Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND...

103
Super-resolution of Positive Sources Veniamin I. Morgenshtern Statistics Department, Stanford Joint work with Emmanuel Cand` es

Transcript of Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND...

Page 1: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Super-resolution of Positive Sources

Veniamin I. Morgenshtern

Statistics Department, Stanford

Joint work with Emmanuel Candes

Page 2: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Diffraction limits resolution:

λc =λLIGHT

2n sin(θ)

MicroscopeObject Detector

Entrance Pupil Exit Pupil

θ

Ernst Abbe

2 / 50

Page 3: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Diffraction limits resolution: λc =λLIGHT

2n sin(θ)

MicroscopeObject Detector

Entrance Pupil Exit Pupil

θ

0 1

Object

0 1

λcDetector

2 / 50

Page 4: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

THE NOBEL PRIZE IN CHEMISTRY 2014POPULAR SCIENCE BACKGROUND

How the optical microscope became a nanoscope

Eric Betzig, Stefan W. Hell and William E. Moerner are awarded the Nobel Prize in Chemistry 2014 for having bypassed a presumed scientific limitation stipulating that an optical microscope can never yield a resolution better than 0.2 micrometres. Using the fluorescence of molecules, scientists can now monitor the interplay between individual molecules inside cells; they can observe disease-related proteins aggregate and they can track cell division at the nanolevel.

Red blood cells, bacteria, yeast cells and spermatozoids. When scientists in the 17th century for the first time studied living organisms under an optical microscope, a new world opened up before their eyes. This was the birth of microbiology, and ever since, the optical microscope has been one of the most important tools in the life-sciences toolbox. Other microscopy methods, such as electron microscopy, require preparatory measures that eventually kill the cell.

Glowing molecules surpassing a physical limitationFor a long time, however, optical microscopy was held back by a physical restriction as to what size of structures are possible to resolve. In 1873, the microscopist Ernst Abbe published an equation demonstrating how microscope resolution is limited by, among other things, the wavelength of the light. For the greater part of the 20th century this led scientists to believe that, in optical microscopes, they would never be able to observe things smaller than roughly half the wavelength of light, i.e., 0.2 micrometres (figure 1). The contours of some of the cells’ organelles, such as the powerhouse mitochondria, were visible. But it was impossible to discern smaller objects and, for instance, to follow the interaction between individual protein molecules in the cell. It is somewhat akin to being able to see the buildings of a city without being able to discern how citizens live and go about their lives. In order to fully understand how a cell functions, you need to be able to track the work of individual molecules.

Abbe’s equation still holds but has been bypassed just the same. Eric Betzig, Stefan W. Hell and William E. Moerner are awarded the Nobel Prize in Chemistry 2014 for having taken optical microscopy into a new dimension using fluorescent molecules. Theoretically there is no longer any structure too small to be studied. As a result, microscopy has become nanoscopy.

ABBE’S DIFFRACTION LIMIT (0.2 µm)

1nm10 nm100 nm1µm10µm100µm1 mm

small moleculeproteinvirusmitochondrionbacteriummammalian cellhairant

Nob

el P

rize®

is a

regi

ster

ed tr

adem

ark

of th

e N

obel

Fou

ndat

ion.

Figure 1. At the end of the 19th century, Ernst Abbe defined the limit for optical microscope resolution to roughly half the wavelength of light, about 0.2 micrometre. This meant that scientists could distinguish whole cells, as well as some parts of the cell called organelles. However, they would never be able to discern something as small as a normal-sized virus or single proteins.[picture from nobelprize.org]

3 / 50

Page 5: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Looking inside the cell: conventional microscopy

microtubule

4 / 50

Page 6: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Nobel Prize in Chemistry 2014

Eric Betzig Stefan W. Hell W.E. Moerner

Invention of single-molecule microscopy

5 / 50

Page 7: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Looking inside the cell

conventional microscopy single-molecule microscopy

6 / 50

Page 8: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Single molecule microscopy(basics)

7 / 50

Page 9: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Controlled photoactivation

Green fluorescent protein (GFP)

11 (15)

Figure 7: (Dickson et al., 1997, Nature 388, 355-358). GFP in state A is excited to A* and returns to A upon photon emission. When I is reached from A, there is no fluorescence until I spontaneously moves to A: blinking. When I moves to N, there is no fluorescence until N is activated to N* by 405 nm excitation and GFP returns to A. Moerner’s demonstration of blinking and photo activation opened the road to exploring a vast space of GFP mutants for novel optical properties. J. Lippincott-Swartz engineered a GFP variant with striking properties (Patterson and Lippincott-Schwartz, 2002). This mutant is initially optically inactive. It can, however, be activated by irradiation at 413 nm and then displays fluorescence when excited at 488 nm. Eventually, after intense irradiation at 488 nm the mutant is irreversibly inactivated by photo bleaching. When Betzig returned to academic science after his post-near-field exile in private industry, he learnt about Lippincott-Schwartz’ mutant and realized that it could possibly solve the problem of finding an optimal way to combine sparse sets of fluorophores with distinct spectral properties to a dense total set of fluorophores. The simple solution would be to activate a very small and thus sparse, random subset of GFP mutant molecules in a biological structure by low-level irradiation at 413 nm. Subsequent irradiation at 488 nm would then be used to determine the positions of the members of the sparse subset at super-resolution, according to Eq. 5 above. When the first subset had been irreversibly inactivated by bleaching, a second small subset could be activated and the positions of its members determined at high resolution, and so on until all subsets had been sampled and used to determine the structure under authentic super-resolution conditions. This fulfilled both the condition of only a sparse subset being observed at a time, and the condition of high-frequency (dense) spatial sampling in order to fulfill the Nyqvist and Shannon theorems, as illustrated in Fig. 8.

