Journal of the American Medical Informatics Association, 26(5), 2019, 462–478

doi: 10.1093/jamia/ocy185
Review

Review

Comparison of blockchain platforms: a systematic review

and healthcare examples

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Tsung-Ting Kuo,1 Hugo Zavaleta Rojas,2 and Lucila Ohno-Machado1,3
1
UCSD Health Department of Biomedical Informatics, University of California San Diego, La Jolla, California, USA,
2
Department of Mathematics, East Los Angeles College, Monterey Park, California, USA, and 3Division of Health Services
Research & Development, VA San Diego Healthcare System, La Jolla, California, USA

Corresponding Author: Lucila Ohno-Machado, MD, PhD, UCSD Health Department of Biomedical Informatics, University
of California San Diego, La Jolla, California, USA ([email protected]).
Received 16 June 2018; Revised 2 December 2018; Editorial Decision 11 December 2018; Accepted 7 January 2019

ABSTRACT
Objectives: To introduce healthcare or biomedical blockchain applications and their underlying blockchain plat-
forms, compare popular blockchain platforms using a systematic review method, and provide a reference for
selection of a suitable blockchain platform given requirements and technical features that are common in
healthcare and biomedical research applications.
Target audience: Healthcare or clinical informatics researchers and software engineers who would like to learn
about the important technical features of different blockchain platforms to design and implement blockchain-
based health informatics applications.
Scope: Covered topics include (1) a brief introduction to healthcare or biomedical blockchain applications and
the benefits to adopt blockchain; (2) a description of key features of underlying blockchain platforms in health-
care applications; (3) development of a method for systematic review of technology, based on the PRISMA
(Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, to investigate blockchain
platforms for healthcare and medicine applications; (4) a review of 21 healthcare-related technical features of 10
popular blockchain platforms; and (5) a discussion of findings and limitations of the review.

Key words: blockchain, distributed ledger technology, systematic review, PRISMA, health and Medicine

INTRODUCTION electronic health records; (2) applications that enhance insurance

claim processes, for example, via the utilization of computer code
Healthcare applications using the blockchain on blockchain (ie, “smart contracts”) (see Supplementary Appen-
technology dix S1),17 management of pre-authorization payments,18 and
Blockchain is a distributed ledger—write once and never erase. “smart health profiles” for insurance applicants or recipients19;
Although originally invented for financial transactions,1 its appli- (3) applications that accelerate clinical or biomedical research,
cations are broad.2–4 Medicine, among these applications, is one such as those that assist with the collection and management of
of the most important and promising areas for adoption of this patient-generated health data for research purposes3,20 and those
new technology.2,3,5–13 Four main categories2 of health or clini- that facilitate data sharing among researchers21; and (4) applica-
cal blockchain applications are found in the literature: (1) those tions that advance biomedical or healthcare through data ledgers,
that improve medical record management (eg, securely storing such as those supporting a decentralized health data sharing back-
patient records),14 securely or scalably share clinical data,15 help bone,22 immutable clinical research protocols,23 and patient con-
control privacy risks,16 and promote security or privacy of sent recording.24

C The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-
nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way,
and that the work is properly cited. For commercial re-use, please [email protected] 462
Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5 463

Key benefits of blockchain for healthcare Hyperledger. An oncology clinical data sharing framework10 for
The main reason for the abovementioned applications to adopt patient care proposes to adopt the Hyperledger platform.43 Also,
blockchain relies on its “off-the-shelf” features that address many Hyperledger was included in the design of a framework to enforce
real-world health science’s needs. For example, decentralized man- Institutional Review Board regulations.11 Additionally, Hyperledger
agement is very useful for organizing digital assets produced by vari- is proposed for a mobile healthcare application44 and for medical
ous institutions (eg, biomedical data, software, and “recipes” or data storage or access45 applications. A working group was formed
workflows frequently used in predictive modeling and analytics). by Hyperledger to cultivate technical or business collaborations for
This allows operations without a hub (ie, no single point of healthcare blockchain applications.46
“ownership” or “control”). This characteristic is especially attrac- MultiChain. ModelChain29 was used to accelerate research and
tive for applications in which users prefer not to rely on a single cen- facilitate quality improvement initiatives by supporting decentral-
tral authority (eg, federated clinical data networks for quality ized cross-institutional predictive modeling. The use of blockchain
improvement, health insurance operations, cross-institutional con- in ModelChain makes it possible for different institutions to im-
sent management without the need for a coordinating center) and in prove predictive power by contributing data to a jointly developed

