Letters
Teresa Liu-Ambrose, PT, PhD registered. This creates the danger that the next clinical trial
Jennifer C. Davis, PhD
Karim M. Khan, MD, PhD
Author Affiliations: Department of Physical Therapy, University of British
Columbia, Vancouver, Canada (Liu-Ambrose); University of British Columbia,
Okanagan, Kelowna, Canada (Davis); Center for Hip Health and Mobility,
University of British Columbia, Vancouver, Canada (Khan).
Corresponding Author: Teresa Liu-Ambrose, PT, PhD, Faculty of Medicine,
Department of Physical Therapy, University of British Columbia, 212-2177
Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada (teresa.ambrose@ubc.ca).
Conflict of Interest Disclosures: Dr Liu-Ambrose reported receiving grants
from the Canadian Institutes of Health Research, Alzheimer’s Society of Canada
Research Program, Heart and Stroke Foundation of Canada, and Jack Brown
and Family Alzheimer Research Foundation Society; being a cofounder and
serving on the executive team of Synaptitude Brain Health Inc; and serving on
the board of directors for the BC Brain Wellness Foundation. She does not
receive personal fees for these roles. No other disclosures were reported.
1. Liu-Ambrose T, Davis JC, Best JR, et al. Effect of a home-based exercise
program on subsequent falls among community-dwelling high-risk older adults
after a fall: a randomized clinical trial. JAMA. 2019;321(21):2092-2100. doi:10.
1001/jama.2019.5795
2. Aeberhard WH, Cantoni E, Heritier S. Robust inference in the negative
binomial regression model with an application to falls data. Biometrics. 2014;70
(4):920-931. doi:10.1111/biom.12212
3. Shumway-Cook A, Silver IF, LeMier M, York S, Cummings P, Koepsell TD.
Effectiveness of a community-based multifactorial intervention on falls and fall
risk factors in community-living older adults: a randomized, controlled trial.
J Gerontol A Biol Sci Med Sci. 2007;62(12):1420-1427. doi:10.1093/gerona/62.12.
1420
4. Robertson MC, Campbell AJ, Gardner MM, Devlin N. Preventing injuries in
older people by preventing falls: a meta-analysis of individual-level data. J Am
Geriatr Soc. 2002;50(5):905-911. doi:10.1046/j.1532-5415.2002.50218.x
5. Northey JM, Cherbuin N, Pumpa KL, Smee DJ, Rattray B. Exercise
interventions for cognitive function in adults older than 50: a systematic review
with meta-analysis. Br J Sports Med. 2018;52(3):154-160. doi:10.1136/bjsports-
2016-096587
6. Davis JC, Best JR, Khan KM, et al. Slow processing speed predicts falls in
older adults with a falls history: 1-year prospective cohort study. J Am Geriatr Soc.
2017;65(5):916-923. doi:10.1111/jgs.14830
Identifying Sepsis Phenotypes
To the Editor A retrospective analysis of data sets from 3 co-
horts by Dr Seymour and colleagues1 reported the identifica-
tion of 4 novel sepsis patient subtypes and was performed to
address the problem of sepsis heterogeneity.2 However, we be-
lieve that the study was limited with regard to advancing in-
dividualized or subtype-directed therapy.
Most clinicians would not be surprised that subgroups can
be identified in cohorts of patients meeting the Sepsis-3
definition.3 A previously healthy, young individual with a uri-
nary tract infection is clinically different from an older pa-
tient (aged >65 years) with multiple comorbidities and severe
pneumonia. More rational patient subgroups can be identi-
fied by using artificial intelligence and mining large data-
bases. However, unsupervised artificial intelligence is not un-
biased because only the data available within the database can
be explored, and only the data that are known or thought to
be important are entered.
Because knowledge of the underlying pathophysiologi-
cal mechanisms associated with multiple organ failure in pa-
tients with sepsis is still limited, the data that are directly re-
lated to the cause or mechanisms of organ failure cannot be
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will be performed in patient subgroups without a common un-
derlying pathophysiology of multiple organ failure, leading to
off-target effects and another unsuccessful trial. For ex-
ample, the pathophysiology of sepsis-associated acute kid-
ney injury differs between patients with septic shock and mul-
tiple organ failure,4 likely representing patients with the δ
phenotype. Hence, within each clinical subphenotype (α, β,
γ, δ), multiple pathophysiological subphenotypes exist that will
likely require multiple different therapeutic strategies.
