Estimating the Additional Hospital Inpatient Cost and Mortality Associated With Selected Hospital-Acquired Conditions

Appendix A. PubMed Search Criteria

Common Search Criteria for Cost

Common Search Criteria for Cost ("Costs and Cost Analysis"[mh] OR "Cost of Illness"[mh] OR "Economics"[mh] OR "Health Care Costs"[mh] OR "Direct Service Costs"[mh] OR "Hospital Costs"[mh] OR "Health Expenditures"[mh] OR cost[tiab] OR costs[tiab] OR expenditure*[tiab] OR expense[tiab] OR spend*[tiab] OR "financial outcome"[tiab] OR "financial outcomes"[tiab] OR "financial impact"[tiab] OR "financial impacts"[tiab] OR "economic impact"[tiab] OR "economic impacts"[tiab] OR "economic outcome"[tiab] OR "economic outcomes"[tiab]) AND (incremental[tiab] OR additional[tiab] OR extra[tiab] OR attribut*[tiab] OR excess[tiab] OR "compared to"[tiab] OR "compared with"[tiab] OR "associated with"[tiab] OR "because of"[tiab] OR "due to"[tiab] OR "caused by"[tiab]) AND (hospital*[tiab] OR inpatient[tiab] OR "Hospital Costs"[mh] OR "intensive care unit"[tiab]) NOT "cost effectiveness"[ti]

 

Common Search Criteria for Mortality "Mortality"[mh] OR "Hospital mortality"[mh] OR mortalit*[tiab] OR death*[tiab] OR fatalit*[tiab]) AND (additional[tiab] OR extra[tiab] OR attribut*[tiab] OR excess[tiab] OR "compared to"[tiab] OR "compared with"[tiab] OR "associated with"[tiab] OR "because of"[tiab] OR "due to"[tiab] OR "caused by"[tiab]

 

Common Exclusions English[lang] AND United States[pl] AND (2000:2017[dp]

 

Adverse Drug Events (("Drug therapy/adverse effects"[mh] OR "drug interactions"[mh] OR "anaphylaxis"[mh] OR "drug overdose"[mh] OR "Drug-related side effects and adverse reactions"[mh] OR "adverse drug event"[tiab] OR "adverse drug events"[tiab] OR "adverse drug reaction"[tiab] OR "adverse drug reactions"[tiab] OR "medication errors"[mh] OR "medication error"[tiab] OR "medication errors"[tiab] OR adverse [tiab] OR "allergic reaction"[tiab] OR "allergic reactions"[tiab] OR "anaphylaxis"[tiab] OR overdose[tiab] OR ((drug[tiab] OR medication[tiab]) AND (harm[tiab] OR injury[tiab]))) AND (("anticoagulants"[mh] OR "anticoagulation"[tiab] OR "anticoagulant"[tiab] OR "4- Hydroxycoumarins"[mh] OR "Acenocoumarol"[mh] OR "Ancrod"[mh] OR "Antithrombin III"[mh] OR "Antithrombin Proteins"[mh] OR "Beta 2-Glycoprotein I"[mh] OR "Blood Coagulation Factor Inhibitors"[mh] OR "Citric Acid"[mh] OR "Dabigatran"[mh] OR "Dalteparin"[mh] OR "Dermatan Sulfate"[mh] OR "Dextrans"[mh] OR "Dicumarol"[mh] OR "Edetic Acid"[mh] OR "Enoxaparin"[mh] OR "Ethyl Biscoumacetate"[mh] OR "Fibrin Fibrinogen Degradation Products"[mh] OR "Gabexate"[mh] OR "Heparin"[mh] OR "Heparin Cofactor II"[mh] OR "Heparin, Low-Molecular-Weight"[mh] OR "Heparinoids"[mh] OR "Hirudins"[mh] OR "Nadroparin"[mh] OR "Pentosan Sulfuric Polyester"[mh] OR "Phenindione"[mh] OR "Phenprocoumon"[mh] OR "Protein C"[mh] OR "Protein S"[mh] OR "Rivaroxaban"[mh] OR "Warfarin"[mh] OR "Hirudin Therapy"[mh]) OR ("analgesics, opioid"[mh] OR opioid*[tiab] OR "Alfentanil"[mh] OR "Alphaprodine"[mh] OR "Buprenorphine"[mh] OR "Buprenorphine, Naloxone Drug Combination"[mh] OR "Butorphanol"[mh] OR "Codeine"[mh] OR "Dextromoramide"[mh] OR "Dextropropoxyphene"[mh] OR "Dihydromorphine"[mh] OR "Diphenoxylate"[mh] OR "Enkephalin, Ala(2)-MePhe(4)-Gly(5)- "[mh] OR "Enkephalin, D- Penicillamine (2,5)- "[mh] OR "Ethylketocyclazocine"[mh] OR "Ethylmorphine"[mh] OR "Etorphine"[mh] OR "Fentanyl"[mh] OR "Heroin"[mh] OR "Hydrocodone"[mh] OR "Hydromorphone"[mh] OR "Levorphanol"[mh] OR "Meperidine"[mh] OR "Meptazinol"[mh] OR "Methadone"[mh] OR "Methadyl Acetate"[mh] OR "Morphine"[mh] OR "Nalbuphine"[mh] OR "Opiate Alkaloids"[mh] OR "Opium"[mh] OR "Oxycodone"[mh] OR "Oxymorphone"[mh] OR "Pentazocine"[mh] OR "Phenazocine"[mh] OR "Phenoperidine"[mh] OR "Pirinitramide"[mh] OR "Promedol"[mh] OR "Sufentanil"[mh] OR "Tilidine"[mh] OR "Tramadol"[mh])) AND ("iatrogenic disease"[mh] OR "nosocomial"[tiab] OR "healthcare associated"[tiab] OR "health care associated"[tiab] OR "hospital acquired"[tiab] OR "inpatient"[tiab] OR "hospitalized"[tiab] OR "hospital related"[tiab] OR "in hospital"[tiab] OR "in hospitals"[tiab] OR "within hospitals"[tiab]))

