
Average Treatment Effect ◽  
Control Group ◽  
Computer Assisted ◽  
Computer Assisted Learning ◽  
Intention To Treat ◽  
Catch Up ◽  
Standard Deviations ◽  
The Impact

In Taiwan, thousands of students from Yuanzhumin (aboriginal) families lag far behind their Han counterparts in academic achievement. When they fall behind, they often have no way to catch up. There is increased interest among both educators and policymakers in helping underperforming students catch up using computer-assisted learning (CAL). The objective of this paper is to examine the impact of an intervention aimed at raising the academic performance of students using an in-home CAL program. According to intention-to-treat estimates, in-home CAL improved the overall math scores of students in the treatment group relative to the control group by 0.08 to 0.20 standard deviations (depending on whether the treatment was for one or two semesters). Furthermore, Average Treatment Effect on the Treated analysis was used for solving the compliance problem in our experiment, showing that in-home CAL raised academic performance by 0.36 standard deviations among compliers. This study thus presents preliminary evidence that an in-home CAL program has the potential to boost the learning outcomes of disadvantaged students.

scholarly journals The Impact of Beta Blockers on Survival in Heart Transplant Recipients: Insights from the Zabrze HTx Registry

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Grzegorz M. Kubiak ◽  
Radosław Kwieciński ◽  
Agnieszka Ciarka ◽  
Andrzej Tukiendorf ◽  
Piotr Przybyłowski ◽  
...  
Keyword(s):  
Beta Blockers ◽  
Rank Test ◽  
Proportional Hazard ◽  
Transplant Recipients ◽  
Entire Cohort ◽  
Reactive Protein ◽  
Cox Proportional Hazard ◽  
Log Rank Test ◽  
Cox Proportional Hazard Regression ◽  
The Impact

Introduction. The data assessing the impact of beta blocker (BB) medication on survival in patients after heart transplantation (HTx) are scarce and unequivocal; therefore, we investigated this population. Methods. We retrospectively analyzed the HTx Zabrze Registry of 380 consecutive patients who survived the 30-day postoperative period. Results. The percentage of patients from the entire cohort taking BBs was as follows: atenolol 24 (17%), bisoprolol 67 (49%), carvedilol 11 (8%), metoprolol 28 (20%), and nebivolol 8 (6%). The patients receiving BBs were older (56.94 ± 14.68 years vs. 52.70 ± 15.35 years, p=0.008) and experienced an onset of HTx earlier in years (11.65 ± 7.04 vs. 7.24 ± 5.78 p≤0.001). They also had higher hematocrit (0.40 ± 0.05 vs. 0.39 ± 0.05, p=0.022) and red blood cells (4.63 (106/μl) ± 0.71 vs. 4.45 (106/μl) ± 0.68, p=0.015). Survival according to BB medication did not differ among the groups (p=0.655) (log-rank test). Univariate Cox proportional hazard regression analysis revealed that the following parameters were associated with unfavorable diagnosis: serum concentration of albumin (g/l) HR: 0.87, 95% CI (0.81–0.94), p=0.0004; fibrinogen (mg/dl) HR: 1.006, 95% CI (1.002–1.008), p=0.0017; and C-reactive protein (mg/l) HR: 1.014, 95% CI (1.004–1.023), p=0.0044. Conclusions. The use of BBs in our cohort of patients after HTx was not associated with survival benefits.

