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# visualization: fun

In Silico Flurries: Computing a world of snow. Scientific American. 23 December 2017

# What if we were to print what we sequence?

Expressing the amount of sequence in the human genome in terms of the number of printed pages has been done before. At the Broad Institute, all of the human reference genome is printed in bound volumes.

At our sequencing facility, we sequence about 1 terabases per day. This is equivalent to 167 diploid human genomes (167 × 6 gigabases). The sequencing is done using a pool of 13 Illumina HiSeq 2500 sequencers, of which about 50% are sequencing at any given time.

A single letter-size page (8.5" × 11") of 6pt Courier using 0.25 inch margins accomodates 18,126 bases on 114 lines. Shown here is a portion of sequence from human chromosome 1. (PDF)

This sequencing is extremely fast.

To understand just how fast this is, consider printing this amount of sequence using a modern office laser printer. Let's pick the HP P3015n which costs about $400—a cheap and fast network printer. It can print at about 40 pages per minute. If we print the sequence at 6pt Courier using 0.25" margins, each 8.5" × 11" page will accomodate 18,126 bases. I chose this font size because it's reasonably legible. To print 1 terabases we need $10^12 / 18126 = 55.2$ million pages. If we print continuously at 40 pages per minute, we need $10^12 / (18126*40*1440) = 957.8$ days. If we had 958 printers working around the clock, we could print everything we sequence and not fall behind. This does not account for time required to replenish toner or paper. ## what's cheaper, sequencing or printing? It costs us about$12,000 to sequence a terabase in reagents. If we do it on a cost-recovery basis, it is about twice that, to include labor and storage. Let's say $25,000 per terabase. Coincidentally, this is about$150 per 1× coverage of a diploid human genome. The cost of sequencing a single genome would be significantly higher because of overhead. To overcome gaps in coverage and to be sensitive to alleles in heterogenous samples, sequencing should be done to 30× or more. For example, we sequence cancer genomes at over 100×. For theory and review see Aspects of coverage in medical DNA sequencing by Wendl et al. and Sequencing depth and coverage: key considerations in genomic analyses by Sims et al.. (Thanks to Nicolas Robine for pointing out that redundant coverage should be mentioned here).

Printing is 44× more expensive than sequencing, per base: 25 n$vs 1.1 μ$.

I should mention that the cost of analyzing the sequenced genome should be considered—this step is always the much more expensive one. In The $1,000 genome, the$100,000 analysis? Mardis asks "If our efforts to improve the human reference sequence quality, variation, and annotation are successful, how do we avoid the pitfall of having cheap human genome resequencing but complex and expensive manual analysis to make clinical sense out of the data?"

The cost of a single printed page (toner, power, etc) is about $0.02–0.05, depending on the printer. Let's be generous and say it's$0.02. To print 55.2 million pages would cost us $1.1M. This is about 44 times as expensive as sequencing. To print what we sequence we would require 958 office laser printers (shown here as HP3015n) at a cost of$1,100,000 per day. (PDF)

Think about this. It's 44× more expensive to merely print a letter on a page than it is to determine it from the DNA of a cell. In other words, to go from the physical molecule to a bit state on a disk is much cheaper than from a bit state on a disk to a representation of the letter on a page.

Per base, our sequencing costs $$25000/10^12 =$25*10^-9$, or 25 nanodollars. At $0.02 and 18,126 bp per page, printing costs $0.02/18126 =$1.1*10^-6$ or 1.1 microdollars.

If at this point you're thinking that printing isn't practical, the fact that the pages would weigh 248,000 kg and stack to 5.5 km should cinch the argument.

The capital cost of sequencing is, of course, much higher. The printers themselves would cost about $400,000 to purchase. The 6 sequencers, on the other hand, cost about$3,600,000.

We sequence at a rate close to the average internet bandwidth available to the public.

At 3.86 Mb/s, we could download a terabase of compressed sequence in a day, assuming the sequence can be compressed by a factor of 3. This level of compression is reasonable—the current human assembly is 938 Mb zipped).

In other words, you would have to be downloading essentially continuously to keep up with our sequencing.

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# Curse(s) of dimensionality

Tue 05-06-2018
There is such a thing as too much of a good thing.

