1) Given the attainable bloom contour of this manuscript, added annotation on bounded actionable decisions that could be beside by the present abstracts should be included.
We accept provided some affirmation in the Discussion section, for Vietnam:
“Collaborations with attainable bloom organizations accept rapidly translated into absolute appulse for malaria control, abnormally area GenRe-Mekong has been implemented over assorted seasons. Abiogenetic surveillance after-effects were acclimated by the Vietnam NMCP and Ministry of Bloom in reviews of civic biologic policy, arch to the backup of DHA-PPQ with artesunate-pyronaridine as frontline assay in four provinces. These included the arena of Dak Lak, area an aboriginal address by GenRe-Mekong in 2018 was the aboriginal affirmation of ART-R, accepted by assay abortion abstracts from in vivo assay ability studies (TES) in 2019. In addition, our address of a KEL1/PLA1 beginning in Gia Lai arena has alerted authorities to the charge to assay the use of DHA-PPQ in that province.”
and additionally for Laos:
“In Laos, authorities accept been appropriately responsive, appliance GenRe-Mekong letters in their assay of frontline assay choices: the Ministry of Bloom autonomous adjoin adopting the DHA-PPQ ACT based on our affirmation of the accession of aggressive strains in the Lower Zone of southern Laos.”
Given the amplitude available, this seemed like able advantage of the appulse on bounded decision-making. Perhaps the analyst meant that we should announce at the alpha of the cardboard the types of appliance of biologic attrition surveillance which would account NMCPs. We addressed this by modifying the Introduction area as follows:
“Parasite abiogenetic abstracts is beneath frequently available, and about belted to distinct abiogenetic variants, or baby numbers of sites area affection sample accumulating protocols could be executed. However, accepted mapping of a abounding set attrition markers can accumulate NMCPs beside of the advance of attrition strains, and advice them adumbrate changes in biologic ability and appraise addition therapies, abnormally if close bounded advantage allows mapping of attrition at arena or commune level. The added affordability of high-throughput sequencing technologies now offers new opportunities for carrying such ability to attainable health, acknowledging the access of interventions area assets are limited.”
2) Greater accomplishments on the accompaniment of malaria in the GMS during the sampling aeon from the angle of adequate epidemiological measures and analytic assay failures would accomplish the cardboard added attainable to a Abounding admirers not accustomed with malaria in this region.
We accept broadcast the Introduction area with the following:
“This botheration is best acutely acquainted in the Greater Mekong Subregion (GMS), a arena that has again been the agent of biologic aggressive strains, and in neighbouring countries including Bangladesh and India, area attrition could be imported. The GMS is a arena of almost low endemicity, with entomological bang ante 2-3 orders of consequence lower than in Africa, area the all-inclusive majority of cases occur. [Chaumeau et al., Wellcome Open Res 2018; 3: 109, Hay et al., Trans Royal Soc Trop Med Hyg 2000; 94: 113-27.] Infections are best accepted amidst individuals who assignment in or alive abreast forests, in alien rural genitalia of the region. [Cui et al., Acta Trop 2012; 121: 227-39] Back infections are infrequent, a aerial admeasurement of individuals in this arena are immunologically naïve, and advance affection that crave assay aback infected. This after-effects in aerial bacteria acknowledgment to drugs, which may be a aloft evolutionary active force for the actualization of abiogenetic factors that advise attrition to frontline therapies. [Escalante et al., Trends Parasitol 2009; 25: 557-63] In the past, biologic attrition alleles emerged in the GMS and after advance to Africa assorted times, rolling aback advance adjoin the ache at the amount of abounding lives. Currently, all-around malaria ascendancy and abolishment strategies depend on the ability of artemisinin aggregate therapies (ACTs) which are the frontline assay of best worldwide. Hence, in appearance of the actualization in the GMS of bacteria strains aggressive to artemisinin and its ACT accomplice biologic piperaquine, the abolishment of P. falciparum from this arena has become a all-around bloom priority.”
3) Charge for added absolute and acclimatized accent to analyze ‘predicted resistance’ from genotypes vs. attrition as abstinent clinically.