 

CAUTI ((("urinary tract infections"[mh] OR "urinary tract infection*"[tiab]) AND (Urinary catheterization[mh] OR urinary catheter*[tiab] OR "catheter associated"[tiab])) OR ("catheter-related infections"[mh] AND "urinary"[tiab]) OR (Urinary Catheterization/adverse effects*[mh) OR "CAUTI"[tiab] OR (("cross infection"[mh] OR "iatrogenic disease"[mh] OR "nosocomial"[tiab] OR "hospital infection"[tiab] OR "hospital infections"[tiab] OR "healthcare associated"[tiab] OR "health care associated"[tiab] OR "hospital acquired"[tiab] OR "hospital related"[tiab]) AND "urinary"[tiab]))

 

CLABSI ((("catheter-related"[tiab] OR "catheter-associated"[tiab] OR "Catheterization, Central Venous/adverse effects"[Mesh] OR "Central Venous Catheters/adverse effects"[mh] OR "Catheters, Indwelling/adverse effects"[mh] OR "umbilical catheter"[tiab] OR central line*[tiab] OR central venous catheter*[tiab]) AND ("bloodstream infection"[tiab] OR "bloodstream infections"[tiab] OR "blood stream infection"[tiab] OR "blood stream infections"[tiab] OR "bacteremia"[tiab] OR "bacteremia"[mh] OR ((Cross infection[mh] OR "cross infection"[tiab] OR "cross infections"[tiab] OR nosocomial[tiab] OR "hospital-acquired infection"[tiab] OR "hospital-acquired infections"[tiab] OR "healthcare-associated infection"[tiab] OR "healthcare-associated infections"[tiab] OR "health care-associated infection"[tiab] OR "health care-associated infections"[tiab]) AND ("bloodstream"[tiab] OR "blood stream"[tiab])))) OR CLABSI[tiab] OR CRBSI[tiab] OR CABSI[tiab] OR CLAB[tiab] OR ("catheter-related infections"[mh] AND ("blood stream"[tiab] OR "bloodstream"[tiab])))

 

Falls ("Accidental Falls" [mh] OR Falls [tiab] OR Falling [tiab] OR Fall [tiab] OR "Accidental Falls" [tiab] OR "Accidental Fall" [tiab] OR Slip [tiab] OR Faller [tiab]) AND (hospital*[tiab] OR inpatient*[tiab] OR "Hospital Costs"[mh] OR "intensive care unit"[tiab] OR "acute care setting"[tiab] OR "hospitalization"[mh] OR "inpatients"[mh] OR "Intensive Care Units"[Mesh])

 

Obstetric Adverse Events ("Inferior Wall Myocardial Infarction"[Mesh] OR "Anterior Wall Myocardial Infarction"[Mesh] OR "Acute Kidney Injury"[Mesh] OR "Respiratory Distress Syndrome, Adult"[Mesh] OR "Embolism, Amniotic Fluid"[Mesh] OR "Aneurysm"[Mesh] OR "Heart Arrest"[Mesh] OR "Ventricular Fibrillation"[Mesh] OR "Disseminated Intravascular Coagulation"[Mesh] OR "Heart Failure"[Mesh] OR "Head Injuries, Closed"[Mesh] OR "Craniocerebral Trauma"[Mesh] OR "Cerebrovascular Trauma"[Mesh] OR "Cerebrovascular Disorders"[Mesh] OR "Pulmonary Edema"[Mesh] OR "Anesthesia, Obstetrical/adverse effects"[Mesh] OR "Anesthesia, Obstetrical/complications"[Mesh] OR "Sepsis"[Mesh] OR "Shock"[Mesh] OR "Anemia, Sickle Cell/complications"[Mesh] OR "Thrombosis/complications"[Mesh] OR "Blood Transfusion"[Mesh] OR "Defibrillators"[Mesh] OR "Interactive Ventilatory Support"[Mesh])

 

Pressure Ulcers (("Pressure Ulcer" [MeSH] OR "Pressure Ulcer" [tiab] OR "Bedsore" [tiab] OR "Bed Sores" [tiab] OR "Decubitus Ulcer" [tiab] OR "Pressure Sore" [MeSH] OR "Pressure Sore" [tiab] OR "Suspected Deep Tissue Injury" [tiab] OR "Pressure Ulcer" [MeSH] OR "Pressure Ulcer" [tiab] OR "osteomyelitis" [MeSH] OR "osteomyelitis" [tiab] OR "tunneling" [tiab] OR "fissure" [tiab]) AND ("hospital acquired" [tiab] OR "healthcare acquired" [tiab] OR "nosocomial" [tiab] OR "hospitalization" [MeSH] OR "hospitalized"[tiab] OR "healthcare associated"[tiab] OR "health care associated"[tiab] OR "health care acquired"[tiab] OR "hospital related"[tiab] OR "inpatient"[tiab] OR "in hospital"[tiab] OR "in hospitals"[tiab] OR "within hospitals"[tiab))

 