We discuss the many ways in which analysis can be confounded when data has a large number of dimensions (variables). Collectively, these are called the "curses of dimensionality".

Nature Methods Points of Significance column: Curse(s) of dimensionality. (read)

Some of these are unintuitive, such as the fact that the volume of the hypersphere increases and then shrinks beyond about 7 dimensions, while the volume of the hypercube always increases. This means that high-dimensional space is "mostly corners" and the distance between points increases greatly with dimension. This has consequences on correlation and classification.

Altman, N. & Krzywinski, M. (2018) Points of significance: Curse(s) of dimensionality Nature Methods 15:399–400.

# Statistics vs Machine Learning

Tue 03-04-2018
We conclude our series on Machine Learning with a comparison of two approaches: classical statistical inference and machine learning. The boundary between them is subject to debate, but important generalizations can be made.

Inference creates a mathematical model of the datageneration process to formalize understanding or test a hypothesis about how the system behaves. Prediction aims at forecasting unobserved outcomes or future behavior. Typically we want to do both and know how biological processes work and what will happen next. Inference and ML are complementary in pointing us to biologically meaningful conclusions.

Nature Methods Points of Significance column: Statistics vs machine learning. (read)

Statistics asks us to choose a model that incorporates our knowledge of the system, and ML requires us to choose a predictive algorithm by relying on its empirical capabilities. Justification for an inference model typically rests on whether we feel it adequately captures the essence of the system. The choice of pattern-learning algorithms often depends on measures of past performance in similar scenarios.

Bzdok, D., Krzywinski, M. & Altman, N. (2018) Points of Significance: Statistics vs machine learning. Nature Methods 15:233–234.

Bzdok, D., Krzywinski, M. & Altman, N. (2017) Points of Significance: Machine learning: a primer. Nature Methods 14:1119–1120.

Bzdok, D., Krzywinski, M. & Altman, N. (2017) Points of Significance: Machine learning: supervised methods. Nature Methods 15:5–6.

# Happy 2018 $\pi$ Day—Boonies, burbs and boutiques of $\pi$

Wed 14-03-2018

Celebrate $\pi$ Day (March 14th) and go to brand new places. Together with Jake Lever, this year we shrink the world and play with road maps.

Streets are seamlessly streets from across the world. Finally, a halva shop on the same block!

A great 10 km run loop between Istanbul, Copenhagen, San Francisco and Dublin. Stop off for halva, smørrebrød, espresso and a Guinness on the way. (details)

Intriguing and personal patterns of urban development for each city appear in the Boonies, Burbs and Boutiques series.

In the Boonies, Burbs and Boutiques of $\pi$ we draw progressively denser patches using the digit sequence 159 to inform density. (details)

No color—just lines. Lines from Marrakesh, Prague, Istanbul, Nice and other destinations for the mind and the heart.

Roads from cities rearranged according to the digits of $\pi$. (details)

The art is featured in the Pi City on the Scientific American SA Visual blog.

Check out art from previous years: 2013 $\pi$ Day and 2014 $\pi$ Day, 2015 $\pi$ Day, 2016 $\pi$ Day and 2017 $\pi$ Day.

# Machine learning: supervised methods (SVM & kNN)

Thu 18-01-2018
Supervised learning algorithms extract general principles from observed examples guided by a specific prediction objective.

We examine two very common supervised machine learning methods: linear support vector machines (SVM) and k-nearest neighbors (kNN).

SVM is often less computationally demanding than kNN and is easier to interpret, but it can identify only a limited set of patterns. On the other hand, kNN can find very complex patterns, but its output is more challenging to interpret.

Nature Methods Points of Significance column: Machine learning: supervised methods (SVM & kNN). (read)

We illustrate SVM using a data set in which points fall into two categories, which are separated in SVM by a straight line "margin". SVM can be tuned using a parameter that influences the width and location of the margin, permitting points to fall within the margin or on the wrong side of the margin. We then show how kNN relaxes explicit boundary definitions, such as the straight line in SVM, and how kNN too can be tuned to create more robust classification.

Bzdok, D., Krzywinski, M. & Altman, N. (2018) Points of Significance: Machine learning: a primer. Nature Methods 15:5–6.