Clinical trials that enriched patient subgroups have not
been very successful. It took 6 years to enroll enough
patients for the SCARLET (Sepsis Coagulopathy Asahi
Recombinant LE Thrombomodulin) trial,5 which still had
a negative outcome. Nevertheless, it is likely that the identifi-
cation of patient subtypes will be transformative in sepsis
care. However, in our opinion, knowledge of the pathophysi-
ological mechanisms of sepsis-mediated multiple organ fail-
ure must be increased to collect additional, more relevant
data sets for mining. By doing so, artificial intelligence will
have a better chance of identifying patient subtypes that can
be treated based on the pathophysiology.
Jill Moser, PhD
Matijs van Meurs, MD, PhD
Jan G. Zijlstra, MD, PhD
Author Affiliations: Department of Critical Care, University Medical Center
Groningen, Groningen, the Netherlands.
Corresponding Author: Jan G. Zijlstra, MD, PhD, Department of Critical Care,
University Medical Center Groningen, Hanzeplein 1, 9700RB, 9713 GZ
Groningen, the Netherlands (j.g.zijlstra@umcg.nl).
Conflict of Interest Disclosures: None reported.
1. Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential
treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321
(20):2003-2017. doi:10.1001/jama.2019.5791
2. Leligdowicz A, Matthay MA. Heterogeneity in sepsis: new biological evidence
with clinical applications. Crit Care. 2019;23(1):80. doi:10.1186/s13054-019-2372-2
3. Singer M, Deutschman CS, Seymour CW, et al. The Third International
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315
(8):801-810. doi:10.1001/jama.2016.0287
4. Aslan A, van den Heuvel MC, Stegeman CA, et al. Kidney histopathology in
lethal human sepsis. Crit Care. 2018;22(1):359. doi:10.1186/s13054-018-2287-3
5. Vincent J-L, Francois B, Zabolotskikh I, et al; SCARLET Trial Group. Effect of
a recombinant human soluble thrombomodulin on mortality in patients with
sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA.
2019;321(20):1993-2002. doi:10.1001/jama.2019.5358
To the Editor Although the analysis of novel clinical pheno-
types for sepsis1 provided a thorough and effective examina-
tion of measures in a number of clinical domains, we believe
that it did not sufficiently explore the data domain of disease
comorbidities. A key component of phenotype, and the phy-
sician’s evaluation, involves medical history, and this infor-
mation, including the interrelationships between comorbidi-
ties, must be considered in the development of phenotypes.
Newer computational methods offer the opportunity to see the
patterns of relationships of disease comorbidities in a more
complete and lifelong way than prior comorbidity stratifica-
tion schema such as the Elixhauser comorbidity index.2
jama.com

Our experience with disease comorbidity analysis shows
that time-ordered disease comorbidity relationships offer
important insights on patient outcomes. Furthermore, these
progression studies often reveal the association between
seemingly unrelated diagnoses and the major diagnoses
highlighted by indices such as the Elixhauser comorbidity
index. Using this approach, our research group built temporal
comorbidity trajectories to examine disease associations in
an entire population.3 When applied to the single diagnosis
of sepsis, this approach gave important information on out-
come, even when the details of the sepsis hospitalization
were not available.4
In addition, machine learning techniques can help create
dynamic comorbidity indices that evolve with changes in pa-
tient outcomes. A neural network approach combined high-
frequency clinical data from intensive care unit hospitaliza-
tions with 20-year disease comorbidity trajectories to predict
outcome in individual patients in the intensive care unit.5 In
this case, especially for sepsis, the analysis of comorbidities
was a far better predictor of outcome than previously used
methods and the addition of acute physiology measures added
to the predictive value.
We do not know the effect such a disease comorbidity
analysis could have on the results of the study by Dr Seymour
and colleagues.1 We suggest that understanding the pheno-
type of critically ill patients should include a more thorough
accounting of the medical history than can be obtained through
commonly used comorbidity indices in addition to high-
frequency clinical measures and laboratory analyses.
Pope L. Moseley, MD
Soren Brunak, PhD
Author Affiliations: Novo Nordisk Foundation Center for Protein Research,
University of Copenhagen, Copenhagen, Denmark.
