Rapid diagnostic tests for diagnosing uncomplicated non‐falciparum or <i>Plasmodium vivax</i> malaria in endemic countries

Katharine Abba; Amanda J Kirkham; Piero L Olliaro; Jonathan J Deeks; Sarah Donegan; Paul Garner; Yemisi Takwoingi

doi:10.1002/14651858.CD011431

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Figure 1

Study flow diagram.

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Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Figure 3

Forest plot of commercial brands of Type 2 tests for detection of non‐falciparum species (verified with microscopy). We ordered studies by continent, age group and study identifier.

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Figure 4

Summary ROC plot of Type 2 tests for detection of non‐falciparum species (verified with microscopy). The black solid circle corresponds to the summary estimate of sensitivity and specificity, and is shown with a 95% confidence region.

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Figure 5

Forest plot of commercial brands of Type 3 tests for detection of non‐falciparum species (verified with microscopy). We ordered studies by continent, age group and study identifier.

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Figure 6

Summary ROC plot of Type 3 tests for detection of non‐falciparum species (verified with microscopy). The black solid circle corresponds to the summary estimate of sensitivity and specificity, and is shown with a 95% confidence region.

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Figure 7

Forest plot of commercial brands of Type 4 tests for detection of non‐falciparum species (verified with microscopy). We ordered studies by continent, age group and study identifier.

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Figure 8

Summary ROC plot of Type 4 tests for detection of non‐falciparum species (verified with microscopy). The black circle corresponds to the summary estimate of sensitivity and specificity, and is shown with a 95% confidence region.

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Figure 9

Forest plot of Type 2, Type 3 and Type 4 tests for detection of non‐falciparum species (verified with microscopy). We ordered studies by continent, age group and study identifier.

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Figure 10

Summary ROC plot comparing Type 2, Type 3 and Type 4 tests for detection of non‐falciparum species (verified with microscopy). The solid circles correspond to the summary estimates of sensitivity and specificity for each test type, and are shown with 95% confidence regions (dotted lines) and 95% prediction regions (dashed lines). The summary points for Type 2 and Type 3 and their 95% confidence regions are identical but the 95% prediction regions differ. The 95% prediction regions illustrate the extent of between study heterogeneity.

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Figure 11

Summary ROC plot of Type 3 tests for detection of non‐falciparum species (verified with PCR). The solid circles correspond to the summary estimate of sensitivity and specificity, and is shown with a 95% confidence region.

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Figure 12

Forest plot of Pf HRP‐2 and Pv pLDH for detection of P. vivax (verified with microscopy). Studies are ordered by continent, age group and study identifier.

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Figure 13

Summary ROC plot Pf HRP‐2 and Pv pLDH for detection of P. vivax (verified with microscopy). The black circle corresponds to the summary estimate of sensitivity and specificity, and is shown with a 95% confidence region.

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Test 1

Non‐falciparum species only, microscopy, Type 2, ICT Combo Cassette.

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Test 2

Non‐falciparum species only, microscopy, Type 2, ICT Malaria Pf/Pv.

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Test 3

Non‐falciparum species only, microscopy, Type 2, NOW Malaria ICT.

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Test 4

Non‐falciparum species only, microscopy, Type 2, Malascan.

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Test 5

Non‐falciparum species only, microscopy, Type 2, VIKIA Ag Pf/Pan.

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Test 6

Non‐falciparum species only, microscopy, Type 2 (All).

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Test 7

Non‐falciparum species only, microscopy, Type 3, Parascreen.

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Test 8

Non‐falciparum species only, microscopy, Type 3, CareStart Pf/Pan.

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Test 9

Non‐falciparum species only, microscopy, Type 3, SD Malaria Antigen Bioline.

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Test 10

Non‐falciparum species only, microscopy, Type 3, First Response Malaria Combo.

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Test 11

Non‐falciparum species only, microscopy, Type 3, One Step Malaria Pf/Pan.

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Test 12

Non‐falciparum species only, microscopy, Type 3 (All).

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Test 13

Non‐falciparum species only, microscopy, Type 4, OptiMAL.

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Test 14

Non‐falciparum species only, microscopy, Type 4, OptiMAL‐IT.

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Test 15

Non‐falciparum species only, microscopy, Type 4, Carestart.

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Test 16

Non‐falciparum species only, microscopy, Type 4 (All).