Venous Thromboembolism (("pulmonary embolism/economics"[MeSH Terms]) OR ("Upper Extremity Deep Vein Thrombosis"[MeSH Terms]) OR ("venous thromboembolism/economics"[MeSH Terms]) OR ("venous thrombosis/economics"[MeSH Terms]) OR ("Pulmonary Infarction"[Mesh]) OR (("deep venous"[tiab] OR "deep vein"[tiab] OR "pulmonary"[tiab]) AND (thrombos*[tiab] OR embolism*[tiab] OR thromboembolism*[tiab]))) AND ("iatrogenic disease"[mh] OR "nosocomial"[tiab] OR "healthcare associated"[tiab] OR "health care associated"[tiab] OR "hospital acquired"[tiab] OR "inpatient"[tiab] OR "hospitalized patients"[tiab] OR "hospital related"[tiab] OR "in hospital"[tiab] OR "in hospitals"[tiab] OR "within hospitals"[tiab])

 

Surgical Site Infections ("cross infection"[mh] OR "hospital acquired" [tiab] OR "healthcare acquired" [tiab] OR "nosocomial" [tiab] OR "hospitalized"[tiab] OR "healthcare associated"[tiab] OR "hospital associated"[tiab] OR "health care associated"[tiab] OR "health care acquired"[tiab] OR "hospital related"[tiab] OR "inpatient"[tiab] OR "in hospital"[tiab] OR "in hospitals"[tiab] OR "within hospitals"[tiab]) AND ("surgical wound infection/economics"[mh] OR "surgical procedures, operative/adverse effects"[mh] OR ("surgical wound infection"[mh] AND prognosis[mh]) OR (("surgical wound infection*"[tiab] OR "surgical site infection*"[tiab]) AND outcome*[tiab]))

 

Ventilator Associated Pneumonia (("Pneumonia, Ventilator-Associated/economics"[mh]) OR ("Ventilator Associated Pneumonia"[tiab] OR "Ventilator-Associated Pneumonia"[tiab] OR "Ventilators, Mechanical/adverse effects"[mh]) OR (("Respiration, Artificial/economics"[mh] OR "Artifical respiration"[tiab]) AND (mechanically ventilat*[tiab] OR mechanical ventilat*[tiab] OR intubat*[tiab] OR ventilator associated*[tiab])) AND ("cross infection"[mh] OR "iatrogenic disease"[mh] OR "hospital acquired" [tiab] OR "healthcare acquired" [tiab] OR "nosocomial" [tiab] OR "healthcare associated"[tiab] OR "hospital associated"[tiab] OR "health care associated"[tiab] OR "health care acquired"[tiab] OR "hospital related"[tiab] OR "inpatient"[tiab] OR "in hospital"[tiab] OR "in hospitals"[tiab]))

 

Clostridium difficile Infections (("Clostridium difficile" [Mesh] OR "Clostridium difficile*" [tiab] OR "C diff"[tiab] OR "Colitis" [Mesh] OR "Colitis" [tiab] OR CDAD[tiab]) AND("cross infection" [Mesh] OR "bacteremia" [Mesh] OR "iatrogenic disease"[MeSH] OR "nosocomial"[tiab] OR "healthcare associated"[tiab] OR "health care associated"[tiab] OR "hospital acquired"[tiab] OR "hospital infection*"[tiab] OR "inpatient"[tiab]))

Appendix B. Excess Mortality Calculations

We define excess mortality as an estimate of additional deaths due to the hospital-acquired condition (HAC). These are expressed as the percentage of HAC cases who die as a result of the HAC.

Calculation:        

Where P(D|E) indicates the probability of death in those with HAC and P(D|not E) indicates the  probability of death in those at risk for, but do not acquire, the HAC.

	Died	Alive
HAC group	a	b
Non-HAC group	c	d

Meta-analysis Method for Estimating Excess Mortality

We calculate the pooled relative risk using meta-analysis and then calculate excess mortality using the pooled RR and an estimate of the underlying mortality rate:

where RR =  represents the underlying mortality in patients at risk for the HAC.

When the underlying mortality was not available from other literature, we used an estimate of the general inpatient mortality rate. This rate, 2 percent, can be thought of as the overall mortality rate among all hospitalized patients, HAC and non-HAC patients. This rate was used for falls and VTE. For all other HACs, the underlying mortality rate was drawn from the published literature. Exhibit B1 shows the underlying mortality rates and a description of the underlying population alongside the meta-analysis-based estimates of excess mortality.

Exhibit B1. Underlying Mortality Rates

HAC	Underlying Population Description	Underlying Mortality Rate	RR (range)	Pooled RR (95% CI)	Excess Mortality Estimate (95% CI)
ADE	Hospitalized patients who are given anticoagulants, hypoglycemic agents, and opioids during hospitalization	0.02a	0.68–3.09	1.61 (1.14, 2.27)	0.012 (0.003–0.025)
CAUTI	Hospitalized patients with urinary catheters	0.071b	1.28–1.97	1.50 (1.06, 2.11)	0.036 (0.004–0.079)
CLABSI	Hospitalized patients with central lines	0.086b	1.86–4.88	2.72 (1.81, 4.10)	0.15 (0.070–0.27)
Falls	All hospitalized patients who are at risk to fall in the hospital	0.02a	3.50	3.50 (2.73, 4.48)	0.050 (0.035–0.070)
OBAE	Estimate was not based on RR and underlying mortality; please see report for details				0.0049 (0.0030–0.013)
Pressure Ulcer	All hospitalized patients who are at risk to have pressure ulcer	0.018c	2.42–5.06	3.26 (1.71, 6.17)	0.041 (0.013–0.093)
SSI	All hospitalized postsurgical patients	0.0114d	1.75–5.70	3.32 (1.79, 6.18)	0.026 (0.009–0.059)
VAP	Hospitalized patients with ventilator	0.3e	0.52–4.90	1.48 (0.64, 3.42)	0.14 (-0.11–0.73)
VTE	All hospitalized patients who are at risk to get VTE	0.02a	1.01–13.63	3.15 (2.02, 4.91)	0.043 (0.040–0.078)
CDI	All hospitalized patients who are at risk to get CDI	0.073f	1.17–9.60	1.60 (1.38, 1.87)	0.044 (0.028–0.064)

^a Hall MJ, Levant S, DeFrances CJ. Trends in Inpatient Hospital Deaths: National Hospital Discharge Survey, 2000–2010 NCHS Data Brief, No. 118. Hyattsville, MD: National Center for Health Statistics; 2013.