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which users want to verify the use of their assets. Another advantage model without transmitting data or the model to a central location.
is the recording of data provenance, which can be vital in applica- The first implementation of ModelChain used a permissioned block-
tions such as clinical decision support and surveillance systems. This chain MultiChain,31 and was applied for predictive analytics in an-
is possible because of blockchain creates an immutable audit trail esthesia.47
that permanently records transactions, so that critical records (eg, These examples constitute early work in this area and attempt to
protected patient information access log) are always available for all show the feasibility of adopting popular, open-source blockchain
in the network to inspect. Figure 1 shows simple examples of how a platforms for health or medicine. There are also some health-related
“block” of transactions (eg, clinical or trial data access records) blockchain applications that do not explicitly reveal their underlying
could be mounted to a blockchain for recording healthcare and re- platforms, such as Luna DNA,48 a proposed genomic and medical re-
search transactions. Our published tutorial on blockchain2 summa- search database (with similar goals as those of Nebula Genomics).49
rizes some key blockchain benefits that are important for health Others may be building an in-house blockchain. However, it is more
sciences and can serve as a first introduction for readers who are cost effective, time efficient, and sustainable to adopt an off-the-shelf
completely unfamiliar with the technology. blockchain platform in the early design and development stages, to
ensure feasibility and demonstrate an operational system before large
investments are made in recreating existing platforms.
Blockchain components to support healthcare
applications Challenges of selecting a blockchain platform for
The basic blockchain technology components that support health-
healthcare
care applications have been introduced in several recent studies,1,2,25
Choosing a proper off-the-shelve blockchain platform for a specific
including the use of hash-chain timestamping and consensus proto-
healthcare or clinical application may be challenging, because there
cols such as Proof of Work (PoW). To solve the scalability issue (ie,
is a wide range of technical features that are critical for its adoption
the size of the whole blockchain grows proportionally to the number
in healthcare projects. For example, there are concerns that adopting
of transactions), there are 3 techniques:1 Merkle tree26–28 (Figure 2),
blockchain would consume too much energy, unnecessarily.50 This
lightweight nodes (Figure 3), and unspent transaction output
concern should not be about blockchain itself, but instead reflects
(Figure 4). As a distributed network, blockchain faces some chal-
lack of understanding of various block-building consensus protocols
lenges,29 such as the famous Byzantine Generals’ Problem, a syn-
that can be selected for a specific blockchain platform. PoW, used in
chronization problem illustrated in Figure 5. Technical details on
Bitcoin, consumes a lot of energy, but other consensus protocols do
how to use the metadata of transactions to store data records and
not. Other concerns involve the openness of a blockchain network
using smart contracts to manage digital assets on a blockchain are
(eg, public or private), ability to modify the code and distribute it
explained in Supplementary Appendix S22–4,30–35 and Supplemen-
(eg, licenses), and need for specific hardware (eg, SGX-enabled
tary Appendix S1,25,36 respectively.
processors).
There are many choices of blockchain platform available today,
such as Ethereum, Hyperledger, and MultiChain, mentioned previ-
SIGNIFICANCE AND RATIONALE ously. A blockchain platforms should be general (ie, not limited to
financial applications) and popular (ie, technically mature and with
Blockchain platforms adopted in healthcare
ample community support to ensure future maintenance). Although
applications
some platforms may not have been adopted in the healthcare do-
To initiate the design and building of a real-world healthcare block-
main so far, they might be considered in the future because of desir-
chain project, one of the critical steps is to select the most suitable
able technical features (eg, support for an energy-efficient consensus
underlying blockchain platform. The 3 main platforms are the fol-
protocol).
lowing.
Ethereum. MedRec37,38 and Patientory39,40 propose the use of a
blockchain based on the Ethereum platform25 for patient-managed The need for a review of blockchain platforms for
health information exchange applications. Nebula Genomics pro- healthcare or clinical informatics
poses to share and analyze genomic data on an Ethereum-based To address the difficulties of blockchain platform selection for
blockchain platform.41 Ethereum was also proposed to be adopted healthcare or clinical applications, a systematic comparison of these
in clinical applications such as clinical data sharing15 and automated platforms in terms of their technical features is critical. Although
remote patient monitoring.42 there are broad reviews of blockchain platforms,51,52 of blockchain
464 Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

(a) Institution I1 Database

(Primary Care) (Clinical Data)

3. Approval
2. Request
1. Request Block Block Block
4. Approval
Patient P1 8. Inspect TC1 TC2 TC3 Clinician C1
(Emergency Department) Blockchain (Emergency Department)
(Transactions of Clinical Data Access)

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9. Inspect
Clinician C2
(Primary Care)

(b)

Figure 1. Healthcare and research examples of immutable recording of transactions. Note that in both examples the actual patient data are stored off-chain and
only the access records (eg, requests for and receipts of records) are stored on-chain as transactions in blocks. (A) Health informatics exchange example: Patient
P1 requests use of data by Clinician C1, institution I1 provides access, and patient P1 and/or primary care clinician C2 are able to see the transaction. (B) Human
subject research example: researcher R1 requests use of trial data, institution I2 provides access, and participant P2 and/or principal investigator R2 are able to see
the transaction.

research frameworks,53 and systematic reviews of blockchain tech- provide a reference for selection of suitable blockchain plat-
nology articles,4 a systematic comparison of blockchain platforms forms for specific requirements encountered in healthcare and
that are relevant for healthcare is still lacking. Such systematic com- biomedicine.
parison can serve as a practical reference for healthcare blockchain
researchers and application designers to choose the appropriate plat-
form for their specific use case (eg, public health, administration,
clinical care), especially, as mentioned previously, in the setting of MATERIALS AND METHODS
healthcare or research institutions that prefer not to cede control to
We adapted the PRISMA (Preferred Reporting Items for System-
a central authority but want to work together.
atic Reviews and Meta-Analyses) statement54,55 to compare block-
chain platforms. PRISMA is a systematic review statement
Objective focusing on reviews that evaluate randomized trials.54,55 To re-
The objective of this study is to compare the most popular block- view blockchain platforms, we modified the checklist items (Sup-
chain platforms using a systematic method, considering the tech- plementary Table S1) and flow diagram (Figure 6) in PRISMA,
nical features that are relevant to healthcare applications, and to and conducted the systematic comparison based on adjusted items.
Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5 465

(a) Block B1 Block B2

... Hash of Block B0 Header Nonce N1 Hash of Block B1 Header Nonce N2 ...

Transaction T11 Transaction T12 Transaction T21 Transaction T22

(b) Block B0 Block B1 Block B2

Hash of Block B0 Header Nonce N1

Merkle Root (Hash of T11-18)

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Hash of T11-14 Hash of T15-18
Merkle Tree

Hash of T11-12 Hash of T13-14 Hash of T15-16 Hash of T17-18

Hash of T11 Hash of T12 Hash of T13 Hash of T14 Hash of T15 Hash of T16 Hash of T17 Hash of T18