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Test 17

Non‐falciparum species only, microscopy, Other Type, Malariagen Malaria.

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Test 18

Non‐falciparum species only, PCR, Type 3, CareStart Pf/Pan.

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Test 19

Non‐falciparum species only, PCR, Type 3, Parascreen.

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Test 20

Non‐falciparum species only, PCR, Type 3, One Step Malaria Pf/Pan.

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Test 21

Non‐falciparum species only, PCR, Type 3, SD Malaria Antigen Bioline.

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Test 22

Non‐falciparum species only, PCR, Type 3 (All).

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Test 23

Non‐falciparum species only, PCR, Type 4, OptiMAL (All).

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Test 24

P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Carestart Pf/Pv (All).

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Test 25

P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Biotech Malaria Pf/Pv.

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Test 26

P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Falcivax.

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Test 27

P. vivax, microscopy, Pf HRp‐2 and Pv pLDH, Onsite Pf/Pv.

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Test 28

P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Pf/Pv Malaria Device.

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Test 29

P. vivax, microscopy, Pf HRP‐2 and Pv pLDH (All).

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Test 30

P. vivax, PCR, Pf HRP‐2 and Pv pLDH, Falcivax.

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Test 31

P. vivax, PCR, Pf HRP‐2 and Pv pLDH, OnSite Pf/Pv.

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Test 32

P. vivax, PCR, Pf HRP‐2 and Pv pLDH, Pf/Pv Malaria Device.

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Test 33

P. vivax, PCR, Pf HRP‐2 and Pv pLDH (All).

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Test 34

P. vivax, PCR, Type 6, PALUTOP (All).

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Summary of findings Performance of RDTs for diagnosis of non‐falciparum or P. vivax malaria

Patients/populations	People presenting with symptoms suggestive of uncomplicated malaria
Prior testing	None
Settings	Ambulatory healthcare settings in P. vivax,P. malariae or P. ovale malaria endemic areas in Asia, Africa and South America
Index tests	Immunochromatography‐based rapid diagnostic tests (RDTs) for non‐falciparum malaria in the absence of P. falciparum co‐infection, or P. vivax malaria with or without other malaria species
Reference standard	Conventional microscopy, polymerase chain reaction (PCR)
Importance	Accurate and fast diagnosis allows appropriate and quick treatment for malaria to be provided
Studies	37 unique publications reporting 47 studies (22,862 participants)
Quality concerns	Poor reporting of patient characteristics, sampling method and reference standard methods were common concerns
Test type	Quantity of evidence Number of evaluations (malaria cases/participants)	Average sensitivity (95% CI)	Average specificity (95% CI)	Prevalence (%)	Consequences in a cohort of 1000
					Missed cases	False positives
Target condition (reference standard): non‐falciparum malaria (microscopy)
Type 2 HRP‐2 (P. falciparum specific) and aldolase (pan‐specific)	11 (958/6879)	78% (73% to 82%)	99% (97% to 99%)	5	11	10
				15	33	9
				30	66	7
Type 3 HRP‐2 (P. falciparum specific) and pLDH (pan‐specific)	23 (1537/11,234)	78% (69% to 84%)	99% (98% to 99%)	5	11	10
				15	33	9
				30	66	7
Type 4 pLDH (P. falciparum specific) and pLDH (pan‐specific)	10 (986/3831)	89% (79% to 95%)	98% (97% to 99%)	5	6	19
				15	17	17
				30	33	14
Target condition (reference standard): non‐falciparum malaria (PCR)
Type 3 HRP‐2 (P. falciparum specific) and pLDH (pan‐specific)	5 (300/1639)	81% (72% to 88%)	99% (97% to 99%)	5	10	10
				15	29	9
				30	57	7
Target condition (reference standard): P.vivax with or without other malaria species (microscopy)
HRP‐2 (P. falciparum specific) and pLDH (P. vivax‐specific)	8 (580/3682)	95% (86% to 99%)	99% (99% to 100%)	5	3	10
				15	8	9
				30	15	7
Conclusions: The majority of studies evaluated RDTs which are designed to differentiate falciparum malaria from non‐falciparum malaria, but cannot differentiate between different non‐falciparum species or identify non‐falciparum malaria species within a mixed infection. In these types of tests, specificity for non‐falciparum malaria in the absence ofP. falciparum infection was high, but sensitivity was low, tests missing between 11% and 22% of non‐falciparum cases. RDTs which are designed to detect P. vivax specifically, whether alone or part of a mixed infection, were more accurate with tests missing less than 5% of P. vivax cases. This review can help decision‐making about which RDT to use, in combination with other published information about in vitro test performance and stability in the field.

