20240722_183212

Clinical

Combining MBMs Multi-Modal Biomarkers and Biomarker Panels

i) Heterogeneity between patients

ii) Heterogeneity between - sensitivity: a) MG number vs function b) proximal vs downstream c) acute vs chronic; TBI symptoms and pathophysiology vary from patient to patient and over time across; therefore, a single biomarker is not sufficient for diagnosis, prognosis, or monitoring

iii) ↑ power (specificity)

결국 이들이 모두 우리익에 듣는다.

NLRP3 clinical

- Pooloed: hard to get 3 pooled samples. Is just average acceptable? - Combined decision making? With CSF BM? - Tspo (and other BMs) difference data prerequisite? But the data won't be available in p1b. - What about mab/lab? For phase 2/3? - Intermediate outcome - PoC as "the earliest point in the drug development process at which the weight of evidence suggests that it is 'reasonably likely' that the key attributes for success are present and the key causes of failure are absent" [risk discharge] TE/PE → DR (ePOC) → Interim 이 i) framework 를 명확히 보이고, ii) 왜 ePOC 이 없는지, 왜 datscan/vmat 이 Epoc 이 못 되는지 명확히 보이자.

20221107

Epoc can mean: phase 1, interim ph2, Gray zone: consider other BM Statistical significance: no need, TSPO longi data: needed before ph1b