T11 T12 T13 T14 T15 T16 T17 T18

Figure 2. To reduce storage, if a block B is “voted” to be correct because the chain is long enough (ie, there are already many blocks created after B), we can dis-
card the transactions contained in B, without changing the hash of B’s header (otherwise all blocks after B would need to be changed). To do this, instead of sav-
ing the content of all transactions directly in a block, we first compute the hash values of each transaction, and then construct a tree structure (a Merkle tree),26–28
to “combine” (ie, hash again) all hash values, and store only the Merkle Root hash value at the block header. This way we can prune the transactions in the tree
later, without changing the Merkle Root and the block header. In other words, the size of the blockchain is now proportional to the number of blocks instead of be-
ing proportional to the number of transactions. (A) An example blockchain without a Merkle tree. The blocks enclose transactions without adopting a Merkle tree.
As a result, the size of a block will grow proportionally to the number of transactions (eg, transaction T12) that are enclosed. (B) A blockchain with a Merkle tree. A
Merkle tree is constructed by hashing paired data (the leaves) to create a parent node iteratively, until a single hash, the Merkle Root,1 remains. In this example,
the transactions (eg, T12) are first encoded into a binary raw-transaction format and then hashed to create the hashes (eg, Hash of T12). Then, hashes such as the
Hash of T12 are paired with other hashes such as the Hash of T11 (if a hash does not have a pair, it simply duplicates itself to be paired) to compute the hash as
their parent node (ie, Hash of T11–12). The pairing/hashing process repeats until only 1 hash (the Merkle Root) remains, and the Merkle tree construction process
is then completed. Finally, by only enclosing the Merkle Root in each block header, the storage space required to verify the integrity/validity of transactions can
be reduced.56 That is, if an attacker tries to change the content of any transaction such as T12, all of the related hashes (ie, Hash of T12, Hash of T11–12, and Hash of
T11–14), and eventually the Merkle Root (ie, Hash of T11–18) will also change and can be easily verified. To enclose this new Merkle Root to pass the verification pro-
cess, the attacker then needs to re-create block B1 and all blocks thereafter, which is computationally expensive and is enough to prevent such modification.2,57 A
Merkle tree is the basis of lightweight nodes described in Figure 3 (ie, the blockchain nodes that only need to verify transactions can store parts of the Merkle
trees to save space, while the full blockchain nodes that need to “mine” new blocks store all of the Merkle trees).

Eligibility criteria and information sources chain platforms names found in these webpages into a candidate list
General purpose blockchain platforms were included. We excluded (see the identification phase in Figure 6).
cryptocurrencies that could not serve as a general-purpose ledger, as
they are less important for biomedical informatics applications. This
way, the results of the systematic comparison could be utilized in Platform selection
healthcare or clinical application areas such as population health, To select the platforms names from the candidate list, we first re-
biomedical and health services research, and healthcare administra- moved all the duplicated blockchain platforms. Next, we aimed at
tion. We utilized Google.com58 as our main search engine, and con- “popular” blockchain platforms, because blockchain is still an
ducted all searches in July 2017. No major blockchain technology emerging technology and the widely used platforms are in general
has emerged as of November 2018. more mature in terms of the technical development, community sup-
port, and long-term maintenance. Intuitively, we could have used
the Google Count (ie, the number of webpages returned by search-
ing the platform name, such as “Bitcoin,” using Google.com) to
Search rank the popularity of the platforms. However, we realized that,
We used the phrase blockchain platforms as the initial search term while certain platform names were specific to the blockchain field
in Google.com. Realizing that the returning results were mostly (eg, “Ethereum”), other platform names were more general (eg,
about either “discussion of multiple blockchain platforms” or “Dash”). Thus, using just the Google Count of platform names
“general introduction of blockchain” (instead of the platforms might unfairly bias the results in favor of more general names.
themselves), we manually reviewed the top 30 ranked webpages To mitigate the bias introduced by common names, our strategy
returned by Google.com, and identified webpages that discussed was to first determine whether a platform name was a dictionary
more than 1 blockchain platform. We then collected all the block- word or not, using the following 2 online dictionary websites:
466 Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

Block B0 Block B1 Block B2

Hash of Block B0 Header Nonce N1

Merkle Root (Hash of T11-18)

Hash of T11-14 Hash of T15-18

Hash of T11-12 Hash of T13-14

Hash of T11 Hash of T12

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T12

Figure 3. Another technique to reduce the need for each user to keep the full history of transactions is to use lightweight nodes together with a Merkle tree. For a
user who only wants to use coins but does not want to “mine” new blocks, the full transaction history (more than 150 GB as of January 2018) is too large, espe-
cially for smartphones. Therefore, a user can adopt lightweight nodes1 so that only the Merkle Branch1 that links the transactions that the user would like to verify
is used. An example of the Merkle Branch for transaction T12 stored on a blockchain lightweight node (eg, on a mobile device), in contrast to the data storage of a
full node (eg, on a personal computer), is shown in this figure. With the use of the Merkle tree, a lightweight node only stores data relevant to specific transactions
(eg, T12) to save space.1 For example, in addition to T12 itself, this lightweight node only needs to store related hashes (ie, Hash of T11, Hash of T13–14, and Hash of
T15–18), instead of storing the full Merkle tree, to make sure T12 is linked to block B1. That is, one can first compute the Hash of T12 using T12, and then compute the
Hash of T11–12 using the Hash of T11 and the Hash of T12. Eventually, one can compute the value of the Merkle Root (Hash of T11–18), and compare it with the one
stored in B1, to make sure T12 has been verified in B1. This way, a lot of required storage space for those lightweight nodes is saved, making applications such as
wallet apps on mobile devices feasible. This verifying process is also known as Simplified Payment Verification.1,59 As a result, users/nodes can be divided into 2
groups: full nodes (the ones storing the whole transaction history and performing mining) and lightweight nodes (ie, the nodes using Simplified Payment Verifi-
cation just for transactions, without mining), thus reducing the storage space for lightweight nodes and improving the scalability of a blockchain network.