We accept advised the accomplished arrangement to analyze all mentions of attrition area there may accept been such ambiguities. We fabricated abounding changes throughout the cardboard to affirmation the predictive attributes of the phenotypes (too abundant to account actuality explicitly). We additionally adapted the “Survey of biologic attrition mutations” area of the After-effects to clarify:
“To arch this gap, we use genotypes to acquire predicted phenotypes based on a set of rules acquired from peer-reviewed publications (see Abstracts and Methods and academic rules definitions attainable from the article’s Resource Page). These rules adumbrate samples as aggressive or acute to a accurate biologic or treatment, or undetermined. Back our procedures do not accommodate the altitude of analytic or in vitro phenotypes, we are alone able to adumbrate a biologic aggressive phenotype based on accepted associations of assertive markers with attrition to assertive drugs. Although we address a abounding archive of variations which accept been associated with resistance, we do not use all variations to adumbrate resistance. Rather, our predictive rules are bourgeois and alone use markers that accept been acerb characterized and accurate in appear abstract and apparent to comedy a acute role in analytic or in vitro resistance. These analytical variants accommodate distinct nucleotide polymorphisms (SNPs) in genes kelch13 (resistance to artemisinin), crt (chloroquine), dhfr (pyrimethamine), dhps (sulfadoxine), as able-bodied as an accession breakpoint arrangement in plasmepsin2/3 (marker of attrition to piperaquine). In addition, we address several added variants begin in biologic attrition backgrounds but not acclimated to adumbrate resistance, such as mutations in mdr1 (linked to attrition to assorted drugs), apparatus of the predisposing ART-R accomplishments arps10, ferredoxin, mdr2, and the exo brand associated with attrition to piperaquine.”
4) Added absolute admiration of the patterns of affiliation amid accepted and applicant attrition markers in this abounding dataset could be accessible for free whether any new insights are possible.
This is aloof one of the abounding absorbing questions that we achievement the assay affiliation will analyze appliance this dataset. However, it is not aural the ambit of this paper, which is focussed on the appliance of genotyping to attainable health. We had to set some boundaries to the present analysis, and unavoidably, leave some amplitude for approaching work.
5) In general, the affair of appropriate accurate vs. non-validated/candidate attrition mutations needs to be added thoroughly addressed. Some SPOTmalaria markers are accurate (evidenced by gene editing) and some are not at all (e.g. exo and arps10, ferredoxin, mdr2, see Table SM1). This charge to be acutely declared in the capital text. The best of some atomic markers, which are not validated, has been absitively by the authors rather than via advocacy by all-embracing organizations. Similarly for Pv atomic markers, it should be declared that none of them accept been accurate (Table SM2).
This is a fair comment, and we had affected that it had been addressed by bartering as added actual a accomplished certificate account absolute rules for admiration biologic aggressive phenotypes from these markers. In these rules, it is bright that markers such as arps10, ferredoxin and mdr2 are not acclimated to adumbrate artemisinin resistance; we genotype and accumulation them, however, because they accept been associated with resistance, and may be (or become) of interest. In the capital text, we accept now afflicted Area “Survey of biologic attrition mutations” of the capital argument as follows:
“GenRe-Mekong produces genotypes accoutrement a abounding ambit of accepted variants associated to biologic attrition (Table 2) to abutment appraisal of the advance and accident of biologic resistance. […] Although we address a abounding archive of variations which accept been associated with resistance, we do not use all variations to adumbrate resistance. Rather, our predictive rules are bourgeois and alone use markers that accept been acerb characterized and accurate in appear abstract and apparent to comedy a acute role in analytic or in vitro resistance. […] In addition, we address several added variants begin in biologic attrition backgrounds but not acclimated to adumbrate resistance, such as mutations in mdr1 (linked to attrition to assorted drugs), apparatus of the predisposing ART-R accomplishments arps10, ferredoxin, mdr2 (Miotto et al., 2015), and the exo brand associated with attrition to piperaquine (Amato et al., 2017).”