P2609H2FPEF score as a prognostic value in HFpEF patients

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Sueta ◽  
T Nishihara ◽  
E Yamamoto ◽  
K Tsujita
Keyword(s):  
Confidence Interval ◽  
Cardiovascular Events ◽  
Left Ventricular ◽  
Hazard Ratio ◽  
Left Ventricular Ejection ◽  
Rank Test ◽  
Characteristic Analysis ◽  
Simple Method ◽  
Log Rank Test ◽  
Cerebrovascular Events

Abstract Background The H2FPEF score is recognized as a simple method to diagnose heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). Purpose We investigated the value of the H2FPEF score in predicting subsequent cardiovascular events in HFpEF patients. Methods This study was a retrospective, single-center, observational study. We calculated the H2FPEF scores for 404 consecutive HFpEF patients. Subjects were subdivided into low- (0–3), intermediate- (4–6), and high-score (7–9) groups and followed for 50-months. The primary and secondary endpoints were composite cardiovascular/ cerebrovascular events (cardiovascular death, non-fatal myocardial infarction, unstable angina pectoris, hospitalization for HF decompensation and non-fatal stroke) occurrence and HF-related events (hospitalization for HF decompensation) occurrence at 50-months, respectively. Results Kaplan–Meier analyses demonstrated a significantly higher incidence of cardiovascular/cerebrovascular events in proportion to a higher H2FPEF score (log-rank test, P=0.005). The HF-related event rate was higher in proportion to the H2FPEF score (log-rank test, P<0.001). Multivariate Cox hazard analyses identified the H2FPEF score (per 1 point) as an independent predictor of cardiovascular and HF-related events (Table, hazard ratio, 1.179; 95% confidence interval, 1.066–1.305; P=0.001 and hazard ratio, 1.288; 95% confidence interval, 1.134–1.463; P=0.001, respectively). Receiver operating characteristic analysis showed that the H2FPEF significantly predicted cardiovascular events (Figure A, AUC 0.626, 95% CI 0.557–0.693; P<0.001) and HF-related events (Figure B, AUC 0.680, 95% CI 0.600–0.759; P<0.001). The cutoff H2FPEF score was 5.5 for the identification of cardiovascular and HF-related events. Conclusion The H2FPEF score is a potentially useful marker for the prediction of cardiovascular and HF-related events in HFpEF patients.

The Impact of Social Support on the Survival of Chinese Peritoneal Dialysis Patients

2008 ◽  
Vol 28 (3) ◽  
pp. 252-258 ◽  
Author(s):  
Cheuk-Chun Szeto ◽  
Kai-Ming Chow ◽  
Bonnie Ching-Ha Kwan ◽  
Man-Ching Law ◽  
Kwok-Yi Chung ◽  
...  
Keyword(s):  
Social Support ◽  
Peritoneal Dialysis ◽  
Rank Test ◽  
Actuarial Survival ◽  
Dialysis Adequacy ◽  
Technique Survival ◽  
Risk Of Death ◽  
Log Rank Test ◽  
Point Increase ◽  
The Impact

Background Social support is an independent risk factor for mortality among new hemodialysis patients. We evaluated the effect of social support on the outcome of Chinese peritoneal dialysis (PD) patients. Methods We studied 167 prevalent PD patients. They completed the Medical Outcomes Study Social Support Survey, Chinese Version (MOS-SSS-C) questionnaire. Patients were followed for 1 year. Outcome measures included change in nutritional status, hospitalization, and technique and actuarial patient survival. Results Actuarial survival was 57.1%, 72.7%, 85.3%, and 88.6% for MOS-SSS-C total score quartiles I, II, III, and IV, respectively (log rank test, p = 0.037). Technique survival was 57.1%, 81.9%, 91.9%, and 91.4% (log rank test, p = 0.0044). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, every 1 point increase in MOS-SSS-C total score was associated with a 0.6% [95% confidence interval (CI) 0.2% – 0.9%, p = 0.003] reduction in the risk of death and a 0.5% (95%CI 0.1% – 1.0%, p = 0.037) reduction in the risk of technique failure. The MOS-SSS-C score had no significant effect on change in nutritional or dialysis adequacy indices, hospitalization, or number of peritonitis episodes in 1 year. Conclusion The degree of social support is an important predictor of actuarial and technique survival in Chinese PD patients. Measures to enhance social support may represent an easily achievable means of improving the clinical outcome of PD patients.

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