Finally, we ranked the blockchain platforms using these “popularity

Transaction T12 scores” and manually reviewed the platforms to select 10 popular plat-
Bob forms being included in our study (see the screening phase in Figure 6).
7 Coins
Output The reason for the manual review instead of just picking the top 10
10 Coins ranked platforms was to compensate for the limitations of our dictio-
Input
nary word strategy. For example, although the blockchain platform
3 Coins
Alice UTXO name NXT is not a dictionary word, it is also a division of World Wres-
tling Entertainment and thus is very popular (ie, high Google Count).
Alice
The manual review considered these types of exceptions to choose the
Figure 4. The ability of coin splitting and combining can further reduce the num- most well-known and highly popular blockchain platforms.
ber of transactions and thus lower the burden of a blockchain network. To do
this, intuitively one can just allow multiple inputs and multiple outputs.1 A spe- Data collection process, data items, and synthesis of
cial type of output is unspent transaction output (UTXO), ie, the “change” that
results
is returned to the sender of the transaction and can be spent (ie, serve as an in-
put) in the future transactions. In this example, Alice has 10 coins, which consti-
For the 10 blockchain platforms (see the included phase in Figure 6),
tute the output of previous transactions. Alice sends 7 coins to Bob and we developed a data sheet to extract the data items (ie, technical fea-
receives 3 coins (UTXO) as change. After this transaction, the 3 coins (UTXO) tures, defined in Table 1), and pilot-tested it on 2 most well-known
are recorded in each full node. If Alice then tries to spend the original 10 coins blockchain platforms: Bitcoin and Ethereum. Two authors (T-TK
instead of the 3 coins, each full node can detect such behavior by checking the and HZR) extracted the data items from included platforms, mainly
UTXO list and reject the transaction accordingly. This way, UTXO helps identify
from the official published whitepapers and official websites, as well
double-spending. That is, each full node maintains a list of UTXO, and com-
as from the other online resources searched using Google.com.
pares the input of new transactions against this list. If an input is not in the list,
the transaction is considered double-spending and will be invalidated.57 These authors then had discussions to resolve the disagreements. If
an agreement was not reachable, the third author (LO-M) was in-
volved in the discussion and made the final decision. After confirm-
Dictionary.com60 and Oxforddictionary.com.61 We considered a ing the data items in the pilot test, we extracted those data items for
platform name as a dictionary word only if it could be found in both each of the selected 10 blockchain platforms.
websites. The only exception was “Bitcoin,” which was included in
both dictionaries because it has become famous recently, and in our
RESULTS
study context we still consider it as a nondictionary name. For a
platform with a name that is not a dictionary word, we simply used Results of platform search and selection
the Google Count of the name (eg, searched “Ethereum” directly) as The search using blockchain platforms on Google.com returned
the score of popularity. For a platform with a name that is a dictio- 23 500 webpages. After manually checking the top 30 returned
nary word, we added an additional keyword “blockchain” while webpages, we identified the following 4 webpages that discussed more
searching (eg, “Dash” AND “blockchain”). than 1 blockchain platform: Medium,62 RadioStud,63 CoinFabrick,51
Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5 467

(a)
General G4 Messengers M4
Messengers M1 General G1 When to Attack ?

Attack Attack
Enemy
Messengers M2 General G2 General G5
City Messengers M5

Messengers M3 General G3 General G6 Messengers M6

(b) When to Attack ? Start Working Work Complete Add to Blockchain

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3pm Lost and Agree

General G1 General G1 General G1 General G1

5pm Lost and Agree

General G2 General G2 General G2 General G2

Win and Broadcast

1pm B
B
General G3 General G3 General G3 General G3
Messengers M3
Block Block Block Block Block Block Block Block Block

1pm

Time T0 Time T1 Time T2 Time T3

(c) General G3 General G5

When-to-Attack is 1pm, PoW is Completed PoW

Messengers M3 Messengers M5

Broadcast to Blockchain Broadcast

Block B0 Block B1 Block B2 Block B3

Previous Blocks
1pm 1pm 1pm
on Blockchain

Block B1 Broadcast
7pm Messengers M6
Broadcast to Blockchain
PoW
Messengers M4
General G6
When-to-Attack is 7pm, PoW is Completed

General G4

Figure 5. The Byzantine Generals’ Problem refers to a distributed set of generals who need to reach a consensus/agreement on the timing of a simultaneous at-
tack by multiple divisions of an army. (A) A simplified example64 of the relaxed version of the Byzantine Generals’ Problem, showing the difficulty generals have
in agreeing on the proper time for an attack. There are several divisions of a Byzantine army camping outside an enemy city, and each division has its own com-
manding general who would like to, with other generals, reach consensus on the time to attack the city. That is, each general could make a decision about when
to attack the city, but to be successful the majority of generals have to come up with an agreement about the attack time. However, the generals can only commu-
nicate with each other via messengers, and such communication form is nonsynchronized (eg, if 2 generals announce 2 different preferred times within a very
close time frame, some generals may receive one time and other generals may receive another time). In this scenario, it is very difficult for the majority of generals
to find a consensus time and execute a successful attack. (B) A Proof-of-Work (PoW) solution to the relaxed version of the Byzantine Generals’ Problem. To deal
with Byzantine Generals’ Problem, many blockchain platforms have created consensus protocols to resolve disagreements within the chain. For example, PoW,
the consensus protocol of the Bitcoin Blockchain, can find a solution to the relaxed version of the Byzantine Generals’ Problem, as described by the author Satoshi
Nakamoto62 and proved by Miller and LaViola.65 The idea is for each general to first decide an attacking time (eg, at T0 in this example) and start to do PoW (eg, at
T1 to find a solution to a difficult-to-compute yet easy-to-verify problem2,66). Once the PoW is completed (eg, general G3 finds the solution at T2), the winning gen-
eral (G3) asks the messengers (M3) to broadcast the block containing G3’s proposed attack time T (1 PM in this example) to the blockchain. Since the verification of
PoW is relatively simple (ie, fast), other generals can verify the PoW easily. They pause their work because they would only be allowed to add their time after the
one proposed by G3. After confirming the PoW is valid, every other general agrees with G3 that the attack will be at 1 PM. (C) The process to reach consensus
among generals. After the first block (B1) with the time 1 PM is added to the blockchain, all generals restart PoW based on the hash of B1 to find the second block
(B2). One important protocol is that all generals will do PoW based on the longest chain, which ensures the consensus. That is, suppose general G4 also completed
the PoW to propose another attack time (7 PM) in block B1’: since another general (G5) has already created a block B2 to support 1 PM, the next general (G6) will only
work on the longest chain to support 1 PM instead of 7 PM, thus the consensus attack time would eventually be 1 PM. Finally, after the blockchain is long enough, ev-
ery general will be confident that the consensus attack time (1 PM) has been agreed by the majority of generals. This is because many generals have been working
on the longest chain, thus the probability of a successful consensus of attack time is now high enough to solve the distributed agreement problem.64
468 Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

Identification
Records Identified through Database Searching Additional Records Identified through Other Sources
(n = 54) (n = 0)

Records after Duplicates Removed

(n = 35)
Screening

Records Screened Records Excluded

(n = 10 ) (n = 25)
Included

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Studies Included in Qualitative Synthesis
(n = 10 )

Figure 6. The adjusted PRISMA flow diagram. We only included 3 phases (ie, identification, screening, and included), because the eligibility criteria were inte-
grated into the search strategy (ie, the PRISMA eligibility phase is integrated into the identification phase).