Summary of findings Performance of RDTs for diagnosis of non‐falciparum or P. vivax malaria

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Table 1. Types of malaria RDTs by antigen combination and parasite species detected

Type of test	Antigen combinations	Possible results
Type 1	HRP‐2 (P. falciparum specific)	No Pf; Pf; invalid
Type 2	HRP‐2 (P. falciparum specific) and aldolase (pan‐specific)	No malaria; Pf or mixed; Pv, Pf, or Pm; invalid
Type 3	HRP‐2 (P. falciparum specific) and pLDH (pan‐specific)	No malaria; Pf or mixed; Pv, Pf, or Pm; invalid
Type 4	pLDH (P. falciparum specific) and pLHD (pan‐specific)	No malaria; Pf or mixed; Pv, Pf, or Pm; invalid
Type 5	pLDH (P. falciparum specific) and pLHD (P. vivax‐specific)	No malaria; Pf; Pv; Pf and Pv; invalid
Type 6	HRP‐2 (P. falciparum specific), pLHD (pan‐specific) and pLDH (P. vivax specific)	No malaria; Pf and Pv ± Po and/or Pm; Pf ± Po and/or Pm; Pv ± Po or Pm; Po or Pm; invalid
Type 7	Aldolase (pan‐specific)	No malaria; Pf, Pv, Po,or Pm; invalid
Other	HRP‐2 (P. falciparum specific) and pLDH (P. vivax specific)	No malaria; Pf; Pv; Pf and Pv; invalid

Table 1. Types of malaria RDTs by antigen combination and parasite species detected

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Table 2. Malaria 'zones' by endemic parasite species and type of test appropriate for each

Zone	Endemic malaria parasites	Geographic area	Appropriate test type
1	P. falciparum only or other species almost always as a mixed infection	Most of sub‐Saharan Africa; lowland Papua New Guinea	Tests using HRP‐2 to detect P. falciparum only (Type 1)
2	Both P. falciparum and P. vivax, most commonly as a single species	Asia and the Americas; Ethiopian highlands	Combination RDTs which detect all species and distinguish between P. falciparum and P. vivax (Types 2 to 6)
3	Non‐falciparum only	Vivax‐only areas of East Asia and Central Asia; some highland areas elsewhere	Pan‐specific or vivax‐specific RDTs (Type 7; Pan‐pLDH only; vivax‐pLDH only)

Table 2. Malaria 'zones' by endemic parasite species and type of test appropriate for each

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Table 3. Number of studies by RDT type and reference standard

Type of RDT	Number of study cohorts (test evaluations) by reference standard
Type of RDT	Microscopy	PCR
Non‐falciparum species in the absence of P. falciparum
Type 2	11 (11)	0 (0)
Type 3	23 (25)	5 (5)
Type 4	10 (11)	1 (1)
Other type	1 (1)	0 (0)
*P. vivax*
Pf HRP2 and Pv pLDH	8 (9)	2 (3)
Type 6	0 (0)	1 (1)

Table 3. Number of studies by RDT type and reference standard

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Table 4. False negatives for non‐falciparum and P. vivax by RDT type