Energy states [Dickson et.al. ’97]

State A is excited to A∗ and returns to A upon photon emission

When I is reached from A there is no fluorescence until Ispontaneously moves to A (blinking)

When I moves to N there is no fluorescence until N is activatedby 405nm light and GFP returns to A

8 / 50

Page 10: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Controlled photoactivation

Green fluorescent protein (GFP)

11 (15)

Figure 7: (Dickson et al., 1997, Nature 388, 355-358). GFP in state A is excited to A* and returns to A upon photon emission. When I is reached from A, there is no fluorescence until I spontaneously moves to A: blinking. When I moves to N, there is no fluorescence until N is activated to N* by 405 nm excitation and GFP returns to A. Moerner’s demonstration of blinking and photo activation opened the road to exploring a vast space of GFP mutants for novel optical properties. J. Lippincott-Swartz engineered a GFP variant with striking properties (Patterson and Lippincott-Schwartz, 2002). This mutant is initially optically inactive. It can, however, be activated by irradiation at 413 nm and then displays fluorescence when excited at 488 nm. Eventually, after intense irradiation at 488 nm the mutant is irreversibly inactivated by photo bleaching. When Betzig returned to academic science after his post-near-field exile in private industry, he learnt about Lippincott-Schwartz’ mutant and realized that it could possibly solve the problem of finding an optimal way to combine sparse sets of fluorophores with distinct spectral properties to a dense total set of fluorophores. The simple solution would be to activate a very small and thus sparse, random subset of GFP mutant molecules in a biological structure by low-level irradiation at 413 nm. Subsequent irradiation at 488 nm would then be used to determine the positions of the members of the sparse subset at super-resolution, according to Eq. 5 above. When the first subset had been irreversibly inactivated by bleaching, a second small subset could be activated and the positions of its members determined at high resolution, and so on until all subsets had been sampled and used to determine the structure under authentic super-resolution conditions. This fulfilled both the condition of only a sparse subset being observed at a time, and the condition of high-frequency (dense) spatial sampling in order to fulfill the Nyqvist and Shannon theorems, as illustrated in Fig. 8.

Energy states [Dickson et.al. ’97]

State A is excited to A∗ and returns to A upon photon emission

When I is reached from A there is no fluorescence until Ispontaneously moves to A (blinking)

When I moves to N there is no fluorescence until N is activatedby 405nm light and GFP returns to A

8 / 50

Page 11: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Controlled photoactivation

Green fluorescent protein (GFP)

11 (15)

Figure 7: (Dickson et al., 1997, Nature 388, 355-358). GFP in state A is excited to A* and returns to A upon photon emission. When I is reached from A, there is no fluorescence until I spontaneously moves to A: blinking. When I moves to N, there is no fluorescence until N is activated to N* by 405 nm excitation and GFP returns to A. Moerner’s demonstration of blinking and photo activation opened the road to exploring a vast space of GFP mutants for novel optical properties. J. Lippincott-Swartz engineered a GFP variant with striking properties (Patterson and Lippincott-Schwartz, 2002). This mutant is initially optically inactive. It can, however, be activated by irradiation at 413 nm and then displays fluorescence when excited at 488 nm. Eventually, after intense irradiation at 488 nm the mutant is irreversibly inactivated by photo bleaching. When Betzig returned to academic science after his post-near-field exile in private industry, he learnt about Lippincott-Schwartz’ mutant and realized that it could possibly solve the problem of finding an optimal way to combine sparse sets of fluorophores with distinct spectral properties to a dense total set of fluorophores. The simple solution would be to activate a very small and thus sparse, random subset of GFP mutant molecules in a biological structure by low-level irradiation at 413 nm. Subsequent irradiation at 488 nm would then be used to determine the positions of the members of the sparse subset at super-resolution, according to Eq. 5 above. When the first subset had been irreversibly inactivated by bleaching, a second small subset could be activated and the positions of its members determined at high resolution, and so on until all subsets had been sampled and used to determine the structure under authentic super-resolution conditions. This fulfilled both the condition of only a sparse subset being observed at a time, and the condition of high-frequency (dense) spatial sampling in order to fulfill the Nyqvist and Shannon theorems, as illustrated in Fig. 8.

Energy states [Dickson et.al. ’97]

State A is excited to A∗ and returns to A upon photon emission

When I is reached from A there is no fluorescence until Ispontaneously moves to A (blinking)

When I moves to N there is no fluorescence until N is activatedby 405nm light and GFP returns to A

8 / 50

Page 12: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Controlled photoactivation

Green fluorescent protein (GFP)

11 (15)

Figure 7: (Dickson et al., 1997, Nature 388, 355-358). GFP in state A is excited to A* and returns to A upon photon emission. When I is reached from A, there is no fluorescence until I spontaneously moves to A: blinking. When I moves to N, there is no fluorescence until N is activated to N* by 405 nm excitation and GFP returns to A. Moerner’s demonstration of blinking and photo activation opened the road to exploring a vast space of GFP mutants for novel optical properties. J. Lippincott-Swartz engineered a GFP variant with striking properties (Patterson and Lippincott-Schwartz, 2002). This mutant is initially optically inactive. It can, however, be activated by irradiation at 413 nm and then displays fluorescence when excited at 488 nm. Eventually, after intense irradiation at 488 nm the mutant is irreversibly inactivated by photo bleaching. When Betzig returned to academic science after his post-near-field exile in private industry, he learnt about Lippincott-Schwartz’ mutant and realized that it could possibly solve the problem of finding an optimal way to combine sparse sets of fluorophores with distinct spectral properties to a dense total set of fluorophores. The simple solution would be to activate a very small and thus sparse, random subset of GFP mutant molecules in a biological structure by low-level irradiation at 413 nm. Subsequent irradiation at 488 nm would then be used to determine the positions of the members of the sparse subset at super-resolution, according to Eq. 5 above. When the first subset had been irreversibly inactivated by bleaching, a second small subset could be activated and the positions of its members determined at high resolution, and so on until all subsets had been sampled and used to determine the structure under authentic super-resolution conditions. This fulfilled both the condition of only a sparse subset being observed at a time, and the condition of high-frequency (dense) spatial sampling in order to fulfill the Nyqvist and Shannon theorems, as illustrated in Fig. 8.

Energy states [Dickson et.al. ’97]

State A is excited to A∗ and returns to A upon photon emission

When I is reached from A there is no fluorescence until Ispontaneously moves to A (blinking)

When I moves to N there is no fluorescence until N is activatedby 405nm light and GFP returns to A

8 / 50

Page 13: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Photoactivated localization microscopy (PALM) Setup

[picture from ZEISS]9 / 50

Page 14: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

PALM Process

Step 1

Step 3. Algorithm needed.

Step 2

Step 4

10 / 50

Page 15: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Antibodies: attach fluorescent molecules to the structure

All off

All on Detector

Cannot resolve the structure!

11 / 50

Page 16: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Antibodies: attach fluorescent molecules to the structure

All off All on

Detector

Cannot resolve the structure!

11 / 50

Page 17: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Antibodies: attach fluorescent molecules to the structure

All off All on Detector

Cannot resolve the structure!

