Data first vs Hypothesis first. Alan Ward. Data first vs Hypothesis first. Hypothesis driven approach Look at the data we have Formulate an hypothesis about .. Do experiments to test the hypothesis As a byproduct, collect more data.
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Data first vs Hypothesis first
Hypothesis driven approach
Weinberg R (2010) Point: Hypotheses first. NATURE 464, 678
Data driven approach
Golub T (2010) Counterpoint: Data first. NATURE 464, 679
“Reports that say that something hasn't
happened are always interesting to me,
because as we know,
there are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don't know. But there are also unknown unknowns – there are things we do not know we don't know.”
—United States Secretary of Defense, Donald Rumsfeld
The Black Swan: The Impact of the Highly Improbable. NassimTaleb
Hypothesis driven research
Non-coding short RNAs
Transcriptional regulation -
Inducers and repressors
Breadth first vs Depth first
A slice up and down
A slice across
Observation has always been part of biology as in the imatinibexample (Golub, 2010)
but DNA sequencing technology has revolutionized observational data collection.
You can see that Weinberg (2010) is arguing that ‘cheap sequencing’ on a massive scale = too much funding for data collection.
And, he doesn’t argue it but you might spend all your time managing the data1
1 Marx, V (2013) Biology: The big challenges of big data. Nature498, 255–260
Depth first or breadth first
Two different strategies for computer search algorithms
Which is best?
That heavily depends on the structure of the search tree and the number and location of solutions. If you know a solution is not far from the root of the tree, a breadth first search (BFS) might be better. If the tree is very deep and solutions are rare, depth first search (DFS) might rootle around forever, but BFS could be faster.
If the tree is very wide, a BFS might need too much memory, so it might be completely impractical. If solutions are frequent but located deep in the tree, BFS could be impractical.
If the search tree is very deep you will need to restrict the search depth for depth first search (DFS), anyway.
Boguski, MS, Lowe, TMJ, Tolstoshev, CM (1993) DbEST - Database For Expressed Sequence Tags. Nature Genetics 4, 332-333
Boguski, MSS (1994) Gene discovery in dbEST. Science265, 1993-4
Boguski, MSS (1995) The turning point in genome research. Trends in Biochemical Sciences20, 295-6
Nagaraj, S (2007) A hitchhiker's guide to expressed sequence tag (EST) analysis. Briefings in Bioinformatics8, 6-21
Species and strain identification in prokaryotes
The modern concept of species dates back to:
Mayr, E. (1942) Systematics and the Origin of Species(Columbia Univ. Press, New York)
Biological species concept: Species are groups of actually or potentially interbreeding natural populations, which are reproductively isolated from other such groups
de Queiroz K (2005) Ernst Mayr and the modern concept of species. ProcNatlAcadSci U S A. 102 Suppl 1: 6600-7.
Bacteria do not interbreed in the same way so defining species in bacteria remained an exercise in clustering organisms with similar, initially phenotypic, characters
Stanier RY. Adaptation, evolutionary and physiological: Or Darwinism among the microorganisms. In: Davies R, Gale EF, editors. Adaptation in Microorganisms, Third Symposium of the Society for General Microbiology. Cambridge: Cambridge University Press; 1953
Goldner M (2007) The genius of Roger Stanier
Can J Infect Dis Med Microbiol 18, 193–194
From the 1960s there was a consensus that all taxonomic information about a bacterium is incorporated in the complete nucleotide sequence of its genome
Wayne et al., in 1987 correlated the measurement of the similarity of DNA of two strains with then currently defined species and concluded that:
A DNA:DNA similarity of 70% and a ΔTm of > 5°C, both are important, marks the boundary of a group of strains which belong to the same species
Wayne, L. G., Brenner, D. J., Colwell, R. R., Grimont, P. A. D., Kandler, O., Krichevsky, M. I., Moore, L. H., Moore, W. E. C., Murray, R. G. E. & other authors (1987). Report of the ad hoc committee on reconciliation of approaches to bacterial systematics. Int J SystBacteriol 37, 463–464.
Measuring DNA similarity by hybridisation is not the same as DNA sequence similarity and it is measured using a number of different techniques
De Ley – rate of renaturation
Ezaki – microplate binding
Elution from hydroxyapatite
The methods are not robust and few labs can do:
Stackebrandtet al. (2002) Report of the Ad Hoc Committee for the re-evaluation of the species definition in bacteriology. Intl J Systematic EvolMicrobiol 52, 1043-1047
Using RT-PCR and Syber Green for DNA melt curve analysis
Gonzalez, JM & Saiz-Jimenez, C (2005) A simple fluorimetric method for the estimation of DNA–DNA relatedness between closely related microorganisms by thermal denaturation temperatures. Extremophiles 9, 75–79
Exactly the same melting program, but this time the DNA from Organism 1 and Organism 2 has been mixed, denatured and then renatured at the optimum temperature for renaturation TOR calculated from the %GC (Tor=0.51(%GC)+47.0) before adding Syber Green and melting
Because DNA:DNA hybridisation compares the whole genome it has remained the “Gold standard” for species delineation but it has several disadvantages:
It requires large amounts of high quality DNA
The methods are difficult to do
Different methods can different results
Reciprocal measurements can be very different
(amount of A binding to B is different from amount of B binding to A)
The experimental measurement has to be made between 2 strains – so to obtain DNA-DNA similarity for 5 strains requires 20 experimental determinations and if a 6th strain needs to be compared another 5 experiments are needed
You can’t build an incremental database
Selander, RK, Caugant, DA, Ochman, H, Musser, JM, Gilmour, MN and Whittam, TS (1986) Methods of multilocus enzyme electrophoresis for bacterial population genetics and systematics. Appl. Environ. Microbiol51, 873-884
Maiden, MCJ, Bygraves, JA, Feil, E, Morelli, G, Russell, JE, Urwin, R, Zhang, Q, Zhou, J, Zurth, K, Caugant, DA, Feavers, IM, Achtman, M, and Spratt, BG (1998) Multilocussequence typing: A portable approach to the identification of clones within populations of pathogenic microorganisms. Proc. Natl. Acad. Sci. USA 95, 3140–3145
The traditional method of data reduction is publication —results are summarized in peer-reviewed journals.
Publications include only the most important results, from experiments that may have been performed over many years.
The published paper is a concise compilation of the data, an interpretation of the results, and a comparison with results obtained by others.
Asignificant fraction of experiments from academic laboratories cannot be repeated in industry1. Reflecting inadequate description of experiments performed on different equipment and on biological samples that were produced with disparate methods.
1 Begley CG & Ellis LM (2012) Drug development: Raise standards for preclinical cancer research Nature 483, 531–3
In 1991 the GenBank On-line Service utilized a Solbourne5/800 running OS/MP 4.0C.The database work was done on a Sun network 4/490 server and workstations running SunOS UNIX version 4.1. The GenBank database was maintained on Sybase relational database management system (RDBMS). Software was developed in ' C language.
In 1990s NCBI scanned the literature for sequences and manually typed them into the database.
Benson, DA, Cavanaugh, M, Clark, K, Karsch-Mizrachi, I, Lipman, DJ, Ostell J and Sayers EW (2013) Genbank
Nucleic Acids Research 41, D36–D42