image and data analysis for spatially resolved...
TRANSCRIPT
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ACTAUNIVERSITATIS
UPSALIENSISUPPSALA
2020
Digital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Science and Technology 1964
Image and Data Analysis forSpatially Resolved Transcriptomics
Decrypting fine-scale spatial heterogeneity of tissue'smolecular architecture
GABRIELE PARTEL
ISSN 1651-6214ISBN 978-91-513-1003-9urn:nbn:se:uu:diva-419173
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Dissertation presented at Uppsala University to be publicly examined in Room 4307,Ångströmlaboratoriet, Lägerhyddsvägen 2, Uppsala, Thursday, 29 October 2020 at 14:00 forthe degree of Doctor of Philosophy. The examination will be conducted in English. Facultyexaminer: Professor Roland Eils (Charité-Universitätsmedizin Berlin and Berlin Institute ofHealth).
AbstractPartel, G. 2020. Image and Data Analysis for Spatially Resolved Transcriptomics. Decryptingfine-scale spatial heterogeneity of tissue's molecular architecture. Digital ComprehensiveSummaries of Uppsala Dissertations from the Faculty of Science and Technology 1964. 59 pp.Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-1003-9.
Our understanding of the biological complexity in multicellular organisms has progressed attremendous pace in the last century and even more in the last decades with the advent ofsequencing technologies that make it possible to interrogate the genome and transcriptome ofindividual cells. It is now possible to even spatially profile the transcriptomic landscape oftissue architectures to study the molecular organization of tissue heterogeneity at subcellularresolution. Newly developed spatially resolved transcriptomic techniques are producing largeamounts of high-dimensional image data with increasing throughput, that need to be processedand analysed for extracting biological relevant information that has the potential to lead to newknowledge and discoveries. The work included in this thesis aims to provide image and dataanalysis tools for serving this new developing field of spatially resolved transcriptomics tofulfill its purpose. First, an image analysis workflow is presented for processing and analysingimages acquired with in situ sequencing protocols, aiming to extract and decode molecularfeatures that map the spatial transcriptomic landscape in tissue sections. This thesis alsopresents computational methods to explore and analyse the decoded spatial gene expressionfor studying the spatial molecular heterogeneity of tissue architectures at different scales.In one case, it is demonstrated how dimensionality reduction and clustering of the decodedgene expression spatial profiles can be exploited and used to identify reproducible spatialcompartments corresponding to know anatomical regions across mouse brain sections fromdifferent individuals. And lastly, this thesis presents an unsupervised computational method thatleverages advanced deep learning techniques on graphs to model the spatial gene expressionat cellular and subcellular resolution. It provides a low dimensional representation of spatialorganization and interaction, finding functional units that in many cases correspond to differentcell types in the local tissue environment, without the need for cell segmentation.
Keywords: iss, image, processing, clustering, deep learning, GCN, graph
Gabriele Partel, Department of Information Technology, Division of Visual Information andInteraction, Box 337, Uppsala University, SE-751 05 Uppsala, Sweden.
© Gabriele Partel 2020
ISSN 1651-6214ISBN 978-91-513-1003-9urn:nbn:se:uu:diva-419173 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-419173)
Defence on Zoom: https://uu-se.zoom.us/j/62337809210
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detector
emission lter
exitation lterobjective
specimen
Dichromaticmirror
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d
d =λ
2 ·NA,
λ NA
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Hyb round 1 Hyb round 2 Hyb round 3 Coding scheme
osmFISH
mRNA 1
mRNA 2
mRNA 3
round
1
round
2
round
3
gene 1gene 2gene 3
round
1
round
2
round
3
gene 1gene 2gene 3gene n
MERFISH
mRNA mRNA mRNA
gene 1gene 2gene 3gene n
bitround 1 round 2 round 3
SeqFISH
mRNA mRNAmRNA
mRNA mRNA mRNA
SeqFISH (smHCR)
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ln
n = 4l
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Anchorprimer
BarcodeLinker(5th base)
Linker5' arm 3' arm
Padlock probe
mRNA
cDNA
cDNA
Cycle 4
Cycle 1
Cycle 2
Ligation& RCA
Padlock probeHybridization
Sample preparationmRNA
Reversetranscription& RNase H
RT primer
GACT
Sequencing
CTGAGNNN
CTGANANN
CTGANNNT
Cycle 3
CTGANNCN
41
42
43
44
Detectabletargets
DAPI +color channels
DAPI +decoded signals
Nucleichannel
Anchorchannel
Tchannel
Gchannel
Cchannel
Acahnnel
Cycle 1 Cycle 2 Cycle 3 Cycle 4 5th base
Mouse braina
b
c
d
IM IRT θ
L IM IR
θL(T (IM , θ), IR)
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IR T (IM )
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Nuclei image Gaussian blurring( = 5)
Watershedlabels
Inverted smoothed image
Thresholded image Histogram
Otzu threshold
Inverteddistance transform
Watershedlabels
ISE
Tw(I) = I − I ◦ SE
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Originalimage
Top-hattransformed
◦
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G = (V,E)V E eu,v ∈ E u v
wu,v
eu,v wu,v
st (G,w, s, t)
s− t C = (S, T ) Vs ∈ S t ∈ T
∑eu,v∈XC
wu,v
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XC ST
XC = {eu,v ∈ E : u ∈ S, v ∈ T}.