Study	Test	Number of false negatives	% false negatives indicating 'no malaria'	*% false negatives indicating 'P. falciparum'*
Type 2 tests
Ashton 2010	ICT Combo	37	22	78
Bell 2001a	ICT Malaria trial 1	16	13	88
Bell 2001b	ICT Malaria trial 2	6	67	33
Fernando 2004	ICT Malaria Pf/Pv	29	100	0
Harani 2006	ICT Malaria Pf/Pv	3	67	33
Singh 2000a	ICT Malaria Pf/Pv	13	62	38
Singh 2010	Malascan	18	67	33
Tjitra 1999	ICT Malaria Pf/Pv	8	75	25
van den Broek 2006	NOW malaria ICT	72	67	33
Wongsrichanalai 2003	ICT Malaria Pf/Pv	9	67	33
van den Broek 2006	OptiMAL‐IT	34	74	26
Median (range)			67 (13 to 100)	33 (0 to 88)
Pooled estimate (95% CI)*			65 (43 to 81)	35 (19 to 57)
Type 3 tests
Ashton 2010	Carestart	37	22	78
Ashton 2010	Parascreen	43	14	86
Bendezu 2010	Parascreen	19	84	16
Bharti 2008	First response	7	100	0
Dev 2004	Diamed OptiMAL	3	100	0
Eibach 2013	CareStart	3	100	0
Elahi 2013	Parascreen	5	60	40
Kosack 2013	SD Bioline	133	89	11
Moges 2012	Carestart	38	89	11
Ratsimbasoa 2007	SD Malaria Antigen Bioline	4	100	0
Singh 2010	Parascreen	13	54	46
Singh 2010	First response	9	33	67
Singh 2010	ParaHIT Total	48	92	8
Trouvay 2013	SD Malaria Ag Pf/Pan	18	78	22
Yan 2013	Pf/Pan Device	24	25	75
Median (range)			84 (14 to 100)	16 (0 to 86)
Pooled estimate (95% CI)			74 (52 to 88)	26 (12 to 48)
Type 4 tests
Andrade 2010	OptiMAL‐IT	0	0	0
Chayani 2004	OptiMAL	3	100	0
Dev 2004	SD Malaria	2	100	0
Kolaczinski 2004	OptiMAL	23	100	0
Metzger 2011	OptiMAL‐IT	30	100	0
Pattanasin 2003	OptiMAL‐IT	26	65	35
Ratsimbasoa 2007	OptiMAL‐IT	2	100	0
Ratsimbasoa 2007	Carestart Malaria	3	33	67
Singh 2003	OptiMAL (field)	0	0	0
Soto Tarazona 2004	OptiMAL	3	100	0
Valecha 2003	OptiMAL	13	77	23
Median (range)			100 (0 to 100)	0 (0 to 67)
Pooled estimate (95% CI)			87 (79 to 92)	13 (8 to 21)
The pooled estimates of the percentage of false negatives indicating 'no malaria' and the percentage of false negatives indicating 'P. falciparum' were computed by using a random effects logistic regression model for Type 2 and Type 3. A fixed effects logistic regression model was used for Type 4. This table shows participants with non‐falciparum malaria monoinfection identified by microscopy who were negative by non‐falciparum monoinfection by RDT, by whether the RDT incorrectly identified the participant as not having malaria, or as having P. falciparum* malaria.

Table 4. False negatives for non‐falciparum and P. vivax by RDT type

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Table 5. Non‐falciparum infections by RDT types verified by microscopy

RDT Type	Study cohort	Participants	Malaria cases	Pooled sensitivity (95% CI) (%)	Pooled specificity (95% CI) (%)	Test¹
Type 2	11	6879	958	78 (73 to 82)	99 (97 to 99)	P = 0.008
Type 3	23	11,234	1537	78 (69 to 85)	99 (98 to 99)
Type 4	10	3831	986	90 (79 to 95)	98 (97 to 99)
Other type	1	262	12	92 (62 to 100)	95 (92 to 98)
¹Likelihood ratio test for evidence of a difference in sensitivity or specificity, or both, between Types 2, 3, and 4. *Only one test brand (randomly selected) from each cohort is included in the analysis of each type.

Table 5. Non‐falciparum infections by RDT types verified by microscopy

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Table 6. Comparisons of RDT types for non‐falciparum infections verified by microscopy

Ratio of sensitivity (95% CI), P value for comparison Ratio of specificity (95% CI), P value for comparison			Type 2	Type 3
		Studies (participants)	11 (6879)	23 (11,234)
	Studies (participants)	Sensitivity (95% CI) Specificity (95% CI)	78 (73 to 82) 99 (97 to 99)	78 (69 to 84) 99 (98 to 99)
Type 2	11 (6879)	78 (73 to 82) 99 (97 to 99)	‐	‐
Type 3	23 (11,234)	78 (69 to 84) 99 (98 to 99)	1.00 (0.89 to 1.12), P = 1.00 1.00 (0.99 to 1.01), P = 0.87	‐
Type 4	10 (3831)	90 (79 to 95) 98 (97 to 99)	0.87 (0.78 to 0.96), P = 0.01 1.00 (0.99 to 1.02), P = 0.52	0.87 (0.76 to 0.99), P = 0.03 1.01 (1.00 to 1.02), P = 0.29
We computed the ratio of sensitivities and specificities by division of the sensitivity and specificity for the column by the sensitivity and specificity for the row. If the ratio of sensitivities is greater than one, the sensitivity of the test for the column is higher than that for the row; if less than one, the sensitivity of the test in the row is higher than in the column. The same applies to the ratio of specificities.