and Mastek.67 We collected the 54 blockchain platform names men- inspection.2,71–74 To improve this, Zcash uses a zero-knowledge proof
tioned in these 4 webpages into the candidate list. There were 35 plat- algorithm known as zk-SNARK, to ensure that the sender, recipient,
forms after removal of duplicates. We ranked the 35 blockchain and amount of a transaction remain private even on a publicly avail-
platforms using our “popularity” score, and manually selected 10 top able blockchain network, and thus improves the privacy or anonymity
ones. The process is shown in Figure 6, while the resulting 10 plat- of the transactions, while verifying the transactions privately to avoid
forms are described in Table 2. the double spending problem. This level of privacy or anonymity is
also highly desirable in healthcare applications. Also, Zcash addresses
Selected platform characteristics the mining centralization issue (Supplementary Appendix S3).75,76
In this subsection, we discuss the details of the 10 blockchain plat- However, as many health-related applications may be run on
forms selected for our systematic review, following the order of the permissioned networks, platforms like Zcash that use PoW are less at-
popularity score shown in Table 2. tractive than others that use different protocols.

Bitcoin Litecoin
Bitcoin, the first well-known and widely used distributed cryptocur- Litecoin is a decentralized global payment network.77 The major
rency, operates a peer-to-peer network without central authority or change of Litecoin, compared with Bitcoin, is that Litecoin has a
banks, and introduced the blockchain technology and platform to faster transaction speed (4 times quicker) at the expense of 4 times
the world.68 The management of transactions and the issuance of smaller storage space and reduced security.77 Also, Litecoin adopts
coins are carried out collectively by the blockchain network.68 Bit- the “Scrypt” hash algorithm77 for the PoW to mitigate the mining
coin uses PoW as its consensus protocol to verify transactions, and centralization issue (Supplementary Appendix S3). Speed could
thus consumes a lot of energy.1 Owing to the success of Bitcoin, become important in healthcare applications in which immediate
many other alternative cryptocurrencies and consensus protocols decisions are needed, but, so far, we have not seen examples of
were proposed and developed, including all other 9 platforms blockchain-based applications in health sciences in which this was a
reviewed in this study. critical factor. For example, we have not encountered situations in
which a healthcare blockchain needed to accommodate as many
Ethereum transactions per minute as credit cards or major retailers’ websites do.
Ethereum is a platform that lets anyone build and use smart-
contract-based decentralized applications that run on blockchain Dash
technology.69 Ethereum focuses on the capability of automatic digi- Dash (or Digital Cash) is a privacy-centric digital currency with in-
tal asset management, and, to do so, it supports smart contracts or stant transactions.78 It is based on the Bitcoin software, and adds an
properties (Supplementary Appendix S1), making the creation of the additional “Masternode” network tier on top of the Bitcoin Block-
asset managing programs easier than when using the scripting lan- chain network.79 The Masternode network is composed of nodes
guage in the Bitcoin Blockchain.25 Ethereum also adapts the PoW that are willing to put “collateral,” such as 1000 DASH coins, to
consensus protocol.25 serve as the full nodes to validate the transactions. The Masternode
offers additional privacy or anonymity to the users via “Darksend”
Zcash (based on the “CoinJoin” technology,79 a process of merging multi-
Zcash is a decentralized and open-source cryptocurrency that offers ple transactions together so that the attacker cannot link the transac-
privacy and anonymity of transactions.70 A challenge of the Bitcoin tions using histories).78,79 Also, the relatively few collateral nodes in
Blockchain is that, although the senders and recipients are repre- the Masternode network can speed-up the validation process, pro-
sented with a hashed address, given enough transaction data, the viding an instant transaction mechanism known as “InstantX.”79
transactions may still be linked or traced through careful analysis and The additional privacy for the users is attractive to healthcare
Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5 469

Table 1. Data items extracted from the blockchain platforms

Category # Data Item Description

Basic Information 1 Official Website URL for the official website of the platform.
2 Software Website Online repository system that keeps track of the source code of the platform.
3 Explorer Website Special type of online website, “explorer,” that keeps track of all the transactions
for the platform. Note that, multiple explorers may exist for the platform which
also serves as a cryptocurrency. In this case, we only list the “official” or the
representative ones. Also, the living public websites do not exist for the non-
cryptocurrency platforms, however, the “explorer” code may be available; in
this case, we list the website of their “explorer” code instead.
4 Main Reference Main official white papers or the other types of articles discussing the platform.
5 Real-World Application Examples of the institutions or companies currently using the platform.

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Blockchain Technology 6 Main Improvement over Bit- Main technical difference from Bitcoin, the first distributed cryptocurrency.
coin
7 Network Permission Permission mechanism of the blockchain network.
8 Consensus Protocol Core protocol used to create a consensus chain of blocks.
9 Special Hardware Requirement Special hardware (ie, besides a normal personal computer) needed to “mine” (ie,
create) new blocks.
10 Smart Contracts Support Capability to support smart contracts/properties.
Public Cryptocurrency 11 Symbol Short name for the cryptocurrency (eg, “BTC” for Bitcoin).80
12 Mining for New Public Coins Capability for participants to “mine” new coins to serve as public cryptocurrency.
13 Anonymous Payment Feature that prevents tracing the origin, destination and amount of the transac-
tions.
14 Rapid Payment Support of the high-speed asset transferring.
15 Coin Limit Maximum amount of the coins that can be created for the cryptocurrency.
16 Coin Value Value of the coin in U.S. dollars.81
17 Average Transaction per Sec- Average speed of transactions (data collected in December 2017). TPSs were aver-
ond (TPS) aged from values on October 5, November 5, and December 5 in 2017.
Application Programming 18 Scripting Language Supported blockchain scripting language (run instructions such as “freezing funds
until a time in the future”82).
19 Open Source Availability of the source code.
20 Main Implementation Lan- Programming languages used to implement the source code for the platform.
guages
21 Software License Copyright license for the source code.

Note that we included cryptocurrency-related data items considering their future plausible use in healthcare/medicine applications.