s − t
π s tπ π
G = (V,E,w, s, t) f Gπ G
π s tfu,v < wu,v eu,v π
S T
cu,v ∈ R
f
c(f) =∑
eu,v∈Efu,v · cu,v.
π st
cu,v ππ π
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Image Segmented image
source
sink
s
t
source
sink
u
v
s
t
wu,v
optimal s-tcut
K hf̂ X1, X2, . . . , Xn
f̂h(x) =1
nh
n∑i=1
K
(x−Xi
h
),
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∫K(t)dt = 1 f̂h(x)
pq
DKL(p||q) =N∑i=1
p(xi) ·p(xi)
q(xi).
p qp q
y
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y = b+∑i
xiwi,
xi wi b
f(y) = (y, 0)
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n
softmax(y) =eyn∑i e
yi
Input layer (L0)
Hidden layer (L1)
Hidden layer (L2)
Output layer (L3)
j
z
Forward pass
i
k
l l
k
j
i
Backward passz
a
x1
x2
x3
w1w2
w3
Neuron Activationfunction
b
y f(y)
bKernel
Receptive eldActivation map
Convolutional layerc
3 ×3
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−M∑c=1
yc (pc),
M ycc pc
c
lwij
∂l
∂wij=
∂l
∂z
∂z
∂yj
∂yj∂wij
,
lz z
jth yj yji j wij
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M
MT cov(X)M
M cov(X)X
cov(X)M = λM,
λ d XX
YY = XM.
X
W HX ≈ WH.
X ∈ Rp×n
W ∈ Rp×r H ∈ R
r×n
p r p < r W
HW
XW W H
W,H‖X −WH‖2F , s.t.W,H ≥ 0.
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XD d d < D d � D
X
k
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G = (V,X,A) V ∈ Rn
A ∈ Rn×n
X ∈ Rm×n
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GCNCNN
uK
uK
u
h0u = Xu ;
hku = σ
⎛⎜⎝Wk
∑v∈N (u)
hk−1v
|N (u)| +Bkhk−1u
⎞⎟⎠ , ∀k ∈ 1, . . . ,K ;
zu = hKu ;
Xu u h
N (u) u σ Wk Bk
zuu u
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D
B
C
FE
A
D
B
C BEF
C
A
A
A
A
h0h1
z
a b
F
C E
C FB E FA
D
A
BC DB E FA
CA
BC D
B C
C E
F E
C F
E
C EB E FA
FC
c
zA
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ec c ξ
ξ =K2
c
2m,
Kc
c mη
η =1
2m
∑c
(ec − γξ),
γ
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a
sa ta
sb tb
b
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Acta Universitatis UpsaliensisDigital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Science and Technology 1964
Editor: The Dean of the Faculty of Science and Technology
A doctoral dissertation from the Faculty of Science andTechnology, Uppsala University, is usually a summary of anumber of papers. A few copies of the complete dissertationare kept at major Swedish research libraries, while thesummary alone is distributed internationally throughthe series Digital Comprehensive Summaries of UppsalaDissertations from the Faculty of Science and Technology.(Prior to January, 2005, the series was published under thetitle “Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Science and Technology”.)
Distribution: publications.uu.seurn:nbn:se:uu:diva-419173
ACTAUNIVERSITATIS
UPSALIENSISUPPSALA
2020