Table 6. Comparisons of RDT types for non‐falciparum infections verified by microscopy

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 Non‐falciparum species only, microscopy, Type 2, ICT Combo Cassette Show forest plot	1	2383

2 Non‐falciparum species only, microscopy, Type 2, ICT Malaria Pf/Pv Show forest plot	7	3151

3 Non‐falciparum species only, microscopy, Type 2, NOW Malaria ICT Show forest plot	1	246

4 Non‐falciparum species only, microscopy, Type 2, Malascan Show forest plot	1	372

5 Non‐falciparum species only, microscopy, Type 2, VIKIA Ag Pf/Pan Show forest plot	1	727

6 Non‐falciparum species only, microscopy, Type 2 (All) Show forest plot	11	6879

7 Non‐falciparum species only, microscopy, Type 3, Parascreen Show forest plot	14	5407

8 Non‐falciparum species only, microscopy, Type 3, CareStart Pf/Pan Show forest plot	4	3544

9 Non‐falciparum species only, microscopy, Type 3, SD Malaria Antigen Bioline Show forest plot	4	3769

10 Non‐falciparum species only, microscopy, Type 3, First Response Malaria Combo Show forest plot	2	663

11 Non‐falciparum species only, microscopy, Type 3, One Step Malaria Pf/Pan Show forest plot	1	606

12 Non‐falciparum species only, microscopy, Type 3 (All) Show forest plot	23	11234

13 Non‐falciparum species only, microscopy, Type 4, OptiMAL Show forest plot	6	1843

14 Non‐falciparum species only, microscopy, Type 4, OptiMAL‐IT Show forest plot	4	1987

15 Non‐falciparum species only, microscopy, Type 4, Carestart Show forest plot	1	195

16 Non‐falciparum species only, microscopy, Type 4 (All) Show forest plot	10	3831

17 Non‐falciparum species only, microscopy, Other Type, Malariagen Malaria Show forest plot	1	262

18 Non‐falciparum species only, PCR, Type 3, CareStart Pf/Pan Show forest plot	1	178

19 Non‐falciparum species only, PCR, Type 3, Parascreen Show forest plot	2	659

20 Non‐falciparum species only, PCR, Type 3, One Step Malaria Pf/Pan Show forest plot	1	606

21 Non‐falciparum species only, PCR, Type 3, SD Malaria Antigen Bioline Show forest plot	1	196

22 Non‐falciparum species only, PCR, Type 3 (All) Show forest plot	5	1639

23 Non‐falciparum species only, PCR, Type 4, OptiMAL (All) Show forest plot	1	313

24 P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Carestart Pf/Pv (All) Show forest plot	3	2000

25 P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Biotech Malaria Pf/Pv Show forest plot	1	250

26 P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Falcivax Show forest plot	2	710

27 P. vivax, microscopy, Pf HRp‐2 and Pv pLDH, Onsite Pf/Pv Show forest plot	2	710

28 P. vivax, microscopy, Pf HRP‐2 and Pv pLDH, Pf/Pv Malaria Device Show forest plot	1	350

29 P. vivax, microscopy, Pf HRP‐2 and Pv pLDH (All) Show forest plot	8	3682

30 P. vivax, PCR, Pf HRP‐2 and Pv pLDH, Falcivax Show forest plot	1	338

31 P. vivax, PCR, Pf HRP‐2 and Pv pLDH, OnSite Pf/Pv Show forest plot	1	338

32 P. vivax, PCR, Pf HRP‐2 and Pv pLDH, Pf/Pv Malaria Device Show forest plot	1	350

33 P. vivax, PCR, Pf HRP‐2 and Pv pLDH (All) Show forest plot	2	688

34 P. vivax, PCR, Type 6, PALUTOP (All) Show forest plot	1	313

Table Tests. Data tables by test

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