11 / 50

Page 18: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

“Blinking” molecules: sparsity

Frame 1

Locate centers of “Gaussian” blobs (parametric estimation)

Combine ∼ 10000 frames.

The structure is now resolved!

12 / 50

Page 19: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

“Blinking” molecules: sparsity

Frame 1

Locate centers of “Gaussian” blobs (parametric estimation)

Combine ∼ 10000 frames.

The structure is now resolved!

12 / 50

Page 20: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

“Blinking” molecules: sparsity

Frame 1

Locate centers of “Gaussian” blobs (parametric estimation)

Combine ∼ 10000 frames.

The structure is now resolved!

12 / 50

Page 21: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

“Blinking” molecules: sparsity

Frame 1

Locate centers of “Gaussian” blobs (parametric estimation)

Combine ∼ 10000 frames.

The structure is now resolved!

12 / 50

Page 22: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

“Blinking” molecules: sparsity

Frame 1 Frame 2 Frame 3

Locate centers of “Gaussian” blobs (parametric estimation)

Combine ∼ 10000 frames.

The structure is now resolved!

12 / 50

Page 23: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

“Blinking” molecules: sparsity

Frame 2

Locate centers of “Gaussian” blobs (parametric estimation)

Combine ∼ 10000 frames.

The structure is now resolved!

12 / 50

Page 24: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Next Frontier: image dynamical processes

Imaging ∼ 10000 frames is slow

Can we make data acquisition faster?

Image ∼ 2500 frames with 4 times more molecules per frame?

parametric estimation works 4 times more active molecules⇒ parametric estimation

does not work

Need powerful super-resolution algorithm!

13 / 50

Page 25: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Next Frontier: image dynamical processes

Imaging ∼ 10000 frames is slow

Can we make data acquisition faster?

Image ∼ 2500 frames with 4 times more molecules per frame?

parametric estimation works 4 times more active molecules⇒ parametric estimation

does not work

Need powerful super-resolution algorithm!

13 / 50

Page 26: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Next Frontier: image dynamical processes

Imaging ∼ 10000 frames is slow

Can we make data acquisition faster?

Image ∼ 2500 frames with 4 times more molecules per frame?

parametric estimation works 4 times more active molecules⇒ parametric estimation

does not work

Need powerful super-resolution algorithm!

13 / 50

Page 27: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Next Frontier: image dynamical processes

Imaging ∼ 10000 frames is slow

Can we make data acquisition faster?

Image ∼ 2500 frames with 4 times more molecules per frame?

parametric estimation works 4 times more active molecules⇒ parametric estimation

does not work

Need powerful super-resolution algorithm!

13 / 50

Page 28: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Theory

Which algorithm?Performance guarantees?

Fundamental limits?

14 / 50

Page 29: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Theory

Which algorithm?Performance guarantees?

Fundamental limits?

14 / 50

Page 30: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Mathematical model (discrete 1D setup for simplicity)

0 1

Object

x(t) =∑i

xiδ(t− ti), xi ≥ 0

0 1

λc = 1/fcDetector

s(t) =

∫flow(t− t′)x(t′)dt′

flow(t) =1

2fc

(sin(2πfct)

πt

)2

15 / 50

Page 31: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Mathematical model (discrete 1D setup for simplicity)

0 1

Object

x(t) =∑i

xiδ(t− ti), xi ≥ 0

0 1

λc = 1/fcDetector

s(t) =

∫flow(t− t′)x(t′)dt′

x = [x0 · · ·xN−1]T ≥ 0 s = Px+ z

P = Ptri is circulant

−N/2 + 1 −fc 0 fc N/2

Triangular spectrum

15 / 50

Page 32: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Mathematical model (discrete 1D setup for simplicity)

0 1

Object

x(t) =∑i

xiδ(t− ti), xi ≥ 0

0 1

λc = 1/fcDetector

s(t) =

∫flow(t− t′)x(t′)dt′

x = [x0 · · ·xN−1]T ≥ 0 s = Px+ z

P = Pflat is circulant

−N/2 + 1 −fc 0 fc N/2

Flat spectrum

15 / 50

Page 33: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Super-resolution factor and stability

x = [x0 · · ·xN−1]T

−N/2 + 1 −fc 0 fc N/2

Triangular spectrum

−N/2 + 1 −fc 0 fc N/2

Flat spectrum

s = Px+ z

SRF , N/(2fc)

Stability: ‖x− x‖?≤ ‖z‖ · (amplification factor)

16 / 50

Page 34: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Super-resolution factor and stability

x = [x0 · · ·xN−1]T

−N/2 + 1 −fc 0 fc N/2

Triangular spectrum

−N/2 + 1 −fc 0 fc N/2

Flat spectrum

s = Px+ z

SRF , N/(2fc)

Stability: ‖x− x‖?≤ ‖z‖ · (amplification factor)

16 / 50

Page 35: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Classical resolution criteria: separation is about λc

Sparrow criterionAbbe criterionRayleigh criterion

1.22�c �c 0.94�c

17 / 50

Page 36: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Rayleigh-regularity: x ∈ R(d, r)

x has fewer than r spikes in every λcd interval [λc , 1/fc]

0 1

≥ 2λc

Separation: R(2, 1)

0 1

λc ≥ 4λc

R(4, 2)

0 1

≥ 6λc

R(6, 3)

18 / 50

Page 37: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Rayleigh-regularity: x ∈ R(d, r)

x has fewer than r spikes in every λcd interval [λc , 1/fc]

0 1

≥ 2λc

Separation: R(2, 1)

0 1

λc ≥ 4λc

R(4, 2)

0 1

≥ 6λc

R(6, 3)

18 / 50

Page 38: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Rayleigh-regularity: x ∈ R(d, r)

x has fewer than r spikes in every λcd interval [λc , 1/fc]

0 1

≥ 2λc

Separation: R(2, 1)

0 1

λc ≥ 4λc

R(4, 2)

0 1

≥ 6λc

R(6, 3)

18 / 50

Page 39: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Rayleigh-regularity: x ∈ R(d, r)

x has fewer than r spikes in every λcd interval [λc , 1/fc]

0 1

≥ 2λc

Separation: R(2, 1)

0 1

λc ≥ 4λc

R(4, 2)

0 1

≥ 6λc

R(6, 3)

18 / 50

Page 40: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795]

