Overall this is a paper of broad interest, detailing a wide variety of issues in 'Big Healthcare Data'. It is well written with good coverage in its review. The author provides an introduction to the characteristics of big data in healthcare, following on to review the various methods and approaches to modelling, extracting knowledge, as well as managing such data. While the paper is quite comprehensive, I do feel there are a some significant areas that I believe need consideration in the manuscript:

The discussion on structured vs. unstructured data is a great addition, however there is no mention of data standards or controlled vocabularies/ontologies that can add more structure to data or can add semantics to unstructured data via markup or annotation. This is an area in which biomedicine/healthcare has actually well-developed, for example with minimum information standards (e.g. MIBBI, MIAME, MIRIAM, CIMR), data standards (e.g. ISA, CDISC, mzML, nmrML), and vocabularies (e.g. SNOMED-CT, MeSH, Gene Ontology etc.). Beyond data standards, there are also a range of domain-specific bio-modelling standards that could also be discussed beyond PMML, such as CellML, SBML, NeuroML, and TumorML.

Furthermore, in the Services and Infrastructure section there are a few efforts that deserve some mention from national and international e-infrastructures, for example, in the USA there are various centres within the NIH's BD2K programme, and in Europe, such as VPH (the Virtual Physiological Human initiative), ELIXIR (the European life-sciences Infrastructure for biological Information) and eTRIKS (European Translational Information & Knowledge Management Services) that utilizes the open-source tranSMART translational data warehouse (a mention could be included about tranSMART under the Exploratory Data Analytics section) that has recently gained much popularity.

A few minor things - there's a typo on line 29, page 3 where 'BDH' I believe should read 'BDH'. Also, Figure 1 I don't believe adds much to the paper and could be removed, while the upper section of Figure 5 with the large letters 'BD', 'I', 'K', 'A', could also be removed as it is already quite clear with the table below that each part is referring to 'Big Data', 'Information', 'Knowledge' and 'Action'.

Level of interest

Please indicate how interesting you found the manuscript:

An article of importance in its field

Quality of written English

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Not suitable for publication unless extensively edited

Declaration of competing interests

Please complete a declaration of competing interests, considering the following questions:

1. Have you in the past five years received reimbursements, fees, funding, or salary from an organisation that may in any way gain or lose financially from the publication of this manuscript, either now or in the future?

2. Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this manuscript, either now or in the future?

3. Do you hold or are you currently applying for any patents relating to the content of the manuscript?

4. Have you received reimbursements, fees, funding, or salary from an organization that holds or has applied for patents relating to the content of the manuscript?

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6. Do you have any non-financial competing interests in relation to this paper?

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I declare that I have no competing interests.

I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.

I agree to the open peer review policy of the journal.

The reviewed version of the manuscript can be seen here:

All revised versions are also available:

The author has taken into account most of the initial comments after the first review, however some minor corrections need to be made, in particular to take care in the formatting and spellings of some of the newly cited methods/standards/projects in the text as well as the URLs. For example, on page 12 the mention of the VPH initiative has the URL www.VHP-institute-org which should instead read www.vph-institute.org. Also the consistency in the use of URL styles (e.g. some have http:// and some don't) indicates to me that the author's changes are somewhat rushed, and really the manuscript needs a thorough proof read and style check.

Level of interest
Please indicate how interesting you found the manuscript:

An article of importance in its field

Quality of written English
Please indicate the quality of language in the manuscript:

Acceptable

Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:

1. Have you in the past five years received reimbursements, fees, funding, or salary from
an organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?

2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?

4. Have you received reimbursements, fees, funding, or salary from an organization that
holds or has applied for patents relating to the content of the manuscript?

5. Do you have any other financial competing interests?

6. Do you have any non-financial competing interests in relation to this paper?

If you can answer no to all of the above, write 'I declare that I have no competing interests'
below. If your reply is yes to any, please give details below.

I I have worked directly on, or collaborated with, some of the standards and projects (ISA,
CDISC, TumorML, VPH, eTRIKS) I recommended that should be included in the paper in first
review, but believe that they be included since they are significant contributions in the field in
scope of the paper.

I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.

I agree to the open peer review policy of the journal.

Author's response to reviews: (http://www.gigasciencejournal.com/imedia/2073544102008157_comment.pdf)