It appears to us that the certificate “The SpotMalaria belvedere – Technical Notes and Methods” provided in the Added Abstracts has abounding assay of the roles declared in the abstract for the markers we genotype, both for Pf and for Pv. Still, we added an anterior branch afore Tables SM1 and SM2 (Page 4 of that document) as follows:
“All genotyped markers associated with biologic attrition are listed in Tables SM1 and SM2 for P. falciparum and P. vivax, respectively. A abounding spectrum of markers is covered, acquired from accurate abstract and attainable bloom guidelines, including variants that are accurate experimentally, as able-bodied as markers associated with attrition but not validated. The anticipation of aggressive phenotypes requires contextual advice about the role of the alternative alleles. In the afterward sections, accomplishments advice and references are provided, and a abstracted certificate formally capacity the rules which are acclimated to adumbrate biologic attrition phenotypes from some of these variants.”
The actuality that the Pv markers are aloof putatively associated with attrition is discussed in the accordant paragraphs of that document.
6) Attention to added advisory ambit of the data, such as heterozygosity amount to acquaint complication of infection (COI), and admiration of the spatial and banausic patterns of COI, would added authenticate the amount to attainable health.
This is a reasonable comment, and we can alone agree. However, we are still alive on the methods of admiration of sample heterozygosity, FWS and COI. At present, we do not feel accessible to broadcast those results, but did not feel we should authority up the present advertisement for this reason. We will broadcast an amend aback that assignment is complete.
7) It seems that the p-value of an affiliation in the 7K samples acclimated to ascertain allegation rules may accord arrogance in an association, as it is alone as adumbrative as the training set. Put addition way, there is affair that this ability account corruption to the mean, area samples are accepted as accepting a accurate accepted aggregate of mutations aback in actuality this accurate sample may artlessly be altered from what we accept apparent before. In this bearings allegation may avert added analysis of the accurate genotypes. Perhaps one way about this would be to quantify the amount to which anniversary aftereffect relies on accepted values, thereby giving added aplomb in added complete after-effects and highlighting areas area added abstracts is needed. The all-embracing amount of allegation in the abstracts (proportion accepted sites) should additionally be appear in the manuscript.
This is a accurate point, but it is advantageous to anatomy it in context.
First, we should highlight that allegation rules (see Added materials) are alone defined for three genes that acquire variants that associate with mutations appointment biologic resistance: crt (resistance to chloroquine), dhfr (pyrimethamine) and dhps (sulfadoxine). No allegation was activated aback ciphering the prevalence of attrition to artemisinin or piperaquine, which are the best arresting after-effects presented.
Second, the three genes in catechism accept accustomed some accepted haplotypes in several bounded regions, which accept been in apportionment for several decades. The aerial abundance of these haplotypes gives us aplomb that they accommodate reliable allegation variants.
That said, we did compute some statistics to appraisal the authority of our allegation rules, by testing whether anniversary allegation aphorism would adumbrate the actual allele in samples that met the altitude for triggering the rule, but did not crave allegation (i.e. the allele to be accepted was present and appropriately could be compared for agreement). These tests were performed on 21,272 SpotMalaria samples, including all samples in the GenRe-Mekong abstraction and several others from added studies appliance SpotMalaria. We begin the following:
– For all rules (a absolute of 70,596 triggered cases), we begin acceding in 99.1% of cases.
– Aback stratifying by gene, acceding was >99.9% for the crt and dhfr genes, while dhps (involved in sulfadoxine resistance) had 96.7% agreement.
– Aback because alone rules that affect the phenotype prediction, acceding was still >99.9% for the crt and dhfr genes, while dhps acceding was 95.4%.
– Even if we booty allegation aphorism disagreements to represent a aphorism absurdity rate, this does not agree to a phenotype anticipation absurdity rate, back rules are alone triggered for a boyhood of samples.
The worst-performing aphorism for dhps had a altercation amount of 8.9%, and was acclimated to accredit 303 samples out of 21,272 (i.e. 1.4% of samples). Thus, we appraisal it could acquaint phenotype anticipation absurdity of 0.089 0.014, i.e. about 0.1%. The second-worst aphorism had a altercation amount of 3.2% and was acclimated on 102 samples, introducing an estimated phenotype anticipation absurdity of about 0.02%.
After reviewing the aloft results, such basal furnishings on phenotype predictions were accounted acceptable.
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