^b Glied S, Cohen B, Liu J, et al. Trends in mortality, length of stay, and hospital charges associated with health care–associated infections, 2006-2012. Amer J Inf Cont. 2016 Sep 1;44(9):983-9.

^c Bauer K, Rock K, Nazzal M, et al. Pressure ulcers in the United States' inpatient population from 2008 to 2012: results of a retrospective nationwide study. Ostomy/wound Mgmt. 2016 Nov;62(11):30.

^d Weiser TG, Semel ME, Simon AE, et al. In-hospital death following inpatient surgical procedures in the United States, 1996–2006. Wrld J of Surg. 2011 Sep 1;35(9):1950-6.

^e Kahn JM, Goss CH, Heagerty PJ, et al. Hospital volume and the outcomes of mechanical ventilation. New Eng J of Med. 2006 Jul 6;355(1):41-50.

^f Pakyz A, Carroll NV, Harpe SE, et al. Economic impact of Clostridium difficile infection in a multihospital cohort of academic health centers. Pharmacotherapy. 2011 Jun 1;31(6):546-51.

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Warren DK, Quadir WW, Hollenbeak CS, et al. Attributable cost of catheter-associated bloodstream infections among intensive care patients in a nonteaching hospital. Crit Care Med. 2006 Aug;34(8):2084-9.

Wilson MZ, Rafferty C, Deeter D, et al. Attributable costs of central line-associated bloodstream infections in a pediatric hematology/oncology population. Am J Infect Control. 2014 Nov;42(11):1157-60.

Wong CA, Recktenwald AJ, Jones ML, et al. The cost of serious fall-related injuries at three Midwestern hospitals. Joint Com J Qual Patiet Saf. 2011 Feb 28;37(2):81-7.

Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide U.S. study. Clin Gastroenterol Hepatol. 2010 Sep;8(9):800-5.

Yi SH, Baggs J, Gould CV, et al. Medicare reimbursement attributable to catheter-associated urinary tract infection in the inpatient setting: a retrospective cohort analysis. Med Care. 2014 Jun;52(6):469-78.

Zhan C, Miller MR. Excess length of stay, charges, and mortality attributable to medical injuries during hospitalization. JAMA. 2003 Oct;290(14):1868-74.

Appendix D. Key Study Characteristics

Exhibit D1. Adverse Drug Events

		Kessler (2013)	Oderda (2007)	Suh (2000)	Classen (2010)	Alexander (2005)	LaPointe (2007)	Seigerman (2014)
Study	Study Year	2009-2010	1990-1999	1998	2004	2004	2005	2009-2010
	Population	Patients with a primary surgical procedure	Adult surgical patients ( >17 y) in a single Utah hospital	All patient (≥2 y) admissions to a single New York hospital	Medicare beneficiaries	Patients with NSTE ACS	Patients with NSTE ACS	Patients with cardiac surgery
	Study Design	Retrospective cohort	Matched cohort	Retrospective matched control	Retrospective cohort	Prospective observational	Prospective observational	Retrospective cohort
	Data Source(s)	Hospital administrative data	Hospital clinical and surveillance data	Hospital pharmacy and medical record reporting systems	MPSMS	CRUSADE National Quality Improvement Initiative Registry	CRUSADE National Quality Improvement Initiative Registry	HCUP-NIS
	Number of Cases	4,537	1,586	131	172	22,480g	13,803	560
	Definition of HAC	ICD-9	Hospital surveillance criteria and Noranjo criteria	WHO	Medication-specific algorithms	Recommended dosing categories	Recommended dosing categories	Non-specified diagnosis
Cost	Cost or Charges Reported	Cost	Cost	Cost
	Attributable	Y	Y	Y
	Year of Cost Data	Not specified	Not specified	Not specified
	Mean Attributable Cost Calculated	$6,721.00	$786.00	$5,483.00
	Standard Error	$347.54	$151.79	$1,959.00
Mortality	Matched Control Sample	Y	Y		N	N	N	N
	Adjusted RR/OR	3.39 (2.42–4.74)	Not reported		Not used in analysis	1.50 (1.03-2.17)	1.31 (0.99-1.73)	1.47 (1.30-1.67)
	SE(logRR)/SE(logOR)	0.161	0.321		0.314	0.190	0.142	0.064

^g Represents the number of instances of a major bleed in the presence of drug therapy administration; some patients received more than one drug therapy.

