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Zhongwei Li
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skills/clinical-decision-support/assets/example_gbm_cohort.md
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skills/clinical-decision-support/assets/example_gbm_cohort.md
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# Example: GBM Molecular Subtype Cohort Analysis
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## Clinical Context
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This example demonstrates a patient cohort analysis stratified by molecular biomarkers, similar to the GBM Mesenchymal-Immune-Active cluster analysis provided as reference.
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## Cohort Overview
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**Disease**: Glioblastoma (GBM), IDH-wild-type
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**Study Population**: n=60 patients with newly diagnosed GBM treated with standard Stupp protocol (temozolomide + radiation → adjuvant temozolomide)
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**Molecular Classification**: Verhaak 2010 subtypes with immune signature refinement
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- **Group A**: Mesenchymal-Immune-Active subtype (n=18, 30%)
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- **Group B**: Other molecular subtypes (Proneural, Classical, Neural) (n=42, 70%)
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**Study Period**: January 2019 - December 2022
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**Data Source**: Single academic medical center, retrospective cohort analysis
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## Biomarker Classification
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### Mesenchymal-Immune-Active Subtype Characteristics
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**Molecular Features**:
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- NF1 alterations (mutations or deletions): 72% (13/18)
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- High YKL-40 (CHI3L1) expression: 100% (18/18, median z-score +2.8)
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- Immune gene signature: Elevated (median ESTIMATE immune score +1250)
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- CD163+ macrophage infiltration: High density (median 195 cells/mm², range 120-340)
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- MES (mesenchymal) signature score: >0.5 (all patients)
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**Clinical Characteristics**:
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- Median age: 64 years (range 42-76)
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- Male: 61% (11/18)
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- Tumor location: Temporal lobe predominant (55%)
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- Multifocal disease: 33% (6/18) - higher than overall cohort
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### Comparison Groups (Other Subtypes)
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**Molecular Features**:
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- Proneural: n=15 (25%) - PDGFRA amplification, younger age
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- Classical: n=18 (30%) - EGFR amplification, chromosome 7+/10-
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- Neural: n=9 (15%) - neuronal markers, may include normal tissue
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## Treatment Outcomes
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### Response Assessment (RANO Criteria)
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**Objective Response Rate** (after chemoradiation, ~3 months):
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- Mesenchymal-Immune-Active: 6/18 (33%) - CR 0, PR 6
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- Other subtypes: 18/42 (43%) - CR 1, PR 17
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- p = 0.48 (Fisher's exact)
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**Interpretation**: No significant difference in initial response rates
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### Survival Outcomes
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**Progression-Free Survival (PFS)**:
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- Mesenchymal-Immune-Active: Median 7.2 months (95% CI 5.8-9.1)
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- Other subtypes: Median 9.5 months (95% CI 8.1-11.3)
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- Hazard Ratio: 1.58 (95% CI 0.89-2.81), p = 0.12
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- 6-month PFS rate: 61% vs 74%
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**Overall Survival (OS)**:
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- Mesenchymal-Immune-Active: Median 12.8 months (95% CI 10.2-15.4)
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- Other subtypes: Median 16.3 months (95% CI 14.7-18.9)
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- Hazard Ratio: 1.72 (95% CI 0.95-3.11), p = 0.073
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- 12-month OS rate: 55% vs 68%
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- 24-month OS rate: 17% vs 31%
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**Interpretation**: Trend toward worse survival in mesenchymal-immune-active subtype, not reaching statistical significance in this cohort size
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### Response to Bevacizumab at Recurrence
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**Subset Analysis** (patients receiving bevacizumab at first recurrence, n=35):
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- Mesenchymal-Immune-Active: n=12
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- ORR: 58% (7/12)
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- Median PFS2 (from bevacizumab start): 6.8 months
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- Other subtypes: n=23
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- ORR: 35% (8/23)
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- Median PFS2: 4.2 months
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- p = 0.19 (Fisher's exact for ORR)
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- HR for PFS2: 0.62 (95% CI 0.29-1.32), p = 0.21
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**Interpretation**: Exploratory finding suggesting enhanced benefit from bevacizumab in mesenchymal-immune-active subtype (not statistically significant with small sample)
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## Safety Profile
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**Treatment-Related Adverse Events** (Temozolomide):
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No significant differences in toxicity between molecular subtypes:
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- Lymphopenia (any grade): 89% vs 86%, p = 0.77
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- Thrombocytopenia (grade 3-4): 22% vs 19%, p = 0.79
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- Fatigue (any grade): 94% vs 90%, p = 0.60
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- Treatment discontinuation: 17% vs 14%, p = 0.77
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## Clinical Implications
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### Treatment Recommendations
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**For Mesenchymal-Immune-Active GBM**:
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1. **First-Line**: Standard Stupp protocol (no change based on subtype)
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- Evidence: No proven benefit for alternative first-line strategies
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- GRADE: 1A (strong recommendation, high-quality evidence)
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2. **At Recurrence - Consider Bevacizumab Earlier**:
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- Rationale: Exploratory data suggesting enhanced anti-angiogenic response
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- Evidence: Mesenchymal GBM has high VEGF expression, angiogenic phenotype