Table 2. Platforms included in this study, as of July 2017

Blockchain Platform Dictionary Word Google Count with Blockchain Google Count Without Blockchain Popularity Score

Bitcoin No 6 800 000 31 900 000 31 900 000

Ethereum No 3 890 000 11 300 000 11 300 000
Zcash No 420 000 5 680 000 5 680 000
Litecoin No 1 680 000 4 770 000 4 770 000
Dash Yes 1 440 000 104 000 000 1 440 000
Peercoin No 157 000 1 440 000 1 440 000
Ripple Yes 1 100 000 14 300 000 1 100 000
Monero No 705 000 1 020 000 1 020 000
MultiChain No 10 200 342 000 342 000
Hyperledger No 562 000 324 000 324 000

applications but the centralization introduced by Masternode is a PoW and eventually switch to Proof of Stake (PoS) (see Supplemen-
downside. tary Appendix S4). While more appropriate for health-related appli-
cations than PoW, PoS may also not be necessary, particularly when
operating in permissioned networks, as the threat of “fake” blocks
Peercoin is less severe. However, for public networks, Peercoin may offer a
Peercoin was derived from Bitcoin to reduce the energy required for good compromise by supporting PoS.
the coin mining process.83 That is, Bitcoin’s PoW algorithm depends
on energy consumption1,2 that, in the long run, will result in lower
motivation for miners to keep building blocks unless transactions Ripple
fees rise to high enough levels to sustain the high energy consump- Ripple is a low-latency blockchain network that atomically settles
tion.83 To avoid this situation, Peercoin proposed to initially adopt and records transactions on a secure distributed database, the Ripple
470 Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

Table 3. Important items to consider when selecting a blockchain platform

Feature Main Options and Implications

Network Permission • Permission-less network: A public blockchain network configuration designed to allow public participation
(eg, some applications that rely on patient-managed data).92
• Permissioned network: A private blockchain network configuration that includes only authorized partici-
pants (eg, networks that exchange information among hospitals).31,43
Consensus Protocol • Proof of Work: A compute-intensive protocol with proof of security; suitable for permission-less blockchain
networks but can also be used in permissioned blockchain networks to increase security. The Bitcoin block-
chain uses this protocol: unfortunately, many people mistakenly believe that all blockchain networks need
to use this typically high-energy consumption protocol, which is not true.1,66
• Proof of Stake: A low-energy consumption protocol that is suitable for healthcare applications operating on
permission-less or permissioned blockchain networks.93–95

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• Mining Diversity: A round-robin, low-energy consumption protocol specifically designed for permissioned
healthcare applications.31 Variations can be designed to suit various needs.
• Kafka: A voting-based, low-energy consumption protocol that can finalize the consensus decision faster (at
least initially), but that requires more time as the number of nodes in the network grows.43
• Proof of Elapsed Time: A lottery-based, low-energy consumption protocol that can scale well for a network
with many nodes while needing more time to reach consensus.43
Special Hardware Requirement • Yes: If special hardware (eg, Intel SGX43) is required, the specifications of the computing environment need
to be confirmed before the healthcare applications can be deployed properly.
• No: If no special hardware is required, the healthcare application can be deployed without further hardware
checking.
Smart Contracts Support • Yes: If the healthcare applications focus on autonomous operations (eg, automatic payment for insurance
claims), the immutable smart contract support can be essential.25,43
• No: If the healthcare applications aim at primarily serving as a ledger (eg, recording access rights or data
transaction records), the blockchain platform without smart contract support would be sufficient.91
Scripting Language • Bitcoin Script: If smart contracts are not required for the healthcare applications, this basic scripting lan-
guage would be sufficient.82,96
• Solidity: The main smart contract language for Ethereum; it is one of the most popular languages for writing
smart contracts.97
• Chaincode: The main smart contract language for Hyperledger Fabric; it is also one of the most popular lan-
guages for writing smart contracts.98
Software License • MIT: A “permissive” license that allows healthcare applications to reuse the source code of the plat-
form.99,100
• GPL: A “copyleft” license that also allows using the source code; the derivative works in some situations
must be open-source too.99,100

Table 4. Basic information

Blockchain Platform Official Software Explorer Main Real-World Application

Website Website Website Reference
66 105 115 1
Bitcoin Microsoft (add Bitcoin to Microsoft Account)131
116 106 116 25
Ethereum MedRec37
70 107 117 75,125
Zcash Adding Zcash technology to J.P. Morgan Quorum enter-
prise blockchain platform(under development)132
80 108 118 80
Litecoin Switzerland’s Falcon Private Bank133
102 109 119 82
Dash Shakepay VISA debit card134
103 110 120 83
Peercoin CoinURL online advertisement135
104 111 121 85,86
Ripple Sumitomo Mitsui Corp and Japan Post Bank for payments
and settlement136
88 112 122 89,90,126–130
Monero Direct Voltage137
34 113 123 31
MultiChain Construtivo as workflow management for infrastructure
projects138
91 114 124 43
Hyperledger IBM Global Financing for Fabric139 and R3 for
Sawtooth140

Consensus Ledger.84 Ripple applies the Ripple Consensus Protocol the Sybil Attack.85,86 The blocks are only validated by the relatively
Algorithm, an alternative algorithm to the high-latency Bitcoin few “Chosen Validators” to enable low-latency transactions. While
Blockchain PoW, for handling the Byzantine Generals’ Problem and reaching consensus, the current distributed ledger is “closed” and
Table 5. Blockchain technology

Blockchain Main Improvement Network Consensus Protocol Special Hardware Requirement Smart Contracts Support
Platform over Bitcoin Permission

Bitcoin N/A Permission-less141 PoW1 No1,66,141 No25

Ethereum Automatic Digital Asset Permission-less or PoW/Proof-of-Stake (Casper)93 No25,101 Yes25
Management Permissioned92
Zcash Privacy/Anonymity Permission-less142 PoW (Equihash)75,143 No125,143,156 No, under development
(Zcash over Ethereum)150
Litecoin ASIC Resistance Permission-less80 PoW (Scrypt hash algorithm)80,132,144 No 80 No80
Dash Privacy/Anonymity Permission-less82 PoW/Proof-of-Service (X11 hash algorithm)82,145 No82,146 No102
Peercoin Long-Term Energy Efficiency Permission-less83 PoW/Proof-of-Stake94,95 No95 No, under development
(PeerScript)151
Ripple Low-Latency Transaction Permission-less (Controlled)104 RPCA/Consensus-and-Validation85,86 No111,147 No, abandoned (Codius)152
Monero Privacy/Anonymity Permission-less88 PoW (Ring CT)90 No148 No88
MultiChain Private/Permissioned Blockchain Network Permissioned31 PoW/Mining Diversity31 No91 No91
Hyperledger Business Blockchain Network Permissioned43 Pluggable, for example, Various, for example, Yes43, for example,
Kafka for Fabric by default, Redundant Byzantine No for Fabric149, Chaincode for Fabric153,
Fault Tolerance for Indy, Proof of Elapsed Time for Yes for Sawtooth (Intel SGX)43 Burrow-EVM Integration
Sawtooth by default, Sumeragi for Iroha43 for Sawtooth154

PoW: Proof of Work.