Exhibit D2. Catheter-Associated Urinary Tract Infection

		Glied (2016)	Yi (2014)	Byrn (2015)	Dasenbrock (2016)	Goudie (2015)	Sammon (2013)	Murthy (2016)
Study	Study Year	2006-2012	2009	2006-2012	2008-2011	2009-2011	1999-2009	2002-2011
	Population	All patients, New York City hospital network	Medicare beneficiaries with ESRD	Patients with colorectal resection	Patients with aneurysmal subarachnoid hemorrhage	Patients 1-17 years of age	Patients with any of 8 surgical oncology procedures	Patients with nontraumatic intracerebral hemorrhage
	Study Design	Matched retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Matched retrospective cohort	Retrospective	Retrospective cohort
	Data Source(s)	Hospital clinical and administrative data	MedPAR, Beneficiary Annual Summary File	University hospital database	HCUP-NIS	HCUP-NIS	HCUP-NIS	HCUP-NIS
	Number of Cases	8,048	884	18	1,793	1,513	105,113	40,018
	Definition of HAC	Lab results and ICD-9	CDC-NHSN	NHSN; NSQIP; ICD-9	ICD-9	ICD-9	ICD-9	ICD-9
Cost	Cost or Charges Reported	Charges	Payment	Cost	Charges	Cost
	Attributable	Y	Y	N	N	Y
	Year of Cost Data	2012	2009	2012	2011h	2011
	Mean Attributable Cost Calculated	$20,857.50	$5,877.13	$11,587.10	$27,858.50	$7,200.00
	Standard Error	$2,365.07	$1,644.05	$5,531.84	$2,164.43	$2,538.82
Mortality	Matched Control Sample	Y	Y				N	N
	Adjusted RR/OR	1.28	1.37 (1.04-1.80) ICU; 1.17 (0.62-2.23) non-ICU				1.97 (1.85-2.10)	1.42 (1.10-1.94)
	SE(logRR)/SE(logOR)	0.054	0.311				0.032	0.145

^h The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

Exhibit D2. Catheter-Associated Urinary Tract Infection continued

		Kilgore (2008)
Study	Study Year	2001-2006
	Population	All hospitalized patients
	Study Design	Retrospective cohort
	Data Source(s)	Cardinal Health MedMined database
	Number of Cases	18,930
	Definition of HAC	Lab results
Cost	Cost or Charges Reported	Cost
	Attributable	Y
	Year of Cost Data	2007
	Mean Attributable Cost Calculated	$3,936.00
	Standard Error	$1,961.26
Mortality	Matched Control Sample
	Adjusted RR/OR
	SE(logRR)/SE(logOR)

Exhibit D3. Central-Line Associated Bloodstream Infections

		Dimick (2001)	Glied (2016)	Warren (2006)	Cohen (2010)	Dasenbrock (2016)	Goudie (2014)	Wilson (2014)
Study	Study Year	1998-1999	2006-2012	1998-2000	2006-2007	2008-2011	2008-2011	2008-2011
	Population	Surgical ICU patients in single Maryland hospital	All patients, New York City hospital network	All ICU patients, suburban St. Louis Missouri hospital	All ICU patients,single Chicago-area hospital	Patients with aneurysmal subarachnoid hemorrhage	Patients under 18 years of age	Pediatric hematology and oncology patients in Mid-Atlantic hospital
	Study Design	Prospective cohort	Matched retrospective cohort	Prospective cohort	Case-control	Retrospective cohort	Matched case-control	Matched prospective cohort
	Data Source(s)	Hospital administrative data	Patients’ electronic medical record and other digital sources	Hospital clinical and administrative data	Hospital administrative data	HCUP-NIS	HCUP-NIS	Hospital clinical and administrative data
	Number of Cases	9	3,603	41	12	77	1,339	60
	Definition of HAC	Catheter colonization	Lab results and ICD-9	CDC-NHSN	ICD-9	ICD-9	AHRQ PQI	Lab results
Cost	Cost or Charges Reported	Cost	Charges	Cost	Cost	Charges	Cost	Cost
	Attributable	Y	Y	Y	Y	N	Y	Y
	Year of Cost Data	1998	2012	2000	2008	2011i	2011	2011j
	Mean Attributable Cost Calculated	$56,167.00	$17,197.00	$11,971.00	$82,005.00	$40,983.42	$55,646.00	$69,332.00
	Standard Error	$39,340.52	$4,425.38	$2,964.34	$15,687.02	$7,366.13	$8,602.71	$17,443.43
Mortality	Matched Control Sample	N	Y	N
	Adjusted RR/OR	4.3 (0.9-19.9)	2.49	Not reported
	SE(logRR)/SE(logOR)	0.322	0.063	0.160

ⁱ The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

^j The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

Exhibit D3. Central-Line Associated Bloodstream Infections continued

		Mendizabal (2016)	Sammon (2013)	Stevens (2014)
Study	Study Year	2000-2010	1999-2009	2008-2010
	Population	Adult patients with epilepsy	Patients with any of 8 surgical oncology procedures	All patients, single tertiary-care hospital
	Study Design	Retrospective cohort	Retrospective	Retrospective cohort
	Data Source(s)	HCUP-NIS	HCUP-NIS	Hospital clinical and administrative data
	Number of Cases	Not reported	47,551	197
	Definition of HAC	AHRQ PSI	ICD-9	CDC-NHSN
Cost	Cost or Charges Reported
	Attributable
	Year of Cost Data
	Mean Attributable Cost Calculated
	Standard Error
Mortality	Matched Control Sample	N	N	N
	Adjusted RR/OR	4.88 (4.02-5.93)	17.29 (16.33-18.31)	2.27 (1.15-4.46)
	SE(logRR)/SE(logOR)	0.099	0.015	0.346

Exhibit D4. Falls

		Memtsoudis (2012)	Bates (1995)	Wong (2011)
Study	Study Year	1998-2007	1987-1991	2004-2006
	Population	Postoperative hip and knee surgery patients	All patients in a single Massachusetts hospital	Adult inpatients in 3 Midwest hospitals
	Study Design	Retrospective cohort	Retrospective case-control	Retrospective case-control
	Data Source(s)	HCUP-NIS	Hospital clinical data	Hospital incident reporting system
	Number of Cases	9,198	62	57
	Definition of HAC	ICD-9	Patient reported as having fallen	Serious fall-related injury
Cost	Cost or Charges Reported	Cost	Charges	Cost
	Attributable	N	Y	Y
	Year of Cost Data	2007k	1991l	2009
	Mean Attributable Cost Calculated	$2,247	$3,802	$13,806
	Standard Error	$90.57	$2,262.97	$6,031.23
Mortality	Matched Control Sample	N
	Adjusted RR/OR	Not reported
	SE(logRR)/SE(logOR)	0.126