MUSIC, ESPRIT [Donoho’92]

x ∈ CN

x ∈ CN x ∈ CN

no stability

stability not understood stability

– Rayleigh-regularity

efficient

efficient combinatorial

[Donoho et al.’90] [Candes & F.-Granda’12] This workx ≥ 0 x ∈ CN x ≥ 0

no stability stability stability– separation Rayleigh-regularity

convex convex convex

19 / 50

Page 41: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795] MUSIC, ESPRIT

[Donoho’92]

x ∈ CN x ∈ CN

x ∈ CN

no stability stability not understood

stability

– –

Rayleigh-regularity

efficient efficient

combinatorial

[Donoho et al.’90] [Candes & F.-Granda’12] This workx ≥ 0 x ∈ CN x ≥ 0

no stability stability stability– separation Rayleigh-regularity

convex convex convex

19 / 50

Page 42: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795] MUSIC, ESPRIT [Donoho’92]x ∈ CN x ∈ CN x ∈ CN

no stability stability not understood stability– – Rayleigh-regularity

efficient efficient combinatorial

[Donoho et al.’90] [Candes & F.-Granda’12] This workx ≥ 0 x ∈ CN x ≥ 0

no stability stability stability– separation Rayleigh-regularity

convex convex convex

R(2r, r)

19 / 50

Page 43: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795] MUSIC, ESPRIT [Donoho’92]x ∈ CN x ∈ CN x ∈ CN

no stability stability not understood stability– – Rayleigh-regularity

efficient efficient combinatorial

[Donoho et al.’90]

[Candes & F.-Granda’12] This work

x ≥ 0

x ∈ CN x ≥ 0

no stability

stability stability

separation Rayleigh-regularity

convex

convex convex

x ≥ 0

19 / 50

Page 44: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795] MUSIC, ESPRIT [Donoho’92]x ∈ CN x ∈ CN x ∈ CN

no stability stability not understood stability– – Rayleigh-regularity

efficient efficient combinatorial

[Donoho et al.’90] [Candes & F.-Granda’12]

This work

x ≥ 0 x ∈ CN

x ≥ 0

no stability stability

stability

– separation

Rayleigh-regularity

convex convex

convex

Works:

0 1

≥ 2λc

R(2, 1)

19 / 50

Page 45: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795] MUSIC, ESPRIT [Donoho’92]x ∈ CN x ∈ CN x ∈ CN

no stability stability not understood stability– – Rayleigh-regularity

efficient efficient combinatorial

[Donoho et al.’90] [Candes & F.-Granda’12]

This work

x ≥ 0 x ∈ CN

x ≥ 0

no stability stability

stability

– separation

Rayleigh-regularity

convex convex

convex

Breaks:

0 1

≥ 4λcR(4, 2)

19 / 50

Page 46: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key contribution

[Prony’1795] MUSIC, ESPRIT [Donoho’92]x ∈ CN x ∈ CN x ∈ CN

no stability stability not understood stability– – Rayleigh-regularity

efficient efficient combinatorial

[Donoho et al.’90] [Candes & F.-Granda’12] This workx ≥ 0 x ∈ CN x ≥ 0

no stability stability stability– separation Rayleigh-regularity

convex convex convex

R(2r, r),x ≥ 0

19 / 50

Page 47: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Main results

Recall:

s = Px+ z−N/2 + 1 −fc 0 fc N/2

spectrum

Solve:minimize ‖s−Px‖1 subject to x ≥ 0

Theorem: [V. Morgenshtern and E. Candes, 2014]

Take P = Ptri or P = Pflat. Assume x ≥ 0, x ∈ R(2r, r). Then,

‖x− x‖1 ≤ c · ‖z‖1 ·(N

2fc

)2r

.

Converse: [V. Morgenshtern and E. Candes, 2014]

For P = Ptri, no algorithm can do better than c · ‖z‖1 ·(N2fc

)2r−1.

20 / 50

Page 48: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Main results

Recall:

s = Px+ z−N/2 + 1 −fc 0 fc N/2

spectrum

Solve:minimize ‖s−Px‖1 subject to x ≥ 0

Theorem: [V. Morgenshtern and E. Candes, 2014]

Take P = Ptri or P = Pflat. Assume x ≥ 0, x ∈ R(2r, r). Then,

‖x− x‖1 ≤ c · ‖z‖1 ·(N

2fc

)2r

.

Converse: [V. Morgenshtern and E. Candes, 2014]

For P = Ptri, no algorithm can do better than c · ‖z‖1 ·(N2fc

)2r−1.

20 / 50

Page 49: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key ideas→ Duality theory: to prove stability we need a low-frequency

trigonometric polynomial that is “curvy”

- [Dohono, et al.’92] construct trigonometric polynomial that isnot “curvy”

- [Candes and Fernandez-Granda’12] construct trigonometricpolynomial that is “curvy”, but construction needs separation

- New construction: multiply “curvy” trigonometric polynomials

“curvy”construction needs no separation

21 / 50

Page 50: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Dual certificate (noiseless case, z = 0)

T is the support of x

Suppose, we can construct a low-frequency trig. polynomial:

q(t) =

fc∑k=−fc

qke−i2πkt, 0 ≤ q(t) ≤ 1, q(ti) = 0 for all ti ∈ T .

Then, x = x.

22 / 50

Page 51: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Dual certificate (noiseless case, z = 0)

T is the support of x

Suppose, we can construct a low-frequency trig. polynomial:

q(t) =

fc∑k=−fc

qke−i2πkt, 0 ≤ q(t) ≤ 1, q(ti) = 0 for all ti ∈ T .

t1 t2 t3

1

Then, x = x.

22 / 50

Page 52: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Dual certificate (noiseless case, z = 0)

T is the support of x

Suppose, we can construct a low-frequency trig. polynomial:

q(t) =

fc∑k=−fc

qke−i2πkt, 0 ≤ q(t) ≤ 1, q(ti) = 0 for all ti ∈ T .

t1 t2 t3

1

Then, x = x.