Table 6. Public cryptocurrency

Blockchain Symbol Mining for Anonymous Rapid Payment Coin Limit Coin Value (in U.S. Dollars, Average Transaction
Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

Platform New Public Coins Payment Updated on per Second

October 1, 2018)

Bitcoin BTC/XBT Yes141 No157,158 No1 21 Million162 6612.8300 3.50170

Ethereum ETH Yes155 No141,157 No25,160 No163 230.4400 5.40170
Zcash ZEC Yes156 Yes (zk-SNARK)75,125 No75,125 21 Million164 129.4500 0.06170
Litecoin LTC Yes80 No80 Yes (Difficulty Adjustment, 84 Million80 60.6800 0.35170
2.5 min per block)80
Dash DASH Yes146 Yes (Darksend/PrivateSend)82,159 Yes (InstantX/Instant-Send)82,161 19 Million165 187.1000 0.07170
Peercoin PPC Yes95 No83 No83 2 Billion166 1.2200 0.01170
Ripple XRP No (Pre-Mining)87 No157 Yes, RippleNet104 100 Billion167,168 0.5807 10.75171
Monero XMR Yes148 Yes (RingCT/Stealth No89,90,128,129 18.4 Million, plus 0.3 XMR per 115.9900 0.06170
Address)89,127,129,130 minute afterwards169
MultiChain N/A No N/A N/A N/A N/A 1000.00172
Hyperledger N/A No N/A N/A N/A N/A Various, for example,
3500.00 for Fabricz173

Because MultiChain and Hyperledger are not public cryptocurrencies, they do not have most of the technical features listed; however, for completeness we still include their transaction speed (ie, the Average Transactions
per Second column).
471

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472 Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

Table 7. Application programming

Blockchain Scripting Language Open Source? Main Implementation Languages Software License
Platform

Bitcoin Bitcoin Script82,96 Yes185 Cþþ185 Bitcoin Core: MIT License194

Ethereum Solidity (similar to C and Java Yes186–190 Go-Ethereum: Go186 Go-Ethereum: Lesser General Public
Script), Serpent (similar to Py- CPP-Ethereum: Cþþ187 License (LGPL) v3.0186
thon), and LLL (similar to Py-Ethereum: Python188 CPP-Ethereum: General Public Li-
Lisp)103,182,183 EthereumJ: Java189 cense (GPL) v3.0187
Parity: Rust190 Py-Ethereum: MIT License188
EthereumJ: General Public License
(GPL) v3.0189
Parity: General Public License (GPL)

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v3.0190
Zcash Bitcoin Script125,150,176 Yes107 Cþþ107 Copyright by the Zcash developers
and the Bitcoin Core developers107
Litecoin Bitcoin Script177 Yes191 Cþþ191 MIT License191
Dash Bitcoin Script82,178 Yes192 Cþþ192 MIT License192
Peercoin Bitcoin Script179,180 Yes193 Cþþ193 MIT License193
Ripple N/A (Java Script for Codius, aban- Yes84 Cþþ84 Various Copyrights84
doned)111,152,181
Monero N/A [GitHub](although the Crypto- Yes195 Cþþ195 Copyright by The Monero Project195
Note white paper states one89)
MultiChain Bitcoin Script182,183 Yes113 Cþþ113 General Public License (GPL) v3.0 113
Hyperledger Various, for example, Yes114 Various, for example, Various, for example,
Go/node.js for Fabric (Chaincode)98, Go for Fabric, Apache License v2.0 for Fabric,
Cþþ, Go, Java, JavaScript, Python, Python for Sawtooth114 Copyright by Intel Corporation for
Rust, or Solidity (through Seth) for Sawtooth114
Sawtooth154,184

considered the most recent one. Also, Ripple coins are “pre-mined” versity can provide consensus and mining securely on the private
and cannot be created during the consensus process.87 Again, if we blockchain network without the need for the computationally inten-
consider that most healthcare applications will use permissioned sive PoW algorithm.31 However, MultiChain does not provide addi-
networks, the advantages of using alternative consensus protocols tional privacy for users as do some other platforms.
are diminished.

Hyperledger
Monero Hyperledger is an open-source collaborative effort created to ad-
Monero is a secure, private, and untraceable cryptocurrency.88 vance permissioned or private, cross-industry blockchain technolo-
Monero offers privacy or anonymity to its users by using the “Ring gies.91 As the use of blockchain must respond to different needs,
Confidential Transactions” (a ring signature algorithm based on Hyperledger provides an infrastructure to include a range of mod-
CryptoNote89 that generates a group signature and in which the ac- ules, such as various smart contract engines.43 Specifically, Hyper-
tual signer cannot be identified) and the “Stealth Address” (an one- ledger includes differentiated blockchain frameworks and tools.43
time address for each transaction) technologies, to obfuscate the ori- Each framework supports different types of consensus protocols.43
gins, destinations, and amounts of all transactions.88 Therefore, the Hyperledger does not support PoW43 and the additional privacy
ability to “hide the destination and origin of transactions”90 is an protection is yet to be included. It should also be noted that Hyper-
important feature of Monero. This platform might be considered in ledger has global collaborations with various companies.
applications in which the privacy or anonymity of patient or partici-
pant users is at stake, although it only supports the high energy con- As we can see from the brief summaries, no platform is perfect,
sumption PoW protocol. and in the future the best features may be adopted by the platforms
that remain in the market. It is unlikely that more than 3 or 4 plat-
forms will become very relevant to healthcare. In terms of platforms
MultiChain
likely to continue to be used for healthcare applications, Ethereum,
MultiChain is a blockchain platform to create and deploy permis-
Hyperledger and MultiChain are at the top of the list because they
sioned or private blockchain networks.31 As a fork of the Bitcoin
combine the most relevant features at the moment.
Blockchain, MultiChain focuses on providing features such as inte-
grating user permission management and improve the data ledger
functions.34 Also, MultiChain supports both Bitcoin Blockchain Results of platform comparison
PoW and “Mining Diversity,” a round-robin-based consensus proto- The features most relevant for healthcare applications are summa-
col.31 The basic idea of Mining Diversity is that, within a private rized in Table 3, and the full comparison results of the extraction
blockchain network, the participants are already “trusted” to some of the 21 data items (Table 1) from the 10 blockchain platforms
extent because they are identifiable entities.31 Therefore, Mining Di- (Table 2) are shown in Tables 4–7.
Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5 473