^k The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

^l The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

Exhibit D5. Obstetric Adverse Events

		Zhan (2003)	Hunt (2016)	Callaghan (2008)	Callaghan (2012)	Creanga (2014)	Grobman (2014)
Study	Study Year	2000	2010	1991-2003	1998-2009	2008-2010	2008-2011
	Population	Women with delivery-related discharge	Women with delivery-related discharge in New York	Women with delivery-related discharges	Women with delivery-related discharges	Women with delivery-related discharges in 7-state sample	Women who delivered ≥23 weeks gestations in any of 25 cohort hospitals
	Study Design	Retrospective cohort	Retrospective cohort	Retrospective	Retrospective	Retrospective	Retrospective cohort
	Data Source(s)	HCUP-NIS	State-level inpatient database	National Hospital Discharge Survey	HCUP-NIS	HCUP-NIS	Eunice Kennedy Shriver National Institute of Child Health & Human Development Maternal-Fetal Medicine Units Network cohort
	Number of Cases	64,879	1,053	257,000	597,920	74,720	332
	Definition of HAC	AHRQ PSI	ICD-9	ICD-9	ICD-9	ICD-9	Geller et al. (2004) morbidity scoring system
Cost	Cost or Charges Reported	Charges	Cost
	Attributable	Y	Y
	Year of Cost Data	2000	2010
	Mean Attributable Cost Calculated	$8.35	$1,091.34
	Standard Error	$28.344	$30.20
Mortality	Matched Control Sample			N	N	N	N
	Adjusted RR/OR			Alternative estimation method used	Alternative estimation method used	Alternative estimation method used	Alternative estimation method used
	SE(logRR)/SE(logOR)			-	-	-	-

Exhibit D6. Pressure Ulcers

		Bauer (2016)	Spector (2016)	Goudie (2015)	Zhan (2003)	Mendizabal (2016)	Lyder (2012)
Study	Study Year	2008-2012	2011–2012	2009-2011	2000	2000-2010	2006-2007
	Population	General hospitalized patients	Adult patients with surgery	Patients 1-17 years of age	General hospitalized patients	Adult patients with epilepsy	Medicare beneficiary FFS sample
	Study Design	Retrospective	Matched retrospective cohort	Matched retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective
	Data Source(s)	HCUP-NIS	HCUP-SID and MPSMS	HCUP-NIS	HCUP-NIS	HCUP-NIS	MPSMS
	Number of Cases	676,435	534	120	843	Not reported	2,313
	Definition of HAC	ICD-9	MPSMS chart review	ICD-9	ICD-9	AHRQ PSI	ICD-9
Cost	Cost or Charges Reported	Charges	Cost	Cost	Charges
	Attributable	N	Y	Y	Y
	Year of Cost Data	Not specified	2011	2011	2000
	Mean Attributable Cost Calculated	$19,900.00	$8,251.00	$19,740.00	$5,422.50
	Standard Error	$149.72	$11,553.78	$11,553.78	$184.00
Mortality	Matched Control Sample	N				N	N
	Adjusted RR/OR	Not reported				2.42 (2.20-2.66)	2.81 (2.44-3.23)
	SE(logRR)/SE(logOR)	0.004				0.048	0.072

Exhibit D7. Surgical Site Infections

		Glied (2016)	Kim (2012)	Boltz (2011)	de Lissovoy (2009)	Eagye (2009)	Sammon (2013)
Study	Study Year	2006-2012	2001-2008	2007-2009	2005	2005-2007	1999-2009
	Population	All patients, New York City hospital network	Adults undergoing radical cystectomy for bladder cancer	Adult general and vascular surgical patients in single hospital	Surgical patients	Patients with ECS procedures in single Connecticut hospital	Patients with any of 8 surgical oncology procedures
	Study Design	Matched retrospective cohort	Retrospective cohort	Retrospective cohort	Matched retrospective cohort	Prospective cohort and case-control	Retrospective
	Data Source(s)	Patients’ electronic medical record and other digital sources	HCUP-NIS	Hospital clinical data	HCUP-NIS	Hospital administrative data	HCUP-NIS
	Number of Cases	1,292	381	186	6,891	46	80,086
	Definition of HAC	Lab results and ICD-9	ICD-9	NSQIP; CDC NNIS	ICD-9	ICD-9	ICD-9
Cost	Cost or Charges Reported	Charges	Cost	Cost	Cost	Cost
	Attributable	Y	N	Y	Y	N
	Year of Cost Data	2012	2008	Not specified	2005	Not specified
	Mean Attributable Cost Calculated	$34,813.00	$36,454.00	$10,497.00	$20,842.00	$21,228.07
	Standard Error	$7,274.19	$2,530.06	$3,532.46	$971.19	$3,844.11
Mortality	Matched Control Sample	Y	N				N
	Adjusted RR/OR	Not reported	5.70 (3.94–8.24)				3.78 (3.56-4.02)
	SE(logRR)/SE(logOR)	0.129	0.188				0.031