22 / 50

Page 53: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to LASSO (x can be negative here)

minimize ‖x‖1 subject to s = Px

x = x iff there existsq ⊥ null(P) and q ∈ ∂‖x‖1

P is orthogonal projection onto theset of low-freq. trig. polynomials:q ⊥ null(P)⇔

q(t) =∑fc

k=−fc qke−i2πkt

q ∈ ∂‖x‖1 ⇔{q(ti) = sign(xi) xi 6= 0

|q(ti)| ≤ 1 xi = 0

descent cone

null(A)

row(A)

polar cone

null(P)

raw(P)

+1

-1

sign(x) (x 6= 0)

23 / 50

Page 54: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to LASSO (x can be negative here)

minimize ‖x‖1 subject to s = Px

x = x iff there existsq ⊥ null(P) and q ∈ ∂‖x‖1

P is orthogonal projection onto theset of low-freq. trig. polynomials:q ⊥ null(P)⇔

q(t) =∑fc

k=−fc qke−i2πkt

q ∈ ∂‖x‖1 ⇔{q(ti) = sign(xi) xi 6= 0

|q(ti)| ≤ 1 xi = 0

null(A)

descent cone

row(A)

polar cone

null(P)

raw(P)

+1

-1

sign(x) (x 6= 0)

23 / 50

Page 55: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to LASSO (x can be negative here)

minimize ‖x‖1 subject to s = Px

x = x iff there existsq ⊥ null(P) and q ∈ ∂‖x‖1

P is orthogonal projection onto theset of low-freq. trig. polynomials:q ⊥ null(P)⇔

q(t) =∑fc

k=−fc qke−i2πkt

q ∈ ∂‖x‖1 ⇔{q(ti) = sign(xi) xi 6= 0

|q(ti)| ≤ 1 xi = 0

null(A)

descent cone

row(A)

polar cone

null(P)

raw(P)

+1

-1

sign(x) (x 6= 0)

23 / 50

Page 56: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to LASSO (x can be negative here)

minimize ‖x‖1 subject to s = Px

x = x iff there existsq ⊥ null(P) and q ∈ ∂‖x‖1

P is orthogonal projection onto theset of low-freq. trig. polynomials:q ⊥ null(P)⇔

q(t) =∑fc

k=−fc qke−i2πkt

q ∈ ∂‖x‖1 ⇔{q(ti) = sign(xi) xi 6= 0

|q(ti)| ≤ 1 xi = 0

null(A)

descent cone

row(A)

polar cone

null(P)

raw(P)

+1

-1

sign(x) (x 6= 0)

23 / 50

Page 57: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to LASSO (x can be negative here)

minimize ‖x‖1 subject to s = Px

x = x iff there existsq ⊥ null(P) and q ∈ ∂‖x‖1

P is orthogonal projection onto theset of low-freq. trig. polynomials:q ⊥ null(P)⇔

q(t) =∑fc

k=−fc qke−i2πkt

q ∈ ∂‖x‖1 ⇔{q(ti) = sign(xi) xi 6= 0

|q(ti)| ≤ 1 xi = 0

null(A)

descent cone

row(A)

polar cone

null(P)

raw(P)

+1

-1

sign(x) (x 6= 0)

23 / 50

Page 58: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Dual certificate (noisy case)

T is the support of x

Suppose, we can construct a low-frequency trig. polynomial:

q(t) =

fc∑k=−fc

qke−i2πkt, 0 ≤ q(t) ≤ 1, q(ti) = 0 for all ti ∈ T .

t1 t2 t3

1

Then, ‖x− x‖1 ≤ 4‖z‖1/ρ.

24 / 50

Page 59: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Dual certificate (noisy case)

T is the support of x

Suppose, we can construct a low-frequency trig. polynomial:

q(t) =

fc∑k=−fc

qke−i2πkt, 0 ≤ q(t) ≤ 1, q(ti) = 0 for all ti ∈ T .

t1− 1N t1+

1N t2− 1

N t2+1N t3− 1

N t3+1N

ρ

1

1

Then, ‖x− x‖1 ≤ 4‖z‖1/ρ.

24 / 50

Page 60: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key ideas- Duality theory: to prove stability we need a low-frequency

trigonometric polynomial that is “curvy”

→ [Dohono, et al.’92] construct trigonometric polynomial that isnot “curvy”

- [Candes and Fernandez-Granda’12] construct trigonometricpolynomial that is “curvy”, but construction needs separation

- New construction: multiply “curvy” trigonometric polynomials

“curvy”construction needs no separation

25 / 50

Page 61: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

[Dohono, et al.’92]: “Classical” q(t)

q(t) =∏t0∈T

1

2[cos(2π(t+ 1/2− t0)) + 1] .

No separation required

Low curvature!

q(t− t0) ≈ (t− t0)2 ⇒ ‖x− x‖1 ≤ ‖z‖1 ·N2

−1/2 1/N 1/2

(0, 1)

ρ

26 / 50

Page 62: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key ideas- Duality theory: to prove stability we need a low-frequency

trigonometric polynomial that is “curvy”

- [Dohono, et al.’92] construct trigonometric polynomial that isnot “curvy”

→ [Candes and Fernandez-Granda’12] construct trigonometricpolynomial that is “curvy”, but construction needs separation

- New construction: multiply “curvy” trigonometric polynomials

“curvy”construction needs no separation

27 / 50

Page 63: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

[Candes, Fernandez-Granda’12]: “Curvy” q(t)

q(t) =∑tj∈T

ajK(t− tj) + corrections,

K(t) . . . low-frequency and “curvy”

Separation between zeros required: T ∈ R(2, 1)

High curvature!

q(t− ti) ≈ f2c (t− ti)2 ⇒ ‖x− x‖1 ≤ c · ‖z‖1 ·

(N

2fc

)2

t1 t2 t3

ρ

≥ 2λc28 / 50

Page 64: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Comparison of Trigonometric Polynomials

−1/2 1/2

(0, 1)

“classical” q(t) ≈ t2

“curvy” q(t) ≈ f2c t

2

29 / 50

Page 65: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Key ideas- Duality theory: to prove stability we need a low-frequency

trigonometric polynomial that is “curvy”

- [Dohono, et al.’92] construct trigonometric polynomial that isnot “curvy”

- [Candes and Fernandez-Granda’12] construct trigonometricpolynomial that is “curvy”, but construction needs separation

→ New construction: multiply “curvy” trigonometric polynomials

“curvy”construction needs no separation

30 / 50

Page 66: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

New construction: curvature without separation

Partition support: T = T1 ∪ T2, r = 2

Regularity: T ∈ R(2 · 2, 2)⇒ Ti ∈ R(4, 1)

t1 t2 t3 t4 t5

q1(t) q2(t)

q(t; fc) = q1(t; fc/2)× q2(t; fc/2)

High curvature!

q(t− ti) ≈f2rc

r2r(t− ti)2r ⇒ ‖x− x‖1 ≤ c · ‖z‖1 ·

(N

2fc

)2r

31 / 50

Page 67: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

New construction: curvature without separation

Partition support: T = T1 ∪ T2, r = 2

Regularity: T ∈ R(2 · 2, 2)⇒ Ti ∈ R(4, 1)

t1 t2 t3 t4 t5

q1(t) q2(t)

q(t; fc) = q1(t; fc/2)× q2(t; fc/2)

High curvature!

q(t− ti) ≈f2rc

r2r(t− ti)2r ⇒ ‖x− x‖1 ≤ c · ‖z‖1 ·

(N

2fc

)2r

31 / 50

Page 68: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Summation vs. multiplication

Remember: q(t) must be frequency-limited to fc!