Comp Bio

PD

region	study cohorts				mRNA			Protein
	SN 99 PD, 86 HC	SN 85 PD, 73 HC	SN 50 PD, 43 HC	SN 151 PD, 130 HC	Altered? (baseline, T0)	Correlation with Baseline severity / progression?	Correlation with each other	Altered?	Longi progression	Correlation with Baseline severity / progression??	Correlation with each other
brain	No gene level info, just pathway level	No	No	No (slight dec)	{Smajić, 2021 #2054} midbrain, all cell types 6 PD, 5 control: ↑ (IL1B, GPNMB and HSP90AA1)			N/A	Not in paper
	No gene level info, just pathway level	No	No	No (slight dec)				N/A	Not in paper
	No gene level info, just pathway level	No	No	No				N/A	Not in paper
	No gene level info, just pathway level	No	No	No (slight dec)				N/A	Not in paper
	No gene level info, just pathway level	No	No	Yes, FC (PD/cont)=1.33, p-val=0.025
	No gene level info, just pathway level	No	No	No (slight dec)
	No gene level info, just pathway level	No	No	No
(continued region rows)	Additional rows visible at left (sample sizes 227 PD, 200 HC under SN, STR, FC, BA9 and 81 PD, 83 HC under SN, PT, GP, BA9): values include = (1.05 increase), Inc (1.45), Inc (1.22).
brain	{Smajić, 2022 #2054}				{Smajić, 2021 #2054} midbrain, all cell types 6 PD, 5 control: ↑ (IL1B, GPNMB and HSP90AA1)	Baseline severity 와 progression 을 구분해야겠다
CSF								(SLIDE13) NLRP3: NA, ASC: NA, GSDMD, HMGB1: na Caspase1: = (majority under LOD) IL1B (majority under LOD) (둘 합치면 n=100 vs 80): PPMI, PDBP 둘다에서 =, but 우리 MetaA: Hedges's hog 0.27 Il18 (all over LOD): =, MIF (all over LOD) =,	Caspase1: = (majority under LOD) reduce IL1B (majority under LOD) reduce Il18 (all over LOD): Faster increase in PD (3.875 Fold) MIF (all over LOD) Faster increase in PD	(SLIDE15,) NLRP3: NA ASC: NA, Caspase1, IL1B, Il18 MIF: all no correlation with BL or progression	Gap! (근데 Daria 는 안 됨, NLRP3&ASC 없으니, 우리가 직접 할까?) 만약 Correlation 있게 나오고,
blood (W/o genetic PD)								아래 값들 다 슬라이드와 틀린데? w/o genetic PD 라 그런가? NLRP3: ↑ X 1.03 (significant x) & 1.08 (significant), ASC: ↑ X 1.05 (significant x) & 1.10 (significant) Caspase1:, ↑ X1.07 (significant) & 1.07 (significant) IL-1B: ↑ X1.12 (significant) & 1.11 (significant) IL18: ↑ X1.02 (significant X) & 1.07 (significant) MIF: ↓ & 1.06 (significant X) HMGB1: ↓ & ↑		(SLIDE14) No correlation, (겨우 HMGB1 만 Baseline UPDRSIII 와 very weak Negative correlation) Baseline severity 와 progression 을 구분해야겠다	(아마 blood) NLRP3 correlation: ASC (~0.5), Caspase-1 (~0.4), Il1b (~0.4), IL18 (~0.2-0.3), MIF (weak Negative correlation)
blood								(slide13) NLRP3, ASC, GSDMD, HMGB1: na Caspase1: (majority below LOD about 30-40% BLOD) -IL1B (majority over LOD, ? 아니 below LOD 인데?)) (둘 합치면 n=100 vs 80): PPMI, PDBP 둘다에서 =, but 우리 MetaA: Hedges's hog 1.41 Il18: = MIF: =	Caspase1: = (about 30-40% BLOD) increase, faster increase in PD IL1B (majority over LOD MIF: (?over LOD) Faster increase in PD Il18 (all over LOD): Faster increase in PD (?Fold)	(SLIDE15,) NLRP3: NA ASC: NA, Caspase1, IL1B, Il18 MIF: all no correlation w BL MDS-UPDRS III [progression 분석] IL1B correlate with UPDRSIII progression (PPMI 에서만) (FDR_BH: 0.0318) MIF correlate with UPDRSIII progression (PPMI 에서만) (FDR_BH: 0.028) Caspase1 과 IL18 은 no correlation.	Gap (but pointless since NLRP3 and ASC are not available)!
(IL1R)								[IL1R] PPMI: BL 에서는 줄어보이고, 비슷하다가, y4 에서 증가, PDBP: no significant finding	[IL1R] PPMI: HC 은 no progression PD 는 progress but heteroscedastic, not linear) PDBP: no significant finding	NLRP3, ASC IL1B, IL18: all slightly ↑,	IL1B: Very weak correlation with & H&Y (Effect size: 0.030, 이것도 PPMI 에서만, 이게 20230217 에 Daria 가 SD NS Biology Monthly Meeting 에서 발표한 건가? ), no correlation with MDS-UPDRS III (ie FDR BH > 0.05), MDS-UPDRS total 은 na

Somascan Interleukins (Protein level: 20230803 excel (somascan.ppmi_assoc_summary-8-3-23.xlsx, 20230804 ppt))

Gene	Somascan Protein ID	Difference PD vs HC?			Missing rate
		20230803	20240312
IL1A	4851-25_1	↑, FDR<0.05	↑, nominal p-value <0.05, FDR>0.05	same
IL1R1	2991-9_2

Uncertain Spans

location	transcription	uncertainty
Comp Bio brain rows	sample-size labels SN 99/86, 85/73, 50/43, 151/130	The exact mapping of each row to its dataset citation is partly cut at the left edge of the body crop; only the values are clearly readable.
Comp Bio header Altered? (baseline, T0)	column-group header for mRNA	Header row spans multiple columns; rendered as a single header for the mRNA group.
결국 이들이 모두 우리익에 듣는다	Korean note 우리익	우리익에 may be a handwritten contraction of 우리에게/우리의에 ; preserved verbatim.
Hedges’s hog 0.27 / 1.41	hog	Source contains apparent typo hog for g (Hedges’s g); preserved verbatim because it appears twice in the page consistently.
IL18 fold	(3.875 Fold)	Trailing fold value verifiable on row but small; preserved as visible.