Corresponding Author: Pope L. Moseley, MD, Faculty of Health and Medical
Sciences, Novo Nordisk Foundation Center for Protein Research, University
of Copenhagen, Blegdamsvej 3A, DK-2200 Copenhagen, Denmark
(pope.moseley@cpr.ku.dk).
Conflict of Interest Disclosures: None reported.
1. Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential
treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321
(20):2003-2017. doi:10.1001/jama.2019.5791
2. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use
with administrative data. Med Care. 1998;36(1):8-27. doi:10.1097/00005650-
199801000-00004
3. Jensen AB, Moseley PL, Oprea TI, et al. Temporal disease trajectories
condensed from population-wide registry data covering 6.2 million patients.
Nat Commun. 2014;5:4022. doi:10.1038/ncomms5022
4. Beck MK, Jensen AB, Nielsen AB, Perner A, Moseley PL, Brunak S. Diagnosis
trajectories of prior multi-morbidity predict sepsis mortality. Sci Rep. 2016;6:
36624. doi:10.1038/srep36624
5. Nielsen AB, Thorsen-Meyer H-C, Belling K, et al. Survival prediction in
intensive-care units based on aggregation of long-term disease history and
acute physiology: a retrospective study of the Danish National Patient Registry
and electronic patient records. Lancet Digital Health. 2019;1(2):e78-e89. doi:10.
1016/S2589-7500(19)30024-X
In Reply We agree with Dr Moser and colleagues that hetero-
geneity in sepsis is an important area of study. Many of the dif-
ferences in patients with sepsis are clinically apparent, and yet
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Letters
unsupervised methods may identify emerging patterns or phe-
notypes not otherwise discernible at the bedside.
We also agree that “unsupervised” methods were not
wholly unsupervised in our study because we relied on the in-
herent choices of clinicians to order examinations or labora-
tory tests or obtain measurements found in the electronic
health record.1 Broadly speaking, these data do not capture the
theoretical universe of randomly observable data in a patient
with sepsis. It may even be that pertinent tests or data that of-
fer a full permutation of this universe are not yet developed.
For now, our models could run only on the observable data.
We also agree that it is a scientific priority to identify phe-
notypes with strong links to the underlying pathophysiologi-
cal mechanism. Further study is warranted to link clinical sep-
sis phenotypes, not just to measurable biomarkers but to the
biology that might explain why one phenotype differs from an-
other. Such steps will move forward novel therapies that are
better predictive of treatment response.
Drs Moseley and Brunak comment that medical history
and comorbidities, and perhaps their underappreciated
dynamic trajectory before sepsis, could contribute to phe-
notypes. We agree that many additional data domains could
refine clustering or partitioning models in patients with sep-
sis. Because this was an “opening volley” using clinical data
in the electronic health record, we made a design choice to
include variables immediately available at presentation in
the emergency department. These steps led to a more con-
strained view of chronic illness. Future embedding of
comorbidity analysis across electronic health records, both
inpatient and outpatient, may facilitate their clinical use in
point-of-care phenotyping.
Christopher W. Seymour, MD, MSc
Derek C. Angus, MD, MPH
Author Affiliations: Department of Critical Care Medicine, University of
Pittsburgh, Pittsburgh, Pennsylvania (Seymour, Angus); Associate Editor, JAMA
(Angus).
Corresponding Author: Christopher W. Seymour, MD, MSc, School of Medicine,
Clinical Research, Investigation, and Systems Modeling of Acute Illness
(CRISMA) Center, Departments of Critical Care Medicine and Emergency
Medicine, University of Pittsburgh, 3550 Terrace St, Scaife Hall, Room 639,
Pittsburgh, PA 15261 (seymourcw@upmc.edu).
Conflict of Interest Disclosures: None reported.
1. Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential
treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321
(20):2003-2017. doi:10.1001/jama.2019.5791
Notice of Retraction. Aboumatar et al.
Effect of a Program Combining Transitional Care
and Long-term Self-management Support
on Outcomes of Hospitalized Patients With Chronic
Obstructive Pulmonary Disease: A Randomized
Clinical Trial. JAMA. 2018;320(22):2335-2343.
To the Editor On behalf of our coauthors, we write to report a
programming error and other errors that affected the results
in our article, “Effect of a Program Combining Transitional Care
and Long-term Self-management Support on Outcomes of
Hospitalized Patients With Chronic Obstructive Pulmonary
(Reprinted) JAMA October 8, 2019 Volume 322, Number 14 1417