[Donoho, et.al.]:

q(t) =∏tj∈T

1

2[cos(2π(t+ 1/2− tj)) + 1]︸ ︷︷ ︸

frequency one

[Candes, Fernandez-Granda]:

q(t) =∑tj∈T

ajK(t− tj)︸ ︷︷ ︸frequency fc

This work:

q(t) =

r∏k=1

∑tjk∈Tk

ajkK(t− tjk)︸ ︷︷ ︸frequency fc/r

32 / 50

Page 69: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Summation vs. multiplication

Remember: q(t) must be frequency-limited to fc!

[Donoho, et.al.]:

q(t) =∏tj∈T

1

2[cos(2π(t+ 1/2− tj)) + 1]︸ ︷︷ ︸

frequency one

[Candes, Fernandez-Granda]:

q(t) =∑tj∈T

ajK(t− tj)︸ ︷︷ ︸frequency fc

This work:

q(t) =

r∏k=1

∑tjk∈Tk

ajkK(t− tjk)︸ ︷︷ ︸frequency fc/r

32 / 50

Page 70: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Summation vs. multiplication

Remember: q(t) must be frequency-limited to fc!

[Donoho, et.al.]:

q(t) =∏tj∈T

1

2[cos(2π(t+ 1/2− tj)) + 1]︸ ︷︷ ︸

frequency one

[Candes, Fernandez-Granda]:

q(t) =∑tj∈T

ajK(t− tj)︸ ︷︷ ︸frequency fc

This work:

q(t) =

r∏k=1

∑tjk∈Tk

ajkK(t− tjk)︸ ︷︷ ︸frequency fc/r

32 / 50

Page 71: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Summation vs. multiplication

Remember: q(t) must be frequency-limited to fc!

[Donoho, et.al.]:

q(t) =∏tj∈T

1

2[cos(2π(t+ 1/2− tj)) + 1]︸ ︷︷ ︸

frequency one

[Candes, Fernandez-Granda]:

q(t) =∑tj∈T

ajK(t− tj)︸ ︷︷ ︸frequency fc

This work:

q(t) =

r∏k=1

∑tjk∈Tk

ajkK(t− tjk)︸ ︷︷ ︸frequency fc/r

32 / 50

Page 72: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Complex vs. positive signals

Why do we need x ≥ 0?

x ≥ 0

Interpolate zero on supp. of x

t1 t2 t3 t4

� 2�c

⇢0

1

1/N

x ∈ CN

Interpolate sign(x) on supp. of x

t1 t2 t3 t4

� 2�c

1q(t3) = 1

�11/N

Does not exist! (Bernstein Th.)

33 / 50

Page 73: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Continuous setup

34 / 50

Page 74: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

fc fixed, N →∞ ⇒ SRFOLD →∞

x(t) x(t) and x(t)

Is the problem hopeless?

No: we need to be less ambitions!

λc

s(t) = (flow ? x)(t)λhi

x(t) = (fhi ? x)(t)

Error=‖fhi ?(x− x)‖1

SRFNEW = λc/λhi

35 / 50

Page 75: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

fc fixed, N →∞ ⇒ SRFOLD →∞

x(t) x(t) and x(t)

Is the problem hopeless?

No: we need to be less ambitions!

λc

s(t) = (flow ? x)(t)λhi

x(t) = (fhi ? x)(t)

Error=‖fhi ?(x− x)‖1

SRFNEW = λc/λhi

35 / 50

Page 76: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

fc fixed, N →∞ ⇒ SRFOLD →∞

x(t) x(t) and x(t)

Is the problem hopeless?

No: we need to be less ambitions!

λc

s(t) = (flow ? x)(t)λhi

x(t) = (fhi ? x)(t)

Error=‖fhi ?(x− x)‖1

SRFNEW = λc/λhi

35 / 50

Page 77: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

fc fixed, N →∞ ⇒ SRFOLD →∞

x(t) x(t) and x(t)

Is the problem hopeless?

No: we need to be less ambitions!

λc

s(t) = (flow ? x)(t)λhi

x(t) = (fhi ? x)(t)

Error=‖fhi ?(x− x)‖1

SRFNEW = λc/λhi

35 / 50

Page 78: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Need new tools

Theorem: [V. Morgenshtern and E. Candes, 2014]

Assume x(t) ≥ 0, x(t) ∈ R(2r, r). Then,

‖fhi ?(x− x)‖1 ≤ c ·(λcλhi

)2r

· ‖z(t)‖1.

Can do: all zeros

t1 t2 t3 t4

⇠ �hi

� 2�c

0

1

Need: arbitrary pattern {0,+ρ}

t1 t2 t3 t4

⇠ �hi

� 2�c

0

1

q0(ti) = 0

36 / 50

Page 79: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Need new tools

Theorem: [V. Morgenshtern and E. Candes, 2014]

Assume x(t) ≥ 0, x(t) ∈ R(2r, r). Then,

‖fhi ?(x− x)‖1 ≤ c ·(λcλhi

)2r

· ‖z(t)‖1.

Can do: all zeros

t1 t2 t3 t4

⇠ �hi

� 2�c

0

1

Need: arbitrary pattern {0,+ρ}

t1 t2 t3 t4

⇠ �hi

� 2�c

0

1

q0(ti) = 0

36 / 50

Page 80: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

2D Super-resolution

� 2.38�c

R(2.38, 2)

Theorem: [V. Morgenshtern and E. Candes, 2014]

Take P = Ptri,2D or P = Pflat,2D. Assume x ≥ 0, x ∈ R(2.38r, r).Then,

‖x− x‖1 ≤ c ·(N

2fc

)2r

δ.