Exhibit D8. Venous Thromboembolism

		Hennessey (2012)	Kim (2012)	Goudie (2015)	Ali (2011)	Gephart (2012)	Mendizabal (2016)	Nguyen (2008)
Study	Study Year	2003-2008	2001-2008	2009-2011	2005	2002-2008	2000-2010	1998-2004
	Population	Patients with head or neck cancers	Adults undergoing radical  cystectomy for bladder cancer	Patients 1-17 years of age	Patients with cirrhosis	Adult patients with thoracic/thoraco-lumbar spinal fusion	Adult patients with epilepsy	Patients with inflammatory bowel disease
	Study Design	Retrospective cohort	Retrospective case control	Matched retrospective cohort	Retrospective cross sectional	Retrospective cohort	Retrospective cohort	Retrospective cohort
	Data Source(s)	HCUP-NIS	HCUP-NIS	HCUP-NIS	HCUP-NIS	HCUP-NIS	HCUP-NIS	HCUP-NIS
	Number of Cases	1,860	219	1,563	8,231	162	Not reported	1,934
	Definition of HAC	ICD-9	ICD-9	ICD-9	ICD-9	ICD-9	AHRQ PSI	ICD-9
Cost	Cost or Charges Reported	Cost	Cost	Cost
	Attributable	Y	N	Y
	Year of Cost Data	2011	2008	2011
	Mean Attributable Cost Calculated	$10,313.28	$27,387	$27,686.00
	Standard Error	$1,159.73	$3,024.31	$8,443.52
Mortality	Matched Control Sample	N	N		N	N	N	N
	Adjusted RR/OR	3.08 (1.56 – 6.12)	5.85 (3.61 – 9.48)		1.01 (0.83, 1.23)	13.63 (6.37-29.16)	3.09 (2.64-3.62)	2.50 (1.83 – 3.43)
	SE(logRR)/SE(logOR)	0.349	0.246		0.100	0.388	0.081	0.160

Exhibit D8. Venous Thromboembolism continued

		Satahoo (2015)	Trinh (2014)	Wu (2010)
Study	Study Year	2005-2009	1999-2009	1998-2006
	Population	Patients with burn injuries	Patients with major cancer surgery	Patients with liver cirrhosis
	Study Design	Retrospective cohort	Retrospective cohort	Retrospective cohort
	Data Source(s)	HCUP-NIS	HCUP-NIS	HCUP-NIS
	Number of Cases	297	33,409	Not reported
	Definition of HAC	ICD-9	ICD-9	ICD-9
Cost	Cost or Charges Reported
	Attributable
	Year of Cost Data
	Mean Attributable Cost Calculated
	Standard Error
Mortality	Matched Control Sample	N	N	N
	Adjusted RR/OR	1.88 (1.147 – 3.075)	5.30 (4.88 – 5.76)	2.30 (2.06 – 2.57)
	SE(logRR)/SE(logOR)	0.252	0.042	0.056

Exhibit D9. Ventilator-Associated Pneumonia

		Cocanour (2005)	Kollef (2012)	Rello (2002)	Restrepo (2010)	Warren (2003)	Apisarnthanarak (2003)	Gupta (2015)
Study	Study Year	2002-2003	2008-2009	1998-1999	2002-2006	1998-1999	2000-2001	2009
	Population	ICU patients with shock trauma in a single Texas tertiary-care hospital	Adults ICU patents, ≥1 day in ICU with mechanical ventilation ≥2 days	All patients admitted to ICU who received mechanical ventilation for >24h	Hospitalized patients in 54 medical centers, nationwide	All patients admitted to ICU in a single Missouri medical center	Extremely pre-term neonates in Missouri hospital	Mechanically ventilated patients <18 y across 16 geographically diverse PICUs
	Study Design	Matched retrospective cohort	Matched retrospective cohort	Matched retrospective cohort	Matched retrospective cohort	Prospective cohort	Prospective and nested cohort	Prospective cohort
	Data Source(s)	Hospital administrative data	Premier Healthcare Informatics Database	MediQual Profile database	NASCENT study	Hospital clinical and administrative data	Hospital clinical data	Hospital CXR
	Number of Cases	93	2,144	816	30	127	19	108
	Definition of HAC	NNIS guideline	ICD-9	ICD-9	ICD-9 and lab results	NNIS criteria	CDC-NNIS	CDC-NHSN
Cost	Cost or Charges Reported	Cost	Cost	Charges	Cost	Cost
	Attributable	Y	Y	N	N	Y
	Year of Cost Data	2003	2009	1999	2005	1999
	Mean Attributable Cost Calculated	$57,158.00	$39,828.00	$20,647.00	$44,331.50	$11,897.00
	Standard Error	$1,045.59	$2,250.00	$1,730.21	$6,731.00	$5,344.23
Mortality	Matched Control Sample	Y	Y	Y	Y		Y	N
	Adjusted RR/OR	Not reported	Not reported	Not reported	Not reported		3.4 (1.2, 12.3)	3.07 (1.36 – 6.90)
	SE(logRR)/SE(logOR)	0.414	0.052	0.062	0.435		0.594	0.414

Exhibit D9. Ventilator-Associated Pneumonia continued

		Josephson (2010)	Klompas (2011)	Klompas (2012)	Sammon (2013)
Study	Study Year	2006-2007	2006-2007	Not specified	1999-2009
	Population	Patients with neurovascular disease in a California hospital	Mechanically ventilated patients >18 y in 3 geographically diverse hospitals	8 U.S. hospital ICUs	Patients with any of 8 surgical oncology procedures
	Study Design	Retrospective	Retrospective matched control	Retrospective	Retrospective cohort
	Data Source(s)	Hospital clinical and administrative	Hospital clinical data	Hospital clinical data	HCUP-NIS
	Number of Cases	24	55	Not reported	87,594
	Definition of HAC	CDC-NHSN	CDC-NHS	Candidate surveillance definitions	ICD-9
Cost	Cost or Charges Reported
	Attributable
	Year of Cost Data
	Mean Attributable Cost Calculated
	Standard Error
Mortality	Matched Control Sample	N	Y	Y	N
	Adjusted RR/OR	1.11 (0.37 – 3.30)	1.1 (0.5 – 2.4)	2.1 (1.3 – 3.3)	4.90 (4.64 – 5.17)
	SE(logRR)/SE(logOR)	0.558	0.395	0.238	0.02