DISCUSSION they are also specialized in different technical characteristics, such as

improving transaction speed, mitigating block mining centralization,
Summary of findings
enhancing user privacy or anonymity, and supporting permissioned
All 10 popular blockchain platforms are open source, which is a key
or private blockchain networks. Based on our findings, which indi-
factor to foster their popularity. Also, 8 of 10 platforms support
cate that most healthcare or biomedical research applications are
cryptocurrencies, which may become important depending on how
still in early stages of conceptualization, we believe that the use of
systems of incentives are designed for different application. As sev-
blockchain technology in the healthcare or medicine domains will
eral blockchain platforms were based on Bitcoin Blockchain (eg,
require a type of social transformation that constitutes a much big-
forked from it or work on top of it), these platforms share similar
ger challenge than the technological one. The ability to think differ-
features, such as adopting the PoW consensus protocol, requiring no
ently and the willingness to change the way our field operates for
special hardware to create new blocks, and being implemented in
decades will require vision, entrepreneurship, and a modest initial
Cþþ. Finally, Zcash, Dash, and Monero focus on privacy or ano-
investment that is likely to pay off in a few years. The inherent vir-
nymity of transaction information, which is important for users like
tues of blockchain (decentralization and immutability of the ledger)

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patients.
presuppose scenarios in which a minimum number of users agree to
Among the healthcare and clinical applications that we are
use and some agree to actively contribute “blocks” and perform
aware of, some are proposed and others are implemented using the
other functions (eg, predictive modeling) for healthcare or biomedi-
blockchain platforms included in this review, especially Ethereum,
cal applications. The transformation will certainly happen if the
Hyperledger, and MultiChain. As more applications of blockchain
proper system of incentives can be put together.
emerge, it will also be important that they adhere to standards that
The future directions of this comparative review include moni-
the health informatics community has been supporting for a long
toring the progress of healthcare applications, comparing the evolu-
time. Thus, it is important that the current somewhat disjoint com-
tion of a larger number of blockchain platforms (through review
munities of blockchain technologists and health informaticists con-
and empirically), and providing targeted suggestions for application-
verge toward more overlap and collaboration to facilitate
specific platform selection in an expanded spectrum of biomedical
standardization of technologies from both sides.
informatics projects.

Limitations
A limitation of this study is that the blockchain technology is rela-
FUNDING
tively new and still emerging, so documentation is somewhat very
limited (eg, out of date or not available because of the fast and con- T-TK and LO-M were partly funded by the National Institutes of Health
tinuing development process), and the applications for healthcare or (OT3OD025462). HZR was supported by the UCSD STARS Program, and
the iDASH Summer Internship Program funded by the National Institutes of
medicine are mostly in early stages (ie, most are proposed systems
Health (T15LM11271). Research reported in this publication was supported
that have yet to be implemented). Therefore, our systematic compar-
by the National Human Genome Research Institute of the National Institutes
ison is restricted by the data and information we could gather from
of Health under Award Number K99/R00HG009680. The content is solely
publicly available resources for each platform. Additionally, we fo- the responsibility of the authors and does not necessarily represent the official
cused on the most popular platforms, and therefore we only views of the National Institutes of Health or of the Veterans Health Adminis-
reviewed the first 30 webpages returned from the initial Google.com tration (VHA).
search (ie, blockchain platforms). After deduplication, we selected
10 of 35 platforms. This selection process may have introduced bias,
because we used not only a popularity ranking, but also a manual
CONTRIBUTORS
screening process. Finally, we extracted 21 data items in 4 categories
(ie, basic information, blockchain technology, public cryptocur- T-TK and HZR mainly conducted the systematic review and drafted
rency, and application programming), which may cover only the the manuscript. LO-M was principal investigator of this study: she
most critical aspects in the selection of the blockchain platforms for provided the original idea, performed overall supervision of the study,
healthcare applications, while several other minor technical features resolved the disagreements in the systematic review process, provided
are yet to be included. Finally, we have not run real controlled cases critical editing, and made several additions to the manuscript.
to verify that the stated speed of transactions is similar to the one
stated in the websites.
SUPPLEMENTARY MATERIAL
CONCLUSION Supplementary material is available at Journal of the American
Medical Informatics Association online.
In this study, we identified healthcare applications of blockchain, as
well as the platforms that have been proposed or implemented by
the state-of-the-art healthcare blockchain studies. To understand
which blockchain platform may be more feasible for healthcare or ACKNOWLEDGMENTS
clinical applications, we conducted a systematic comparison of 21 The authors would like to thank Xiaoqian Jiang, PhD, for organizing the
characteristics for 10 popular blockchain platforms, to support iDASH (integrating Data for Analysis, Anonymization, and SHaring) Summer
health informatics researchers in the selection of the most suitable Internship Program, and Elisa Maldonado, PhD, for organizing the Summer
platform for their specific application. We discussed critical block- Training Academy for Research Success (STARS) Program at University of
California, San Diego, in 2017. The authors would also like to thank Jeremy
chain implementation features, introduced these platforms, and
Blackstone for his support of HZR during his UCSD STARS internship.
compared the technical features that are most relevant to healthcare.
Our results show that most platforms share similar features, but Conflict of interest statement. None declared.
474 Journal of the American Medical Informatics Association, 2019, Vol. 26, No. 5

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