New: number of spikes is linear in the number of observations37 / 50

Page 81: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Improving microscopes

Collaboration with Moerner Lab, C.A. Sing-Long, E. Candes

38 / 50

Page 82: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Reconstruction of 3D signals from 2D data

z

Double-helix PSF

Normal PSFpicture from [Pavani and Piston'08]

2D double-helix data

minimize1

2‖s−Px‖22 + λσ‖ diag(w)x‖1

subject to x ≥ 0

P contains double-helix PSF slices

39 / 50

Page 83: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Reconstruction of 3D signals from 2D data

z

Double-helix PSF

Normal PSFpicture from [Pavani and Piston'08]

2D double-helix data

minimize1

2‖s−Px‖22 + λσ‖ diag(w)x‖1

subject to x ≥ 0

P contains double-helix PSF slices

39 / 50

Page 84: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Preliminary result: 4 times faster than state-of-the-art

10000 CVX problems solvedTFOCS first order solver

millions of variables40 / 50

Page 85: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Flexible framework: smooth background separation

minimize 12‖s−P(x+ b)‖22 + λσ‖x‖1

subject to x ≥ 0b low freq. trig. polynomial (background)

41 / 50

Page 86: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Comparison of super-resolution algorithms

Work in progress:

Need to carefully compare super-resolution algorithms in practice

Naive matched-filtersAlgebraic methods: MUSIC, ESPRIT, ...Convex-optimization algorithms with different regularizers

Realistic physical model

Noise: quantum noise and out-of-focus backgroundPoint-spread function (P) uncertainty and variationRotation of single molecules...

Test images (phantoms):

Different densities of sourcesDifferent spacial distributionsCorrect answer should always be known

Create a database of test cases for quick algorithm assessment

42 / 50

Page 87: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Conclusion

Convex optimization is a near-optimal methodfor super-resolution of positive sources

Flexibility and good practical performance

Non-asymptotic precise stability bounds

Rayleigh-regularity is fundamental: separation between spikes isonly one part of the picture

43 / 50

Page 88: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Lots of questions remain

What is the best regularizer in the presence of stochastic noise?

Fast parallel solver exploiting the structure of the problem

Theory for Double-Helix reconstruction: 3D signal from 2Dobservations

Tractable near-optimal algorithm for complex-valued signals?

Sparse regression where the design matrix has highlycorrelated columns:

A = [a1, . . . ,aN ]Shift-invariance: 〈ak,al〉 = 〈ak+r,al+r〉〈ak,ak+r〉 is large for small r〈ak,ak+r〉 decays quickly with rMinimum separation likely needed in generalIf all elements in A are nonnegative and the signal isnonnegative, regularity might be enough

44 / 50

Page 89: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Lots of questions remain

What is the best regularizer in the presence of stochastic noise?

Fast parallel solver exploiting the structure of the problem

Theory for Double-Helix reconstruction: 3D signal from 2Dobservations

Tractable near-optimal algorithm for complex-valued signals?

Sparse regression where the design matrix has highlycorrelated columns:

A = [a1, . . . ,aN ]Shift-invariance: 〈ak,al〉 = 〈ak+r,al+r〉〈ak,ak+r〉 is large for small r〈ak,ak+r〉 decays quickly with rMinimum separation likely needed in generalIf all elements in A are nonnegative and the signal isnonnegative, regularity might be enough

44 / 50

Page 90: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Acknowledgements

Swiss National Science Foundation Fellowship

Simons Foundation

Theory: collaboration with E. Candes

Motivation and applications: collaboration with W.E. Moerner,C.A. Sing-Long, M.D. Lew, A. Backer, S.J. Sahl

Helpful discussions and related work: C. Fernandez-Granda,M. Soltanolkotabi, R. Heckel

45 / 50

Page 91: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Thank you

46 / 50

Page 92: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Backup slides

47 / 50

Page 93: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Proof of Lemma

Set: h = x− x, T = {l/N : hl < 0}

⊂ supp(x).Dual vector ql = q(l/N) satisfies:

Pflatq = q, ‖q‖∞ = 1, and

{ql = 0, l/N ∈ Tql > ρ, otherwise.

On the one hand:

|〈q− ρ/2,h〉| = |〈P(q− ρ/2),h〉| = |〈q− ρ/2,Ph〉|≤ ‖q− ρ/2‖∞‖Ph‖1 ≤ ‖Px− s+ s−Px‖1≤ ‖Px− s‖1 + ‖s−Px‖1≤ 2‖Px− s‖1 ≤ 2‖z‖1.

On the other hand:

|〈q− ρ/2,h〉| =∣∣∣∣∣N−1∑l=0

(ql − ρ/2)hl∣∣∣∣∣ =

N−1∑l=0

(ql − ρ/2)hl ≥ ρ‖h‖1/2.

Combining: ‖h‖1 ≤ 4‖z‖1/ρ.

48 / 50

Page 94: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Proof of Lemma

Set: h = x− x, T = {l/N : hl < 0}⊂ supp(x).

Dual vector ql = q(l/N) satisfies:

Pflatq = q, ‖q‖∞ = 1, and

{ql = 0, l/N ∈ Tql > ρ, otherwise.

On the one hand:

|〈q− ρ/2,h〉| = |〈P(q− ρ/2),h〉| = |〈q− ρ/2,Ph〉|≤ ‖q− ρ/2‖∞‖Ph‖1 ≤ ‖Px− s+ s−Px‖1≤ ‖Px− s‖1 + ‖s−Px‖1≤ 2‖Px− s‖1 ≤ 2‖z‖1.

On the other hand:

|〈q− ρ/2,h〉| =∣∣∣∣∣N−1∑l=0

(ql − ρ/2)hl∣∣∣∣∣ =

N−1∑l=0

(ql − ρ/2)hl ≥ ρ‖h‖1/2.

Combining: ‖h‖1 ≤ 4‖z‖1/ρ.

48 / 50

Page 95: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Proof of Lemma

Set: h = x− x, T = {l/N : hl < 0}⊂ supp(x).Dual vector ql = q(l/N) satisfies:

Pflatq = q, ‖q‖∞ = 1, and

{ql = 0, l/N ∈ Tql > ρ, otherwise.

On the one hand:

|〈q− ρ/2,h〉| = |〈P(q− ρ/2),h〉| = |〈q− ρ/2,Ph〉|≤ ‖q− ρ/2‖∞‖Ph‖1 ≤ ‖Px− s+ s−Px‖1≤ ‖Px− s‖1 + ‖s−Px‖1≤ 2‖Px− s‖1 ≤ 2‖z‖1.

On the other hand:

|〈q− ρ/2,h〉| =∣∣∣∣∣N−1∑l=0

(ql − ρ/2)hl∣∣∣∣∣ =

N−1∑l=0

(ql − ρ/2)hl ≥ ρ‖h‖1/2.

Combining: ‖h‖1 ≤ 4‖z‖1/ρ.