Exhibit D10. Clostridium difficile Infections

		Donnelly (2015)	Glance (2011)	Kim (2012)	Lagu (2014)	Pakyz (2011)	Sundaram (2014)	Tabak (2013)
Study	Study Year	2012-2014	2005-2006	2001-2008	2004-2010	2002-2007	2008-2011	2007-2008
	Population	Patients with solid organ transplant	Trauma patients LOS >3 days	Adults undergoing radical  cystectomy for bladder cancer	Adult, non-surgical patients with sepsis	Adult patients	Adult patients with primary diagnosis of alcoholic hepatitis	Adult patients in six Pennsylvania hospitals
	Study Design	Retrospective cohort	Retrospective	Retrospective cohort	Retrospective cohort	Retrospective	Retrospective	Retrospective
	Data Source(s)	University Health System Consortium Clinical Database	HCUP-NIS	HCUP-NIS	Premier Healthcare Informatics Database	University Health System Consortium Clinical Database	HCUP-NIS	Clinical research database
	Number of Cases	1,109	768	73	2,368	10,857	177	282
	Definition of HAC	ICD-9	ICD-9	ICD-9	ICD-9, lab results, and treatment codes	ICD-9 and treatment codes	ICD-9	Toxin Assay
Cost	Cost or Charges Reported	Cost	Cost	Cost	Cost	Cost	Charges	Cost
	Attributable	Y	Y (ratio)	N	Y	N	N	Y
	Year of Cost Data	2014	2011m	2008	2010	2007	2011	2013n
	Mean Attributable Cost Calculated	$27,890.65	$14,905.00	$22,634.00	$4,924.00	$27,160.00	$3,894.00	$6,117.00
	Standard Error	$1,617.07	$1,147.00	$3,346.00	$1,244.00	$249.00	$1,382.00	$2,274.00
Mortality	Matched Control Sample	N	N	N	Y	Y	N	Y
	Adjusted RR/OR	1.22 (0.9-1.65)	1.87 (1.31-2.66)	2.11 (1.04-4.28)	Not reported	Not reported	1.75 (1.01-3.03)	1.61
	SE(logRR)/SE(logOR)	0.155	0.181	0.361	0.060	0.037	0.280	0.214

^m The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

ⁿ The year of cost data is not specified; the last year of the study period was used for the purpose of this analysis.

Exhibit D10. Clostridium difficile Infections continued

		Damle (2014)	O’Brien (2007)	Flagg (2014)	Keshavamurthy (2014)	Lemaire (2015)	Lesperance (2011)	Luo (2015)
Study	Study Year	2008-2012	1999-2003	2004-2008	2005-2011	2002-2009	2004-2006	2005-2011
	Population	Adult patients with colorectal resection and malignancy	All hospitalizations in a single Massachusetts hospital database with primary or secondary diagnosis of CDAD	Patients who underwent cardiac surgery	Patients who underwent cardiac surgery in a single Ohio hospital	Patients who underwent coronary artery bypass grafting and valvular surgery	Patients who underwent colonic resection during hospital admission	Adult patients with leukemia
	Study Design	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort	Retrospective cohort
	Data Source(s)	University Health System Consortium Database	Hospital database	HCUP-NIS	Hospital clinical data and REDCap database	HCUP-NIS	HCUP-NIS	HCUP-NIS
	Number of Cases	1,266	3,692	2,581	145	Not reported	10,077	42,438
	Definition of HAC	ICD-9	ICD-9	ICD-9	Lab testing	ICD-9	ICD-9	ICD-9
Cost	Cost or Charges Reported	Cost	Cost
	Attributable	Y	Y
	Year of Cost Data	2008	2005
	Mean Attributable Cost Calculated	$14,130.00	$13,675.00
	Standard Error	$465.00	$583.00
Mortality	Matched Control Sample			Y	Y	N	N	N
	Adjusted RR/OR			Not reported	Not reported	2.0 (1.65-2.35) (CABG) 1.9 (1.51-2.39) VS	1.19 (1.11-1.29)	1.17 (1.13-1.22)
	SE(logRR)/SE(logOR)			0.089	0.276	0.095	0.038	0.02

Exhibit D10. Clostridium difficile Infections Ccontinued

		Skovrlj (2014)
Study	Study Year	2002-2011
	Population	Patients with lumbar spine surgery for degenerative diagnoses
	Study Design	Retrospective
	Data Source(s)	HCUP-NIS
	Number of Cases	2,867
	Definition of HAC	ICD-9
Cost	Cost or Charges Reported
	Attributable
	Year of Cost Data
	Mean Attributable Cost Calculated
	Standard Error
Mortality	Matched Control Sample	N
	Adjusted RR/OR	9.6 (5.17-17.83)
	SE(logRR)/SE(logOR)	0.316

Appendix E. Forest Plots

Adverse Drug Events

 

Catheter-Associated Urinary Tract Infection 

 

Central-Line Associated Bloodstream Infections

 

Falls

 

Obstetric Adverse Events

 

Pressure Ulcers

 

Surgical Site Infections

 

Venous Thromboembolism

 

Ventilator-Associated Pneumonia

 

Clostridium difficile Infections