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- GRADE: 2C (conditional recommendation, low-quality evidence from subset)
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3. **Clinical Trial Enrollment - Immunotherapy Combinations**:
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- Rationale: High immune cell infiltration may predict immunotherapy benefit
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- Targets: PD-1/PD-L1 blockade ± anti-CTLA-4 or anti-angiogenic agents
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- Evidence: Ongoing trials (CheckMate-498, CheckMate-548 showed negative results, but did not select for immune-active)
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- GRADE: R (research recommendation)
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**For Other GBM Subtypes**:
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- Standard treatment per NCCN guidelines
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- Consider tumor treating fields (Optune) after radiation completion
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- Clinical trials based on specific molecular features (EGFR amplification → EGFR inhibitor trials)
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### Prognostic Information
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**Counseling Patients**:
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- Mesenchymal-immune-active subtype associated with trend toward shorter survival (12.8 vs 16.3 months)
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- Not definitive due to small sample size and confidence intervals overlapping
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- Prospective validation needed
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- Should not alter standard first-line treatment
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## Study Limitations
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1. **Small Sample Size**: n=18 in mesenchymal-immune-active group limits statistical power
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2. **Retrospective Design**: Potential selection bias, unmeasured confounders
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3. **Single Institution**: May not generalize to other populations
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4. **Heterogeneous Recurrence Treatment**: Not all patients received bevacizumab; treatment selection bias
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5. **Molecular Classification**: Based on bulk tumor RNA-seq; intratumoral heterogeneity not captured
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6. **No Central Pathology Review**: Molecular classification performed locally
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## Future Directions
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1. **Prospective Validation**: Confirm survival differences in independent cohort (n>100 per group for adequate power)
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2. **Biomarker Testing**: Develop clinically feasible assay for mesenchymal-immune subtype identification
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3. **Clinical Trial Design**: Immunotherapy combinations targeting mesenchymal-immune-active GBM specifically
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4. **Mechanistic Studies**: Investigate why mesenchymal-immune GBM may respond better to bevacizumab
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5. **Longitudinal Analysis**: Track molecular subtype evolution over treatment course
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## Data Presentation Example
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### Baseline Characteristics Table
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```
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Characteristic Mesenchymal-IA (n=18) Other (n=42) p-value
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Age, years (median [IQR]) 64 [56-71] 61 [53-68] 0.42
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Sex, n (%)
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Male 11 (61%) 24 (57%) 0.78
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Female 7 (39%) 18 (43%)
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ECOG PS, n (%)
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0-1 15 (83%) 37 (88%) 0.63
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2 3 (17%) 5 (12%)
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Tumor location
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Frontal 4 (22%) 15 (36%) 0.35
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Temporal 10 (56%) 16 (38%)
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Parietal/Occipital 4 (22%) 11 (26%)
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Extent of resection
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Gross total 8 (44%) 22 (52%) 0.58
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Subtotal 10 (56%) 20 (48%)
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MGMT promoter methylated 5 (28%) 18 (43%) 0.27
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```
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### Survival Outcomes Summary
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```
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Endpoint Mesenchymal-IA Other HR (95% CI) p-value
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Median PFS, months (95% CI) 7.2 (5.8-9.1) 9.5 (8.1-11.3) 1.58 (0.89-2.81) 0.12
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6-month PFS rate 61% 74%
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Median OS, months (95% CI) 12.8 (10.2-15.4) 16.3 (14.7-18.9) 1.72 (0.95-3.11) 0.073
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12-month OS rate 55% 68%
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24-month OS rate 17% 31%
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```
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## Key Takeaways
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1. **Molecular heterogeneity exists** in GBM with distinct subtypes
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2. **Mesenchymal-immune-active subtype** characterized by NF1 alterations, immune infiltration
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3. **Trend toward worse prognosis** but not statistically significant (power limitations)
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4. **Potential bevacizumab benefit** hypothesis-generating, requires prospective validation
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5. **Immunotherapy target**: High immune infiltration rational for checkpoint inhibitor trials
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6. **Clinical implementation pending**: Need prospective validation before routine subtyping
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## References
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1. Verhaak RG, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110.
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2. Wang Q, et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017;32(1):42-56.
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3. Stupp R, et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. NEJM. 2005;352(10):987-996.
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4. Gilbert MR, et al. Bevacizumab for Newly Diagnosed Glioblastoma. NEJM. 2014;370(8):699-708.
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5. NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2024.
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---
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**This example demonstrates**:
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- Biomarker-based stratification methodology
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- Outcome reporting with appropriate statistics
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- Clinical contextualization of findings
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- Evidence-based recommendations with grading
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- Transparent limitation discussion
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- Structure suitable for pharmaceutical/clinical research documentation
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