48 / 50

Page 96: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Proof of Lemma

Set: h = x− x, T = {l/N : hl < 0}⊂ supp(x).Dual vector ql = q(l/N) satisfies:

Pflatq = q, ‖q‖∞ = 1, and

{ql = 0, l/N ∈ Tql > ρ, otherwise.

On the one hand:

|〈q− ρ/2,h〉| = |〈P(q− ρ/2),h〉| = |〈q− ρ/2,Ph〉|≤ ‖q− ρ/2‖∞‖Ph‖1 ≤ ‖Px− s+ s−Px‖1≤ ‖Px− s‖1 + ‖s−Px‖1≤ 2‖Px− s‖1 ≤ 2‖z‖1.

On the other hand:

|〈q− ρ/2,h〉| =∣∣∣∣∣N−1∑l=0

(ql − ρ/2)hl∣∣∣∣∣ =

N−1∑l=0

(ql − ρ/2)hl ≥ ρ‖h‖1/2.

Combining: ‖h‖1 ≤ 4‖z‖1/ρ.

48 / 50

Page 97: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Proof of Lemma

Set: h = x− x, T = {l/N : hl < 0}⊂ supp(x).Dual vector ql = q(l/N) satisfies:

Pflatq = q, ‖q‖∞ = 1, and

{ql = 0, l/N ∈ Tql > ρ, otherwise.

On the one hand:

|〈q− ρ/2,h〉| = |〈P(q− ρ/2),h〉| = |〈q− ρ/2,Ph〉|≤ ‖q− ρ/2‖∞‖Ph‖1 ≤ ‖Px− s+ s−Px‖1≤ ‖Px− s‖1 + ‖s−Px‖1≤ 2‖Px− s‖1 ≤ 2‖z‖1.

On the other hand:

|〈q− ρ/2,h〉| =∣∣∣∣∣N−1∑l=0

(ql − ρ/2)hl∣∣∣∣∣ =

N−1∑l=0

(ql − ρ/2)hl ≥ ρ‖h‖1/2.

Combining: ‖h‖1 ≤ 4‖z‖1/ρ.

48 / 50

Page 98: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Proof of Lemma

Set: h = x− x, T = {l/N : hl < 0}⊂ supp(x).Dual vector ql = q(l/N) satisfies:

Pflatq = q, ‖q‖∞ = 1, and

{ql = 0, l/N ∈ Tql > ρ, otherwise.

On the one hand:

|〈q− ρ/2,h〉| = |〈P(q− ρ/2),h〉| = |〈q− ρ/2,Ph〉|≤ ‖q− ρ/2‖∞‖Ph‖1 ≤ ‖Px− s+ s−Px‖1≤ ‖Px− s‖1 + ‖s−Px‖1≤ 2‖Px− s‖1 ≤ 2‖z‖1.

On the other hand:

|〈q− ρ/2,h〉| =∣∣∣∣∣N−1∑l=0

(ql − ρ/2)hl∣∣∣∣∣ =

N−1∑l=0

(ql − ρ/2)hl ≥ ρ‖h‖1/2.

Combining: ‖h‖1 ≤ 4‖z‖1/ρ.

48 / 50

Page 99: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to Bernstein theorem

Consider: q(t) =∑fc

k=−fc qke−i2πkt with ‖q‖∞ ≤ 1

Then: ‖q′‖∞ ≤ 2fc

“Curvy” q(t) has best possible curvature!

Since

q(ti) = 0

q′(ti) = 0

‖q‖∞ ≤ 1

We conclude:

‖q′‖∞ ≤ 2fc ⇒ ‖q′′‖∞ ≤ (2fc)2

⇒ q(t− ti) ≤ (2fc)2(t− ti)2

⇒ q(ti + 1/N) ≤ (2fc)2

N2=

1

SRF2

49 / 50

Page 100: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to Bernstein theorem

Consider: q(t) =∑fc

k=−fc qke−i2πkt with ‖q‖∞ ≤ 1

Then: ‖q′‖∞ ≤ 2fc

“Curvy” q(t) has best possible curvature!

Since

q(ti) = 0

q′(ti) = 0

‖q‖∞ ≤ 1

We conclude:

‖q′‖∞ ≤ 2fc ⇒ ‖q′′‖∞ ≤ (2fc)2

⇒ q(t− ti) ≤ (2fc)2(t− ti)2

⇒ q(ti + 1/N) ≤ (2fc)2

N2=

1

SRF2

49 / 50

Page 101: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

Connection to Bernstein theorem

Consider: q(t) =∑fc

k=−fc qke−i2πkt with ‖q‖∞ ≤ 1

Then: ‖q′‖∞ ≤ 2fc

“Curvy” q(t) has best possible curvature!

Since

q(ti) = 0

q′(ti) = 0

‖q‖∞ ≤ 1

We conclude:

‖q′‖∞ ≤ 2fc ⇒ ‖q′′‖∞ ≤ (2fc)2

⇒ q(t− ti) ≤ (2fc)2(t− ti)2

⇒ q(ti + 1/N) ≤ (2fc)2

N2=

1

SRF2

49 / 50

Page 102: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

New tools

1 Control behavior on separated set

2 Multiply

q(t) = q1(t)× q2(t)

0 = q′(t3) = q′1(t3)q2(t3) + q1(t3)q′2(t3)

t1 t2 t3 t4

q1(t) q2(t)

⇠ �hi

� 2�c

0

1

t1 t2 t3 t4

⇠ �hi

� 2�c

0

1

q0(ti) = 0

3 Sum

q(t) =∑r

r∏k=1

∑tjk∈Tk

ajkK(t− tjk)︸ ︷︷ ︸frequency fc/r

50 / 50

Page 103: Statistics Department, Stanford - FAUTHE NOBEL PRIZE IN CHEMISTRY 2014 POPULAR SCIENCE BACKGROUND How the optical microscope became a nanoscope Eric Betzig, Stefan W. Hell and William

New tools

1 Control behavior on separated set

2 Multiply

q(t) = q1(t)× q2(t)

0 = q′(t3) = q′1(t3)q2(t3) + q1(t3)q′2(t3)

t1 t2 t3 t4

q1(t) q2(t)

⇠ �hi

� 2�c

0

1

t1 t2 t3 t4

⇠ �hi

� 2�c

0

1

q0(ti) = 0

3 Sum

q(t) =∑r

r∏k=1

∑tjk∈Tk

ajkK(t− tjk)︸ ︷︷ ︸frequency fc/r

50 / 50